WorldWideScience

Sample records for counter-regulatory anti-parasite cytokine

  1. Polymorphisms in Plasmodium vivax Circumsporozoite Protein (CSP) Influence Parasite Burden and Cytokine Balance in a Pre-Amazon Endemic Area from Brazil

    Science.gov (United States)

    Ribeiro, Bruno de Paulo; Cassiano, Gustavo Capatti; de Souza, Rodrigo Medeiros; Cysne, Dalila Nunes; Grisotto, Marcos Augusto Grigolin; de Azevedo dos Santos, Ana Paula Silva; Marinho, Cláudio Romero Farias; Machado, Ricardo Luiz Dantas; Nascimento, Flávia Raquel Fernandes

    2016-01-01

    Mechanisms involved in severe P. vivax malaria remain unclear. Parasite polymorphisms, parasite load and host cytokine profile may influence the course of infection. In this study, we investigated the influence of circumsporozoite protein (CSP) polymorphisms on parasite load and cytokine profile in patients with vivax malaria. A cross-sectional study was carried out in three cities: São Luís, Cedral and Buriticupu, Maranhão state, Brazil, areas of high prevalence of P. vivax. Interleukin (IL)-2, IL-4, IL-10, IL-6, IL-17, tumor necrosis factor alpha (TNF-α, interferon gamma (IFN-γ and transforming growth factor beta (TGF-β were quantified in blood plasma of patients and in supernatants from peripheral blood mononuclear cell (PBMC) cultures. Furthermore, the levels of cytokines and parasite load were correlated with VK210, VK247 and P. vivax-like CSP variants. Patients infected with P. vivax showed increased IL-10 and IL-6 levels, which correlated with the parasite load, however, in multiple comparisons, only IL-10 kept this association. A regulatory cytokine profile prevailed in plasma, while an inflammatory profile prevailed in PBMC culture supernatants and these patterns were related to CSP polymorphisms. VK247 infected patients showed higher parasitaemia and IL-6 concentrations, which were not associated to IL-10 anti-inflammatory effect. By contrast, in VK210 patients, these two cytokines showed a strong positive correlation and the parasite load was lower. Patients with the VK210 variant showed a regulatory cytokine profile in plasma, while those infected with the VK247 variant have a predominantly inflammatory cytokine profile and higher parasite loads, which altogether may result in more complications in infection. In conclusion, we propose that CSP polymorphisms is associated to the increase of non-regulated inflammatory immune responses, which in turn may be associated with the outcome of infection. PMID:26943639

  2. Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes

    DEFF Research Database (Denmark)

    Pham, Minh-Long; Kolb, H; Battelino, T

    2013-01-01

    Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes.......Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes....

  3. The mRNA expression of pro- and anti-inflammatory cytokines in T regulatory cells in children with type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Maria Górska

    2010-06-01

    Full Text Available Type 1 diabetes mellitus (T1DM is caused by the autoimmune-mediated destruction of insulin-producing beta cells in the pancreas. T regulatory cells (Tregs represent an active mechanism of suppressing autoreactive T cells that escape central tolerance. The aim of our study was to test the hypothesis that T regulatory cells express pro- and anti-inflammatory cytokines, elements of cytotoxicity and OX40/4-1BB molecules. The examined group consisted of 50 children with T1DM. Fifty two healthy individuals (control group were enrolled into the study. A flow cytometric analysis of T-cell subpopulations was performed using the following markers: anti-CD3, anti-CD4, anti-CD25, anti-CD127, anti-CD134 and anti-CD137. Concurrently with the flow cytometric assessment of Tregs we separated CD4+CD25+CD127dim/- cells for further mRNA analysis. mRNA levels for transcription factor FoxP3, pro- and anti-inflammatory cytokines (interferon gamma, interleukin-2, interleukin-4, interleukin-10, transforming growth factor beta1 and tumor necrosis factor alpha, activatory molecules (OX40, 4-1BB and elements of cytotoxicity (granzyme B, perforin 1 were determined by real-time PCR technique. We found no alterations in the frequency of CD4+CD25highCD127low cells between diabetic and control children. Treg cells expressed mRNA for pro- and anti-inflammatory cytokines. Lower OX40 and higher 4-1BB mRNA but not protein levels in Treg cells in diabetic patients compared to the healthy children were noted. Our observations confirm the presence of mRNA for pro- and anti-inflammatory cytokines in CD4+CD25+CD127dim/- cells in the peripheral blood of children with T1DM. Further studies with the goal of developing new strategies to potentiate Treg function in autoimmune diseases are warranted.

  4. Cytokine balance in human malaria: does Plasmodium vivax elicit more inflammatory responses than Plasmodium falciparum?

    Directory of Open Access Journals (Sweden)

    Raquel M Gonçalves

    Full Text Available BACKGROUND: The mechanisms by which humans regulate pro- and anti-inflammatory responses on exposure to different malaria parasites remains unclear. Although Plasmodium vivax usually causes a relatively benign disease, this parasite has been suggested to elicit more host inflammation per parasitized red blood cell than P. falciparum. METHODOLOGY/PRINCIPAL FINDINGS: We measured plasma concentrations of seven cytokines and two soluble tumor necrosis factor (TNF-α receptors, and evaluated clinical and laboratory outcomes, in Brazilians with acute uncomplicated infections with P. vivax (n = 85, P. falciparum (n = 30, or both species (n = 12, and in 45 asymptomatic carriers of low-density P. vivax infection. Symptomatic vivax malaria patients, compared to those infected with P. falciparum or both species, had more intense paroxysms, but they had no clear association with a pro-inflammatory imbalance. To the contrary, these patients had higher levels of the regulatory cytokine interleukin (IL-10, which correlated positively with parasite density, and elevated IL-10/TNF-α, IL-10/interferon (IFN-γ, IL-10/IL-6 and sTNFRII/TNF-α ratios, compared to falciparum or mixed-species malaria patient groups. Vivax malaria patients had the highest levels of circulating soluble TNF-α receptor sTNFRII. Levels of regulatory cytokines returned to normal values 28 days after P. vivax clearance following chemotherapy. Finally, asymptomatic carriers of low P. vivax parasitemias had substantially lower levels of both inflammatory and regulatory cytokines than did patients with clinical malaria due to either species. CONCLUSIONS: Controlling fast-multiplying P. falciparum blood stages requires a strong inflammatory response to prevent fulminant infections, while reducing inflammation-related tissue damage with early regulatory cytokine responses may be a more cost-effective strategy in infections with the less virulent P. vivax parasite. The early induction

  5. Anti-money laundering and counter-terrorist financing in the Luxembourg investment fund market

    OpenAIRE

    Dietz, Andrea

    2017-01-01

    The field of Anti-Money Laundering and Counter-Terrorist Financing in their current form have had an important impact on the financial world for almost half a century. Today, Money Laundering and Terrorist Financing pose a threat to the integrity of the financial markets and systems worldwide. The intention behind implementing a regulatory Anti-Money Laundering and Counter-Terrorist Financing framework is to cut off the financial resources of criminals and to follow back the traces that finan...

  6. Immune response to Taenia solium cysticerci after anti-parasitic therapy.

    Science.gov (United States)

    Singh, Aloukick K; Singh, Satyendra K; Singh, Amrita; Gupta, Kamlesh K; Khatoon, Jahanarah; Prasad, Amit; Rai, Ravi P; Gupta, Rakesh K; Tripathi, Mukesh; Husain, Nuzhat; Prasad, Kashi N

    2015-10-01

    Albendazole is the drug of choice for Taenia solium infection. Concomitant administration of steroid has been advocated to avoid adverse reactions to albendazole therapy in neurocysticercosis. Some T. solium cysticerci (larvae) respond to albendazole therapy while others do not and the reasons remain unexplained. We hypothesise that the immune response differs between treatment responder and non-responder cysticerci and this may determine the outcome. Twenty swine naturally infected with T. solium were purchased from the market and the infection was confirmed by magnetic resonance imaging. Swine were divided into two groups; swine in group 1 were treated with albendazole and those in group 2 were treated with albendazole plus steroid (prednisolone). All the animals underwent follow-up MRIs at 6 and 12 weeks after start of therapy and were then sacrificed. Tissues surrounding the cysticerci were collected and studied for the expression of different cytokines by reverse transcriptase PCR and ELISA. Albendazole therapy was found to be more effective in parasite killing than albendazole plus steroid (94.11% versus 70.96%, P=0.011). Albendazole therapy provoked a pro-inflammatory, Th1 (IFN-γ) and pleiotropic (IL-6) cytokine response around the dead cysticerci. Despite a heavy parasite burden in the brain, all the pigs treated with albendazole plus steroid survived. In this group of animals, a mixed pro-inflammatory Th1, Th2 (IL-4) and regulatory cytokine (IL-10) response was associated with responder cysticerci. Further, Th2 and regulatory cytokine responses were associated with non-responder cysticerci. Copyright © 2015 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

  7. Parasite load induces progressive spleen architecture breakage and impairs cytokine mRNA expression in Leishmania infantum-naturally infected dogs.

    Science.gov (United States)

    Cavalcanti, Amanda S; Ribeiro-Alves, Marcelo; Pereira, Luiza de O R; Mestre, Gustavo Leandro; Ferreira, Anna Beatriz Robottom; Morgado, Fernanda N; Boité, Mariana C; Cupolillo, Elisa; Moraes, Milton O; Porrozzi, Renato

    2015-01-01

    Canine Visceral Leishmaniasis (CVL) shares many aspects with the human disease and dogs are considered the main urban reservoir of L. infantum in zoonotic VL. Infected dogs develop progressive disease with a large clinical spectrum. A complex balance between the parasite and the genetic/immunological background of the host are decisive for infection evolution and clinical outcome. This study comprised 92 Leishmania infected mongrel dogs of various ages from Mato Grosso, Brazil. Spleen samples were collected for determining parasite load, humoral response, cytokine mRNA expression and histopathology alterations. By real-time PCR for the ssrRNA Leishmania gene, two groups were defined; a low (lowP, n = 46) and a high parasite load groups (highP, n = 42). When comparing these groups, results show variable individual humoral immune response with higher specific IgG production in infected animals but with a notable difference in CVL rapid test optical densities (DPP) between highP and lowP groups. Splenic architecture disruption was characterized by disorganization of white pulp, more evident in animals with high parasitism. All cytokine transcripts in spleen were less expressed in highP than lowP groups with a large heterogeneous variation in response. Individual correlation analysis between cytokine expression and parasite load revealed a negative correlation for both pro-inflammatory cytokines: IFNγ, IL-12, IL-6; and anti-inflammatory cytokines: IL-10 and TGFβ. TNF showed the best negative correlation (r2 = 0.231; pdogs with high parasite load associated with a structural modification in the splenic lymphoid micro-architecture. We also discuss the possible mechanism responsible for the uncontrolled parasite growth and clinical outcome.

  8. Dual Role of GM-CSF as a Pro-Inflammatory and a Regulatory Cytokine: Implications for Immune Therapy

    Science.gov (United States)

    Bhattacharya, Palash; Budnick, Isadore; Singh, Medha; Thiruppathi, Muthusamy; Alharshawi, Khaled; Elshabrawy, Hatem; Holterman, Mark J.

    2015-01-01

    Granulocyte macrophage colony stimulating factor (GM-CSF) is generally recognized as an inflammatory cytokine. Its inflammatory activity is primarily due its role as a growth and differentiation factor for granulocyte and macrophage populations. In this capacity, among other clinical applications, it has been used to bolster anti-tumor immune responses. GM-CSF-mediated inflammation has also been implicated in certain types of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. Thus, agents that can block GM-CSF or its receptor have been used as anti-inflammatory therapies. However, a review of literature reveals that in many situations GM-CSF can act as an anti-inflammatory/regulatory cytokine. We and others have shown that GM-CSF can modulate dendritic cell differentiation to render them “tolerogenic,” which, in turn, can increase regulatory T-cell numbers and function. Therefore, the pro-inflammatory and regulatory effects of GM-CSF appear to depend on the dose and the presence of other relevant cytokines in the context of an immune response. A thorough understanding of the various immunomodulatory effects of GM-CSF will facilitate more appropriate use and thus further enhance its clinical utility. PMID:25803788

  9. Anti-regulatory T cells

    DEFF Research Database (Denmark)

    Andersen, Mads Hald

    2017-01-01

    responses to tumours or inhibiting autoimmunity development. However, recent studies report the discovery of self-reactive pro-inflammatory T cells—termed anti-regulatory T cells (anti-Tregs)—that target immune-suppressive cells. Thus, regulatory cells can now be defined as both cells that suppress immune...... reactions as well as effector cells that counteract the effects of suppressor cells and support immune reactions. Self-reactive anti-Tregs have been described that specifically recognize human leukocyte antigen-restricted epitopes derived from proteins that are normally expressed by regulatory immune cells......Our initial understanding of immune-regulatory cells was based on the discovery of suppressor cells that assure peripheral T-cell tolerance and promote immune homeostasis. Research has particularly focused on the importance of regulatory T cells (Tregs) for immune modulation, e.g. directing host...

  10. Trichuris suis ova therapy for allergic rhinitis does not affect allergen-specific cytokine responses despite a parasite-specific cytokine response

    DEFF Research Database (Denmark)

    Bourke, C.D.; Mutapi, F.; Nausch, N.

    2012-01-01

    Parasitic helminths have been shown to reduce inflammation in most experimental models of allergic disease, and this effect is mediated via cytokine responses. However, in humans, the effects of controlled helminth infection on cytokine responses during allergy have not been studied....

  11. Medicinal Plants: A Source of Anti-Parasitic Secondary Metabolites

    Directory of Open Access Journals (Sweden)

    Michael Wink

    2012-10-01

    Full Text Available This review summarizes human infections caused by endoparasites, including protozoa, nematodes, trematodes, and cestodes, which affect more than 30% of the human population, and medicinal plants of potential use in their treatment. Because vaccinations do not work in most instances and the parasites have sometimes become resistant to the available synthetic therapeutics, it is important to search for alternative sources of anti-parasitic drugs. Plants produce a high diversity of secondary metabolites with interesting biological activities, such as cytotoxic, anti-parasitic and anti-microbial properties. These drugs often interfere with central targets in parasites, such as DNA (intercalation, alkylation, membrane integrity, microtubules and neuronal signal transduction. Plant extracts and isolated secondary metabolites which can inhibit protozoan parasites, such as Plasmodium, Trypanosoma, Leishmania, Trichomonas and intestinal worms are discussed. The identified plants and compounds offer a chance to develop new drugs against parasitic diseases. Most of them need to be tested in more detail, especially in animal models and if successful, in clinical trials.

  12. Toward a new generation of vaccines: the anti-cytokine therapeutic vaccines.

    Science.gov (United States)

    Zagury, D; Burny, A; Gallo, R C

    2001-07-03

    Pathological conditions, such as cancers, viral infections, and autoimmune diseases, are associated with abnormal cytokine production, and the morbidity associated with many medical disorders is often directly a result of cytokine production. Because of the absence of negative feedback control occurring in some pathophysiologic situations, a given cytokine may flood and accumulate in the extracellular compartment of tissues or tumors thereby impairing the cytokine network homeostasis and contributing to local pathogenesis. To evaluate whether the rise of anti-cytokine Abs by vaccination is an effective way to treat these pathological conditions without being harmful to the organism, we have analyzed each step of the cytokine process (involving cytokine production, target response, and feedback regulation) and have considered them in the local context of effector--target cell microenvironment and in the overall context of the macroenvironment of the immune system of the organism. In pathologic tissues, Abs of high affinity, as raised by anti-cytokine vaccination, should neutralize the pool of cytokines ectopically accumulated in the extracellular compartment, thus counteracting their pathogenic effects. In contrast, the same Abs should not interfere with cytokine processes occurring in normal tissues, because under physiologic conditions cytokine production by effector cells (induced by activation but controlled by negative feedback regulation) does not accumulate in the extracellular compartment. These concepts are consistent with results showing that following animal and human anti-cytokine vaccination, induction of high-affinity Abs has proven to be safe and effective and encourages this approach as a pioneering avenue of therapy.

  13. Plasticity of regulatory T cells under cytokine pressure.

    Science.gov (United States)

    Diaconu, Carmen C; Neagu, Ana I; Lungu, Răzvan; Tardei, Graţiela; Alexiu, Irina; Bleotu, Coralia; Economescu, Mihaela Chivu; Bumbăcea, Roxana S; Pele, Irina; Bumbăcea, Dragoş

    2010-01-01

    CD4+ T helper (Th) cells have been divided into different subsets as defined by their cytokine products and functions after their activation. CD4+ T cell subsets are continuously discovered and until now Th1, Th2, Th9, Th17, and regulatory T (Treg) cells have been almost unanimously recognized but yet not completely characterized. The selective production of cytokines by each of the subsets is probably the master key of the mechanisms of immune regulation. The cytokine milieu is extremely important on deciding the fate of T cells. Generally, more than one cytokine is needed for differentiating to a particular lineage and just recently it was shown that this status quo of commitment could be challenged. It is well known that cytokines bind to Type I/II cytokine receptors signaling via Janus kinases (JAKs) followed by activation of Signal Transducer and Activator of Transcription (STAT). STAT molecules work together with other transcription factors (Foxp3, RORgammat and RORalpha, T-bet, GATA3, Runx 1, NFAT, etc.) also controlled by cytokines, in modulating the Th phenotype and functions. In this review, we analyze the plasticity of Treg population focusing on the most recent discoveries on how microenvironmental cytokines refine/modify Treg phenotype and function, thus changing their fate.

  14. Anti-parasitic effects of plant secondary metabolites on swine nematodes

    DEFF Research Database (Denmark)

    Williams, A.R.; Pena-Espinoza, Miguel Angel; Fryganas, Christos

    Organic production presents challenges to animal health and productivity. In organic pig production, animals must have access to outdoor pastures which increases exposure to gastrointestinal parasites. Moreover, the routine use of synthetic anti-parasitic drugs is not allowed. Thus, novel parasite...

  15. Regulatory volume decrease in Leishmania mexicana: effect of anti-microtubule drugs

    Directory of Open Access Journals (Sweden)

    Francehuli Dagger

    2013-02-01

    Full Text Available The trypanosomatid cytoskeleton is responsible for the parasite's shape and it is modulated throughout the different stages of the parasite's life cycle. When parasites are exposed to media with reduced osmolarity, they initially swell, but subsequently undergo compensatory shrinking referred to as regulatory volume decrease (RVD. We studied the effects of anti-microtubule (Mt drugs on the proliferation of Leishmania mexicana promastigotes and their capacity to undergo RVD. All of the drugs tested exerted antiproliferative effects of varying magnitudes [ansamitocin P3 (AP3> trifluoperazine > taxol > rhizoxin > chlorpromazine]. No direct relationship was found between antiproliferative drug treatment and RVD. Similarly, Mt stability was not affected by drug treatment. Ansamitocin P3, which is effective at nanomolar concentrations, blocked amastigote-promastigote differentiation and was the only drug that impeded RVD, as measured by light dispersion. AP3 induced 2 kinetoplasts (Kt 1 nucleus cells that had numerous flagella-associated Kts throughout the cell. These results suggest that the dramatic morphological changes induced by AP3 alter the spatial organisation and directionality of the Mts that are necessary for the parasite's hypotonic stress-induced shape change, as well as its recovery.

  16. A Trematode Parasite Derived Growth Factor Binds and Exerts Influences on Host Immune Functions via Host Cytokine Receptor Complexes.

    Directory of Open Access Journals (Sweden)

    Azad A Sulaiman

    2016-11-01

    Full Text Available The trematode Fasciola hepatica is responsible for chronic zoonotic infection globally. Despite causing a potent T-helper 2 response, it is believed that potent immunomodulation is responsible for rendering this host reactive non-protective host response thereby allowing the parasite to remain long-lived. We have previously identified a growth factor, FhTLM, belonging to the TGF superfamily can have developmental effects on the parasite. Herein we demonstrate that FhTLM can exert influence over host immune functions in a host receptor specific fashion. FhTLM can bind to receptor members of the Transforming Growth Factor (TGF superfamily, with a greater affinity for TGF-β RII. Upon ligation FhTLM initiates the Smad2/3 pathway resulting in phenotypic changes in both fibroblasts and macrophages. The formation of fibroblast CFUs is reduced when cells are cultured with FhTLM, as a result of TGF-β RI kinase activity. In parallel the wound closure response of fibroblasts is also delayed in the presence of FhTLM. When stimulated with FhTLM blood monocyte derived macrophages adopt an alternative or regulatory phenotype. They express high levels interleukin (IL-10 and arginase-1 while displaying low levels of IL-12 and nitric oxide. Moreover they also undergo significant upregulation of the inhibitory receptor PD-L1 and the mannose receptor. Use of RNAi demonstrates that this effect is dependent on TGF-β RII and mRNA knock-down leads to a loss of IL-10 and PD-L1. Finally, we demonstrate that FhTLM aids newly excysted juveniles (NEJs in their evasion of antibody-dependent cell cytotoxicity (ADCC by reducing the NO response of macrophages-again dependent on TGF-β RI kinase. FhTLM displays restricted expression to the F. hepatica gut resident NEJ stages. The altered fibroblast responses would suggest a role for dampened tissue repair responses in facilitating parasite migration. Furthermore, the adoption of a regulatory macrophage phenotype would allow

  17. Leukocyte Lysis and Cytokine Induction by the Human Sexually Transmitted Parasite Trichomonas vaginalis.

    Directory of Open Access Journals (Sweden)

    Frances Mercer

    2016-08-01

    Full Text Available Trichomonas vaginalis (Tv is an extracellular protozoan parasite that causes the most common non-viral sexually transmitted infection: trichomoniasis. While acute symptoms in women may include vaginitis, infections are often asymptomatic, but can persist and are associated with medical complications including increased HIV susceptibility, infertility, pre-term labor, and higher incidence of cervical cancer. Heightened inflammation resulting from Tv infection could account for these complications. Effective cellular immune responses to Tv have not been characterized, and re-infection is common, suggesting a dysfunctional adaptive immune response. Using primary human leukocyte components, we have established an in vitro co-culture system to assess the interaction between Tv and the cells of the human immune system. We determined that in vitro, Tv is able to lyse T-cells and B-cells, showing a preference for B-cells. We also found that Tv lysis of lymphocytes was mediated by contact-dependent and soluble factors. Tv lysis of monocytes is far less efficient, and almost entirely contact-dependent. Interestingly, a common symbiont of Tv, Mycoplasma hominis, did not affect cytolytic activity of the parasite, but had a major impact on cytokine responses. M. hominis enabled more diverse inflammatory cytokine secretion in response to Tv and, of the cytokines tested, Tv strains cleared of M. hominis induced only IL-8 secretion from monocytes. The quality of the adaptive immune response to Tv is therefore likely influenced by Tv symbionts, commensals, and concomitant infections, and may be further complicated by direct parasite lysis of effector immune cells.

  18. Leukocyte Lysis and Cytokine Induction by the Human Sexually Transmitted Parasite Trichomonas vaginalis

    Science.gov (United States)

    Mercer, Frances; Diala, Fitz Gerald I.; Chen, Yi-Pei; Molgora, Brenda M.; Ng, Shek Hang; Johnson, Patricia J.

    2016-01-01

    Trichomonas vaginalis (Tv) is an extracellular protozoan parasite that causes the most common non-viral sexually transmitted infection: trichomoniasis. While acute symptoms in women may include vaginitis, infections are often asymptomatic, but can persist and are associated with medical complications including increased HIV susceptibility, infertility, pre-term labor, and higher incidence of cervical cancer. Heightened inflammation resulting from Tv infection could account for these complications. Effective cellular immune responses to Tv have not been characterized, and re-infection is common, suggesting a dysfunctional adaptive immune response. Using primary human leukocyte components, we have established an in vitro co-culture system to assess the interaction between Tv and the cells of the human immune system. We determined that in vitro, Tv is able to lyse T-cells and B-cells, showing a preference for B-cells. We also found that Tv lysis of lymphocytes was mediated by contact-dependent and soluble factors. Tv lysis of monocytes is far less efficient, and almost entirely contact-dependent. Interestingly, a common symbiont of Tv, Mycoplasma hominis, did not affect cytolytic activity of the parasite, but had a major impact on cytokine responses. M. hominis enabled more diverse inflammatory cytokine secretion in response to Tv and, of the cytokines tested, Tv strains cleared of M. hominis induced only IL-8 secretion from monocytes. The quality of the adaptive immune response to Tv is therefore likely influenced by Tv symbionts, commensals, and concomitant infections, and may be further complicated by direct parasite lysis of effector immune cells. PMID:27529696

  19. Delineation of diverse macrophage activation programs in response to intracellular parasites and cytokines.

    Directory of Open Access Journals (Sweden)

    Shuyi Zhang

    2010-03-01

    Full Text Available The ability to reside and proliferate in macrophages is characteristic of several infectious agents that are of major importance to public health, including the intracellular parasites Trypanosoma cruzi (the etiological agent of Chagas disease and Leishmania species (etiological agents of Kala-Azar and cutaneous leishmaniasis. Although recent studies have elucidated some of the ways macrophages respond to these pathogens, the relationships between activation programs elicited by these pathogens and the macrophage activation programs elicited by bacterial pathogens and cytokines have not been delineated.To provide a global perspective on the relationships between macrophage activation programs and to understand how certain pathogens circumvent them, we used transcriptional profiling by genome-wide microarray analysis to compare the responses of mouse macrophages following exposure to the intracellular parasites T. cruzi and Leishmania mexicana, the bacterial product lipopolysaccharide (LPS, and the cytokines IFNG, TNF, IFNB, IL-4, IL-10, and IL-17. We found that LPS induced a classical activation state that resembled macrophage stimulation by the Th1 cytokines IFNG and TNF. However, infection by the protozoan pathogen L. mexicana produced so few transcriptional changes that the infected macrophages were almost indistinguishable from uninfected cells. T. cruzi activated macrophages produced a transcriptional signature characterized by the induction of interferon-stimulated genes by 24 h post-infection. Despite this delayed IFN response by T. cruzi, the transcriptional response of macrophages infected by the kinetoplastid pathogens more closely resembled the transcriptional response of macrophages stimulated by the cytokines IL-4, IL-10, and IL-17 than macrophages stimulated by Th1 cytokines.This study provides global gene expression data for a diverse set of biologically significant pathogens and cytokines and identifies the relationships between

  20. Regulatory T-Cell-Associated Cytokines in Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Akiko Okamoto

    2011-01-01

    Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disease characterized by autoantibody production, complement activation, and immune complex deposition, resulting in tissue and organ damage. An understanding of the mechanisms responsible for homeostatic control of inflammation, which involve both innate and adoptive immune responses, will enable the development of novel therapies for SLE. Regulatory T cells (Treg play critical roles in the induction of peripheral tolerance to self- and foreign antigens. Naturally occurring CD4+CD25+ Treg, which characteristically express the transcription factor forkhead box protein P3 (Foxp3, have been intensively studied because their deficiency abrogates self-tolerance and causes autoimmune disease. Moreover, regulatory cytokines such as interleukin-10 (IL-10 also play a central role in controlling inflammatory processes. This paper focuses on Tregs and Treg-associated cytokines which might regulate the pathogenesis of SLE and, hence, have clinical applications.

  1. Th-17 regulatory cytokines IL-21, IL-23, and IL-6 enhance neutrophil production of IL-17 cytokines during asthma.

    Science.gov (United States)

    Halwani, Rabih; Sultana, Asma; Vazquez-Tello, Alejandro; Jamhawi, Amer; Al-Masri, Abeer A; Al-Muhsen, Saleh

    2017-11-01

    In a subset of severe asthma patients, chronic airway inflammation is associated with infiltration of neutrophils, Th-17 cells and elevated expression of Th-17-derived cytokines (e.g., interleukin [IL]-17, IL-21, IL-22). Peripheral neutrophils from allergic asthmatics are known to express higher IL-17 cytokine levels than those from healthy subjects, but the regulatory mechanisms involved are not well understood. We hypothesize that Th-17 regulatory cytokines could modulate IL-17 expression in neutrophils. Peripheral blood neutrophils isolated from asthmatics were stimulated with IL-21, IL-23, and IL-6 cytokines and their ability to produce IL-17A and IL-17F was determined relative to healthy controls. Signal transducer and activator of transcription 3 (STAT3) phosphorylation levels were measured in stimulated neutrophil using flow cytometry. The requirement for STAT3 phosphorylation was determined by blocking its activation using a specific chemical inhibitor. Stimulating asthmatic neutrophils with IL-21, 23, and 6 enhanced the production of IL-17A and IL-17F at significantly higher levels comparatively to healthy controls. Stimulating neutrophils with IL-21, IL-23, and IL-6 cytokines enhanced STAT3 phosphorylation, in all cases. Interestingly, inhibiting STAT3 phosphorylation using a specific chemical inhibitor dramatically blocked the ability of neutrophils to produce IL-17, demonstrating that STAT3 activation is the major factor mediating IL-17 gene expression. These findings suggest that neutrophil infiltration in lungs of severe asthmatics may represent an important source of pro-inflammatory IL-17A and -F cytokines, a production enhanced by Th-17 regulatory cytokines, and thus providing a feedback mechanism that sustains inflammation. Our results suggest that STAT3 pathway could be a potential target for regulating neutrophilic inflammation during severe asthma.

  2. Helminths and skewed cytokine profiles increase tuberculin skin test positivity in Warao Amerindians

    NARCIS (Netherlands)

    Verhagen, L. M.; Hermans, P. W. M.; Warris, A.; de Groot, R.; Maes, M.; Villalba, J. A.; del Nogal, B.; van den Hof, S.; Mughini Gras, L.; van Soolingen, D.; Pinelli, E.; de Waard, J. H.

    2012-01-01

    The immune regulatory mechanisms involved in the acquisition of Mycobacterium tuberculosis infection in children are largely unknown. We investigated the influence of parasitic infections, malnutrition and plasma cytokine profiles on tuberculin skin test (TST) positivity in Warao Amerindians in

  3. The guanylhydrazone CNI-1493: an inhibitor with dual activity against malaria-inhibition of host cell pro-inflammatory cytokine release and parasitic deoxyhypusine synthase.

    Science.gov (United States)

    Specht, Sabine; Sarite, Salem Ramadan; Hauber, Ilona; Hauber, Joachim; Görbig, Ulf F; Meier, Chris; Bevec, Dorian; Hoerauf, Achim; Kaiser, Annette

    2008-05-01

    Malaria is still a major cause of death in the tropics. There is an urgent need for new anti-malarial drugs because drug-resistant plasmodia frequently occur. Over recent years, we elucidated the biosynthesis of hypusine, a novel amino acid contained in eukaryotic initiation factor 5A (eIF-5A) in Plasmodium. Hypusine biosynthesis involves catalysis of deoxyhypusine synthase (DHS) in the first step of post-translational modification. In a screen for new inhibitors of purified plasmodium DHS, CNI-1493, a novel selective pro-inflammatory cytokine inhibitor used in clinical phase II for the treatment of Crohn's disease, inhibited the enzyme of the parasite 3-fold at a concentration of 2 microM. In vitro experiments with 200 microM CNI-1493 in Plasmodium-infected erythrocytes, which lack nuclei and DHS protein, showed a parasite clearance within 2 days. This can presumably be attributed to an anti-proliferating effect because of the inhibition of DHS by the parasite. The determined IC50 of CNI-1493 was 135.79 microM after 72 h. In vivo application of this substance in Plasmodium berghei ANKA-infected C57BL/6 mice significantly reduced parasitemia after dosage of 1 mg/kg or 4 mg/kg/body weight and prevented death of mice with cerebral malaria. This effect was paralleled by a decrease in serum TNF levels of the mice. We suggest that the new mechanism of CNI-1493 is caused by a decrease in modified eIF-5A biosynthesis with a downstream effect on the TNF synthesis of the host. From the current data, we consider CNI-1493 to be a promising drug for anti-malarial therapy because of its combined action, i.e., the decrease in eIF-5A biosynthesis of the parasite and host cell TNF biosynthesis.

  4. Regulatory hotspots in the malaria parasite genome dictate transcriptional variation.

    Directory of Open Access Journals (Sweden)

    Joseph M Gonzales

    2008-09-01

    Full Text Available The determinants of transcriptional regulation in malaria parasites remain elusive. The presence of a well-characterized gene expression cascade shared by different Plasmodium falciparum strains could imply that transcriptional regulation and its natural variation do not contribute significantly to the evolution of parasite drug resistance. To clarify the role of transcriptional variation as a source of stain-specific diversity in the most deadly malaria species and to find genetic loci that dictate variations in gene expression, we examined genome-wide expression level polymorphisms (ELPs in a genetic cross between phenotypically distinct parasite clones. Significant variation in gene expression is observed through direct co-hybridizations of RNA from different P. falciparum clones. Nearly 18% of genes were regulated by a significant expression quantitative trait locus. The genetic determinants of most of these ELPs resided in hotspots that are physically distant from their targets. The most prominent regulatory locus, influencing 269 transcripts, coincided with a Chromosome 5 amplification event carrying the drug resistance gene, pfmdr1, and 13 other genes. Drug selection pressure in the Dd2 parental clone lineage led not only to a copy number change in the pfmdr1 gene but also to an increased copy number of putative neighboring regulatory factors that, in turn, broadly influence the transcriptional network. Previously unrecognized transcriptional variation, controlled by polymorphic regulatory genes and possibly master regulators within large copy number variants, contributes to sweeping phenotypic evolution in drug-resistant malaria parasites.

  5. Activation of counter-regulatory mechanisms in a rat renal acute rejection model

    Directory of Open Access Journals (Sweden)

    Salomon Daniel R

    2008-02-01

    Full Text Available Abstract Background Microarray analysis provides a powerful approach to identify gene expression alterations following transplantation. In patients the heterogeneity of graft specimens, co-morbidity, co-medications and the challenges in sample collection and preparation complicate conclusions regarding the underlying mechanisms of graft injury, rejection and immune regulation. Results We used a rat kidney transplantation model with strict transplant and sample preparation procedures to analyze genome wide changes in gene expression four days after syngeneic and allogeneic transplantation. Both interventions were associated with substantial changes in gene expression. After allogeneic transplantation, genes and pathways related to transport and metabolism were predominantly down-regulated consistent with rejection-mediated graft injury and dysfunction. Up-regulated genes were primarily related to the acute immune response including antigen presentation, T-cell receptor signaling, apoptosis, interferon signaling and complement cascades. We observed a cytokine and chemokine expression profile consistent with activation of a Th1-cell response. A novel finding was up-regulation of several regulatory and protective genes after allogeneic transplantation, specifically IL10, Bcl2a1, C4bpa, Ctla4, HO-1 and the SOCS family. Conclusion Our data indicate that in parallel with the predicted activation of immune response and tissue injury pathways, there is simultaneous activation of pathways for counter regulatory and protective mechanisms that would balance and limit the ongoing inflammatory/immune responses. The pathophysiological mechanisms behind and the clinical consequences of alterations in expression of these gene classes in acute rejection, injury and dysfunction vs. protection and immunoregulation, prompt further analyses and open new aspects for therapeutic approaches.

  6. Dual anti-inflammatory and anti-parasitic action of topical ivermectin 1% in papulopustular rosacea.

    Science.gov (United States)

    Schaller, M; Gonser, L; Belge, K; Braunsdorf, C; Nordin, R; Scheu, A; Borelli, C

    2017-11-01

    Recently, therapy of rosacea with inflammatory lesions (papulopustular) has improved substantially with the approval of topical ivermectin 1% cream. It is assumed to have a dual mode of action with anti-inflammatory capacities and anti-parasitic effects against Demodex, which however has not yet been demonstrated in vivo. To find scientific rationale for the dual anti-inflammatory and anti-parasitic mode of action of topical ivermectin 1% cream in patients with rosacea. A monocentric pilot study was performed including 20 caucasion patients with moderate to severe rosacea, as assessed by investigator global assessment (IGA score ≥3) and a Demodex density ≥15/cm 2 . Patients were treated with topical ivermectin 1% cream once daily (Soolantra ® ) for ≥12 weeks. The density of Demodex mites was assessed with skin surface biopsies. Expression of inflammatory and immune markers was evaluated with RT-PCR and by immunofluorescence staining. The mean density of mites was significantly decreased at week 6 and week 12 (P < 0.001). The gene expression levels of IL-8, LL-37, HBD3, TLR4 and TNF-α were downregulated at both time points. Reductions in gene expression were significant for LL-37, HBD3 and TNF-α at both follow-up time points and at week 12 for TLR4 (all P < 0.05). Reduced LL-37 expression (P < 0.05) and IL-8 expression were confirmed on the protein level by immunofluorescence staining. All patients improved clinically, and 16 of 20 patients reached therapeutic success defined as IGA score ≤1. Topical ivermectin 1% cream acts by a dual, anti-inflammatory and anti-parasitic mode of action against rosacea by killing Demodex spp. in vivo, in addition to significantly improving clinical signs and symptoms in the skin. © 2017 European Academy of Dermatology and Venereology.

  7. IL-10: A Multifunctional Cytokine in Viral Infections

    Directory of Open Access Journals (Sweden)

    José M. Rojas

    2017-01-01

    Full Text Available The anti-inflammatory master regulator IL-10 is critical to protect the host from tissue damage during acute phases of immune responses. This regulatory mechanism, central to T cell homeostasis, can be hijacked by viruses to evade immunity. IL-10 can be produced by virtually all immune cells, and it can also modulate the function of these cells. Understanding the effects of this multifunctional cytokine is therefore a complex task. In the present review we discuss the factors driving IL-10 production and the cellular sources of the cytokine during antiviral immune responses. We particularly focus on the IL-10 regulatory mechanisms that impact antiviral immune responses and how viruses can use this central regulatory pathway to evade immunity and establish chronic/latent infections.

  8. Association of pro-inflammatory cytokines and iron regulatory protein 2 (IRP2 with Leishmania burden in canine visceral leishmaniasis.

    Directory of Open Access Journals (Sweden)

    Paulo Ricardo Porfírio do Nascimento

    Full Text Available Leishmania infantum infection in humans and dogs can evolve with a wide range of clinical presentations, varying from asymptomatic infections to visceral leishmaniasis. We hypothesized that the immune response elicited by L. infantum infection could modulate whether the host will remain asymptomatic or progress to disease. A total of 44 dogs naturally infected with L. infantum were studied. Leishmania burden was estimated in the blood and spleen by qPCR. The expression of IFN-γ, TNF-α, IL-10 and Iron Regulatory Protein 2 (IRP2 were determined in the spleen by quantitative PCR. Sera cytokines were evaluated by ELISA. Dogs were grouped in quartiles according parasite burden. Increased expression of IFN-γ and TNF-α was associated with reduced Leishmania burden, whereas increased IL-10 and IRP2 expressions were associated with higher Leishmania load. Increased plasma albumin and IFN-γ expression explained 22.8% of the decrease in parasite burden in the spleen. These data confirm that lower IFN-γ response and higher IL-10 correlated with increased parasite load and severity of the visceral leishmaniasis in dogs. The balance between the branches of immune response and the intracellular iron availability could determine, in part, the course of Leishmania infection.

  9. Cytokine responses to the anti-schistosome vaccine candidate antigen glutathione-S-transferase vary with host age and are boosted by praziquantel treatment.

    Directory of Open Access Journals (Sweden)

    Claire D Bourke

    2014-05-01

    Full Text Available Improved helminth control is required to alleviate the global burden of schistosomiasis and schistosome-associated pathologies. Current control efforts rely on the anti-helminthic drug praziquantel (PZQ, which enhances immune responses to crude schistosome antigens but does not prevent re-infection. An anti-schistosome vaccine based on Schistosoma haematobium glutathione-S-transferase (GST is currently in Phase III clinical trials, but little is known about the immune responses directed against this antigen in humans naturally exposed to schistosomes or how these responses change following PZQ treatment.Blood samples from inhabitants of a Schistosoma haematobium-endemic area were incubated for 48 hours with or without GST before (n = 195 and six weeks after PZQ treatment (n = 107. Concentrations of cytokines associated with innate inflammatory (TNFα, IL-6, IL-8, type 1 (Th1; IFNγ, IL-2, IL-12p70, type 2 (IL-4, IL-5, IL-13, type 17 (IL-17A, IL-21, IL-23p19 and regulatory (IL-10 responses were quantified in culture supernatants via enzyme-linked immunosorbent assay (ELISA. Factor analysis and multidimensional scaling were used to analyse multiple cytokines simultaneously.A combination of GST-specific type 2 (IL-5 and IL-13 and regulatory (IL-10 cytokines was significantly lower in 10-12 year olds, the age group at which S. haematobium infection intensity and prevalence peak, than in 4-9 or 13+ year olds. Following PZQ treatment there was an increase in the number of participants producing detectable levels of GST-specific cytokines (TNFα, IL-6, IL-8, IFNγ, IL-12p70, IL-13 and IL-23p19 and also a shift in the GST-specific cytokine response towards a more pro-inflammatory phenotype than that observed before treatment. Participant age and pre-treatment infection status significantly influenced post-treatment cytokine profiles.In areas where schistosomiasis is endemic host age, schistosome infection status and PZQ treatment affect the

  10. Chalcones from Chinese liquorice inhibit proliferation of T cells and production of cytokines

    DEFF Research Database (Denmark)

    Barfod, Lea; Kemp, Kåre; Hansen, Majbritt

    2002-01-01

    Licochalcone A (LicA), an oxygenated chalcone, has been shown to inhibit the growth of both parasites and bacteria. In this study, we investigated the effect of LicA and four synthetic analogues on the activity of human peripheral blood mononuclear cell proliferation and cytokine production. Four...... out of five chalcones tested inhibited the proliferation of lymphocytes measured by thymidine incorporation and by flow cytometry. The production of pro- and anti-inflammatory cytokines from monocytes and T cells was also inhibited by four of five chalcones. Furthermore, intracellular detection...... of cytokines revealed that the chalcones inhibited the production rather than the release of the cytokines. Taken together, these results indicate that LicA and some analogues may have immunomodulatory effects, and may thus be candidates not only as anti-microbial agents, but also for the treatment of other...

  11. Pro- and Anti-Inflammatory Cytokines Release in Mice Injected with Crotalus durissus terrificus Venom

    Directory of Open Access Journals (Sweden)

    A. Hernández Cruz

    2008-01-01

    Full Text Available The effects of Crotalus durissus terrificus venom (Cdt were analyzed with respect to the susceptibility and the inflammatory mediators in an experimental model of severe envenomation. BALB/c female mice injected intraperitoneally presented sensibility to Cdt, with changes in specific signs, blood biochemical and inflammatory mediators. The venom induced reduction of glucose and urea levels and an increment of creatinine levels in serum from mice. Significant differences were observed in the time-course of mediator levels in sera from mice injected with Cdt. The maximum levels of IL-6, NO, IL-5, TNF, IL-4 and IL-10 were observed 15 min, 30 min, 1, 2 and 4 hours post-injection, respectively. No difference was observed for levels of IFN-γ. Taken together, these data indicate that the envenomation by Cdt is regulated both pro- and anti-inflammatory cytokine responses at time-dependent manner. In serum from mice injected with Cdt at the two first hours revealed of pro-inflammatory dominance. However, with an increment of time an increase of anti-inflammatory cytokines was observed and the balance toward to anti-inflammatory dominance. In conclusion, the observation that Cdt affects the production of pro- and anti-inflammatory cytokines provides further evidence for the role played by Cdt in modulating pro/anti-inflammatory cytokine balance.

  12. Supplementation of xanthophylls decreased proinflammatory and increased anti-inflammatory cytokines in hens and chicks.

    Science.gov (United States)

    Gao, Yu-Yun; Xie, Qing-Mei; Jin, Ling; Sun, Bao-Li; Ji, Jun; Chen, Feng; Ma, Jing-Yun; Bi, Ying-Zuo

    2012-11-28

    The present study investigated the effects of xanthophylls (containing 40 % of lutein and 60 % of zeaxanthin) on proinflammatory cytokine (IL-1β, IL-6, interferon (IFN)-γ and lipopolysaccharide-induced TNF-α factor (LITAF)) and anti-inflammatory cytokine (IL-4 and IL-10) expression of breeding hens and chicks. In Expt 1, a total of 432 hens were fed diets supplemented with 0 (as the control group), 20 or 40 mg/kg xanthophylls (six replicates per treatment). The liver, duodenum, jejunum and ileum were sampled at 35 d of the trial. The results showed that both levels of xanthophyll addition decreased IL-1β mRNA in the liver and jejunum, IL-6 mRNA in the liver, IFN-γ mRNA in the jejunum and LITAF mRNA in the liver compared to the control group. Expt 2 was a 2 × 2 factorial design. Male chicks hatched from 0 or 40 mg/kg xanthophyll diet of hens were fed a diet containing either 0 or 40 mg/kg xanthophylls. The liver, duodenum, jejunum and ileum were collected at 0, 7, 14 and 21 d after hatching. The results showed that in ovo xanthophylls decreased proinflammatory cytokine expression (IL-1β, IL-6, IFN-γ and LITAF) in the liver, duodenum, jejunum and ileum and increased anti-inflammatory cytokine expression (IL-4 and IL-10) in the liver, jejunum and ileum mainly at 0-7 d after hatching. In ovo effects gradually vanished and dietary effects began to work during 1-2 weeks after hatching. Dietary xanthophylls modulated proinflammatory cytokines (IL-1β, IL-6 and IFN-γ) in the liver, duodenum, jejunum and ileum and anti-inflammatory cytokine (IL-10) in the liver and jejunum mainly from 2 weeks onwards. In conclusion, xanthophylls could regulate proinflammatory and anti-inflammatory cytokine expression in different tissues of hens and chicks.

  13. U.S. and Department of Defense Building Partnership Capacity and Counter/Anti-Corruption: A Symbiotic Relationship or One at Odds

    Science.gov (United States)

    2016-02-16

    AIR WAR COLLEGE AIR UNIVERSITY U.S. AND DEPARTMENT OF DEFENSE BUILDING PARTNERSHIP CAPACITY AND COUNTER/ANTI-CORRUPTION: A SYMBIOTIC ...Extortion,” DoD BPC and counter/anti-corruption have resulted in both a symbiotic relationship and one at odds. This uncomfortable dichotomy has led to...extraversion as “Soft Extortion” have all led DoD BPC and counter/anti-corruption efforts into a relationship that is both symbiotic and one at odds

  14. Identifying rapidly parasiticidal anti-malarial drugs using a simple and reliable in vitro parasite viability fast assay.

    Science.gov (United States)

    Linares, María; Viera, Sara; Crespo, Benigno; Franco, Virginia; Gómez-Lorenzo, María G; Jiménez-Díaz, María Belén; Angulo-Barturen, Íñigo; Sanz, Laura María; Gamo, Francisco-Javier

    2015-11-05

    The emergence of Plasmodium falciparum resistance to artemisinins threatens to undermine the effectiveness of artemisinin-based combination anti-malarial therapy. Developing suitable drugs to replace artemisinins requires the identification of new compounds that display rapid parasite killing kinetics. However, no current methods fully meet the requirements to screen large compound libraries for candidates with such properties. This study describes the development and validation of an in vitro parasite viability fast assay for identifying rapidly parasiticidal anti-malarial drugs. Parasite killing kinetics were determined by first culturing unlabelled erythrocytes with P. falciparum in the presence of anti-malarial drugs for 24 or 48 h. After removing the drug, samples were added to erythrocytes pre-labelled with intracellular dye to allow their subsequent identification. The ability of viable parasites to re-establish infection in labelled erythrocytes could then be detected by two-colour flow cytometry after tagging of parasite DNA. Thus, double-stained erythrocytes (with the pre-labelled intracellular dye and the parasite DNA dye) result only after establishment of new infections by surviving parasites. The capacity of the test anti-malarial drugs to eliminate viable parasites within 24 or 48 h could, therefore, be determined. The parasite viability fast assay could be completed within 48 h following drug treatment and distinguished between rapidly parasiticidal anti-malarial drugs versus those acting more slowly. The assay was validated against ten standard anti-malarial agents with known properties and results correlated well with established methods. An abbreviated assay, suitable for adaption to medium-high throughput screening, was validated and applied against a set of 20 compounds retrieved from the publically available Medicines for Malaria Venture 'Malaria Box'. The quantification of new infections to determine parasite viability offers important

  15. Effect of Anti-Parasite Chemotherapeutic Agents on Immune Reactions.

    Science.gov (United States)

    1980-08-01

    observations). Similar effects of a number of other alkylating agents have been noticed (9, and personal observa- tions). Similarly, corticosteroids inhibit...Wellham, L. L., and Sigel, M. M. Ef- fect of anti-cancer chemotherapeutic agents on immune reactions of mice. I. Comparison of two nitrosoureas . J...7 D-Ri138 852 EFFECT OF ANTI-PARASITE CHEMOTHERAPEUTIC AGENTS ON i/i IMMUNE REACTIONS(U) SOUTH CAROLINA UNIV COLUMBIA DEPT OF MICROBIOLOGY AND

  16. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway

    Science.gov (United States)

    Pavlov, Valentin A.; Parrish, William R.; Rosas-Ballina, Mauricio; Ochani, Mahendar; Puerta, Margot; Ochani, Kanta; Chavan, Sangeeta; Al-Abed, Yousef; Tracey, Kevin J.

    2015-01-01

    The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the “cholinergic anti-inflammatory pathway,” defined as neural signals transmitted via the vagus nerve that inhibit cytokine release through a mechanism that requires the alpha7 subunit-containing nicotinic acetylcholine receptor (α7nAChR). Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks, but despite considerable importance, little is known about the molecular basis for central regulation of the vagus nerve-based cholinergic anti-inflammatory pathway. Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF production during endotoxemia. Peripheral administration of the acetylcholinesterase inhibitor galantamine significantly reduced serum TNF levels through vagus nerve signaling, and protected against lethality during murine endotoxemia. Administration of a centrally-acting muscarinic receptor antagonist abolished the suppression of TNF by galantamine, indicating that suppressing acetylcholinesterase activity, coupled with central muscarinic receptors, controls peripheral cytokine responses. Administration of galantamine to α7nAChR knockout mice failed to suppress TNF levels, indicating that the α7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of galantamine. These findings show that inhibition of brain acetylcholinesterase suppresses systemic inflammation through a central muscarinic receptor-mediated and vagal- and α7nAChR-dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor can be utilized to suppress abnormal inflammation to therapeutic advantage. PMID:18639629

  17. Cytokines, antibodies and histopathological profiles during Giardia infection and VSP-based vaccination.

    Science.gov (United States)

    Serradell, Marianela C; Gargantini, Pablo R; Saura, Alicia; Oms, Sergio R; Rupil, Lucía L; Berod, Luciana; Sparwasser, Tim; Luján, Hugo D

    2018-03-19

    Giardiasis is one of the most common human intestinal diseases worldwide. Several experimental animals have been used to evaluate Giardia infections, with gerbils ( Meriones unguiculatus ) being the most valuable model due to their high susceptibility to Giardia infection, abundant shedding of cysts, and pathophysiological alterations and signs of disease similar to those observed in humans. Here we report cytokine and antibody profiles both during the course of Giardia infection in gerbils and after immunization with a novel oral vaccine comprising a mixture of purified Variant-specific Surface Proteins (VSPs). Transcript levels of representative cytokines of different immune profiles as well as macro- and micro-tissue alterations were assessed in Peyer's patches, mesenteric lymph nodes and spleens. During infection, cytokine responses showed a biphasic profile: an early induction of Th1 (IFN-γ, IL-1β, IL-6 and TNF), Th17 (IL-17) and Th2 (IL-4) cytokines, together with intestinal alterations typical of inflammation, followed by a shift toward a predominant Th2 (IL-5) response, likely associated with a counter-regulatory mechanism. Conversely, immunization with an oral vaccine comprising the entire repertoire of VSPs specifically showed high levels of IL-17, IL-6, IL-4 and IL-5, without obvious signs of inflammation. Both immunized and infected animals developed local (intestinal S-IgA) and systemic (serum IgG) humoral immune responses against VSPs; however, only infected animals showed evident signs of giardiasis. This is the first comprehensive report of cytokine expression and anti- Giardia antibody production during infection and VSP vaccination in gerbils, a reliable model of the human disease. Copyright © 2018 American Society for Microbiology.

  18. Cytokine-Modulating Strategies and Newer Cytokine Targets for Arthritis Therapy

    Directory of Open Access Journals (Sweden)

    Shivaprasad H. Venkatesha

    2014-12-01

    Full Text Available Cytokines are the key mediators of inflammation in the course of autoimmune arthritis and other immune-mediated diseases. Uncontrolled production of the pro-inflammatory cytokines such as interferon-γ (IFN-γ, tumor necrosis factor α (TNFα, interleukin-6 (IL-6, and IL-17 can promote autoimmune pathology, whereas anti-inflammatory cytokines including IL-4, IL-10, and IL-27 can help control inflammation and tissue damage. The pro-inflammatory cytokines are the prime targets of the strategies to control rheumatoid arthritis (RA. For example, the neutralization of TNFα, either by engineered anti-cytokine antibodies or by soluble cytokine receptors as decoys, has proven successful in the treatment of RA. The activity of pro-inflammatory cytokines can also be downregulated either by using specific siRNA to inhibit the expression of a particular cytokine or by using small molecule inhibitors of cytokine signaling. Furthermore, the use of anti-inflammatory cytokines or cytokine antagonists delivered via gene therapy has proven to be an effective approach to regulate autoimmunity. Unexpectedly, under certain conditions, TNFα, IFN-γ, and few other cytokines can display anti-inflammatory activities. Increasing awareness of this phenomenon might help develop appropriate regimens to harness or avoid this effect. Furthermore, the relatively newer cytokines such as IL-32, IL-34 and IL-35 are being investigated for their potential role in the pathogenesis and treatment of arthritis.

  19. Foetal immune programming: hormones, cytokines, microbes and regulatory T cells.

    Science.gov (United States)

    Hsu, Peter; Nanan, Ralph

    2014-10-01

    In addition to genetic factors, environmental cues play important roles in shaping the immune system. The first environment that the developing foetal immune system encounters is the uterus. Although physically the mother and the foetus are separated by the placental membranes, various factors such as hormones and cytokines may provide "environmental cues" to the foetal immune system. Additionally, increasing evidence suggests that prenatal maternal environmental factors, particularly microbial exposure, might significantly influence the foetal immune system, affecting long-term outcomes, a concept termed foetal immune programming. Here we discuss the potential mediators of foetal immune programming, focusing on the role of pregnancy-related hormones, cytokines and regulatory T cells, which play a critical role in immune tolerance. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. The antimalarial drug, Ro 42-1611 (arteflene), does not affect cytoadherence and cytokine-inducing properties of Plasmodium falciparum malaria parasites

    DEFF Research Database (Denmark)

    Jakobsen, P H; Staalsø, T; Bendtzen, K

    1995-01-01

    The purpose of this study was to investigate the ability of the antimalarial drug, Ro 42-1611 to block parasite mediated cytokine induction in vitro as well as cytoadherence of infected erythrocytes to melanoma cells in vitro. The biological activity of Ro 42-1611 was confirmed as it blocked...... to melanoma cells. The therapeutic effect of To 42-1611 appears to be confined to its parasite killing activity....

  1. Violacein Treatment Modulates Acute and Chronic Inflammation through the Suppression of Cytokine Production and Induction of Regulatory T Cells.

    Directory of Open Access Journals (Sweden)

    Liana Verinaud

    Full Text Available Inflammation is a necessary process to control infection. However, exacerbated inflammation, acute or chronic, promotes deleterious effects in the organism. Violacein (viola, a quorum sensing metabolite from the Gram-negative bacterium Chromobacterium violaceum, has been shown to protect mice from malaria and to have beneficial effects on tumors. However, it is not known whether this drug possesses anti-inflammatory activity. In this study, we investigated whether viola administration is able to reduce acute and chronic autoimmune inflammation. For that purpose, C57BL/6 mice were intraperitoneally injected with 1 μg of LPS and were treated with viola (3.5mg/kg via i.p. at the same time-point. Three hours later, the levels of inflammatory cytokines in the sera and phenotypical characterization of leukocytes were determined. Mice treated with viola presented a significant reduction in the production of inflammatory cytokines compared with untreated mice. Interestingly, although viola is a compound derived from bacteria, it did not induce inflammation upon administration to naïve mice. To test whether viola would protect mice from an autoimmune inflammation, Experimental Autoimmune Encephalomyelitis (EAE-inflicted mice were given viola i.p. at disease onset, at the 10th day from immunization. Viola-treated mice developed mild EAE disease in contrast with placebo-treated mice. The frequencies of dendritic cells and macrophages were unaltered in EAE mice treated with viola. However, the sole administration of viola augmented the levels of splenic regulatory T cells (CD4+Foxp3+. We also found that adoptive transfer of viola-elicited regulatory T cells significantly reduced EAE. Our study shows, for the first time, that violacein is able to modulate acute and chronic inflammation. Amelioration relied in suppression of cytokine production (in acute inflammation and stimulation of regulatory T cells (in chronic inflammation. New studies must be

  2. Plasmodium falciparum: characterization of toxin-associated proteins and identification of a hemoglobin containing parasite cytokine stimulator

    DEFF Research Database (Denmark)

    Kristensen, G; Jakobsen, P H

    1996-01-01

    ]-methionine and immunoprecipitated the labeled antigens with an antiserum against IMP which blocks malaria parasite-induced TNF production. We detected four proteins associated with IMP when the immunoprecipitates were separated by SDS-PAGE and analyzed by autoradiography. To evaluate the capacity of different P. falciparum......Previous studies have indicated the inositol monophosphate (IMP) is a component of the malaria parasite toxin that induces cytokines such as tumour necrosis factor (TNF). To further characterize the toxin we have labeled Plasmodium falciparum in vitro cultures with [14C]inositol or [35S...

  3. Financial Worldwide Crisis: The Anti-Counter Cycle of Australia

    Directory of Open Access Journals (Sweden)

    Joao NEGREIROS

    2013-12-01

    Full Text Available If Australia has been subject to major influences by the United States and European countries, why is its economy healthier than their counter partners? What are the economic foundations that underline this anti-counter cycle of financial worldwide crisis from Australia? What are some of the lessons that countries from Europe that have not fared during the current financial worldwide crisis should learn from Australia? The purpose of this paper is to review the present Australian management system. Four changes are identified including embracement of corporate governance, a shift to adopt more R&D activities, a shift to adopt environmental sustainability practices and emerging corporate social responsibility. On the conclusions settings, a recap and recommendation on how Portugal, a member of the PIGS (Portugal, Italy, Greece and Spain Southern European Countries club forgot to embrace directives that have been applied in Australia, to avoid the actual financial and identity crisis.

  4. Combined antiparasitic and anti-inflammatory effects of the natural polyphenol curcumin on turbot scuticociliatosis.

    Science.gov (United States)

    Mallo, N; DeFelipe, A P; Folgueira, I; Sueiro, R A; Lamas, J; Leiro, J M

    2017-02-01

    The histiophagous scuticociliate Philasterides dicentrarchi is the aetiological agent of scuticociliatosis, a parasitic disease of farmed turbot. Curcumin, a polyphenol from Curcuma longa (turmeric), is known to have antioxidant and anti-inflammatory properties. We investigated the in vitro effects of curcumin on the growth of P. dicentrarchi and on the production of pro-inflammatory cytokines in turbot leucocytes activated by parasite cysteine proteases. At 100 μm, curcumin had a cytotoxic effect and completely inhibited the growth of the parasite. At 50 μm, curcumin inhibited the protease activity of the parasite and expression of genes encoding two virulence-associated proteases: leishmanolysin-like peptidase and cathepsin L-like. At concentrations between 25 and 50 μm, curcumin inhibited the expression of S-adenosyl-L-homocysteine hydrolase, an enzyme involved in the biosynthesis of the amino acids methionine and cysteine. At 100 μm, curcumin inhibited the expression of the cytokines tumour necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) produced in turbot leucocytes activated by parasite proteases. Results show that curcumin has a dual effect on scuticociliatosis: an antiparasitic effect on the catabolism and anabolism of ciliate proteins, and an anti-inflammatory effect that inhibits the production of proinflammatory cytokines in the host. The present findings suggest the potential usefulness of this polyphenol in treating scuticociliatosis. © 2016 John Wiley & Sons Ltd.

  5. Cytokine profile and pathology in human leishmaniasis

    Directory of Open Access Journals (Sweden)

    Ribeiro-de-Jesus A.

    1998-01-01

    Full Text Available The clinical spectrum of leishmaniasis and control of the infection are influenced by the parasite-host relationship. The role of cellular immune responses of the Th1 type in the protection against disease in experimental and human leishmaniasis is well established. In humans, production of IFN-g is associated with the control of infection in children infected by Leishmania chagasi. In visceral leishmaniasis, an impairment in IFN-g production and high IL-4 and IL-10 levels (Th2 cytokines are observed in antigen-stimulated peripheral blood mononuclear cells (PBMC. Moreover, IL-12 restores IFN-g production and enhances the cytotoxic response. IL-10 is the cytokine involved in down-regulation of IFN-g production, since anti-IL-10 monoclonal antibody (mAb restores in vitro IFN-g production and lymphoproliferative responses, and IL-10 abrogates the effect of IL-12. In cutaneous and mucosal leishmaniasis, high levels of IFN-g are found in L. amazonensis-stimulated PBMC. However, low or absent IFN-g levels were observed in antigen-stimulated PBMC from 50% of subjects with less than 60 days of disease (24 ± 26 pg/ml. This response was restored by IL-12 (308 ± 342 pg/ml and anti-IL-10 mAb (380 ± 245 pg/ml (P<0.05. Later during the disease, high levels of IFN-g and TNF-a are produced both in cutaneous and mucosal leishmaniasis. After treatment there is a decrease in TNF-a levels (366 ± 224 pg/ml before treatment vs 142 ± 107 pg/ml after treatment, P = 0.02. Although production of IFN-g and TNF-a might be involved in the control of parasite multiplication in the early phases of Leishmania infection, these cytokines might also be involved in the tissue damage seen in tegumentary leishmaniasis

  6. CHARACTERISTICS OF NEUROPEPTIDE-CYTOKINE IMMUNITY LINKS IN PATIENTS WITH COMBINED CARDIOVASCULAR PATHOLOGY, PROCEEDING WITH ANXIETY/DEPRESSION DISORDER

    Directory of Open Access Journals (Sweden)

    A. V. Gertsev

    2018-01-01

    Full Text Available To date, pathogenetic events underlying coronary heart disease and hypertensive syndrome should be regarded as complex reactions of neuroimmune interactions characterized by activation of proinflammatory cytokines, opiate receptors and endogenous opioid peptides. These changes are mediated by high activity of basic regulatory systems that increase myocardial resistance to acute and chronic ischemic damage. However, there is lack of data concerning severity of these changes in the course of complicated coronary heart disease and hypertension, which occur in the background of anxiety-depressive disorders.The aim of present study was to assess regulatory disturbances at the level of neuropeptide-cytokine pool in the patients with polymorbid cardiovascular disease accomplished by anxiety and depressive conditions. Clinical examination of 85 patients (males aged 35 to 45 years, with complicated cardiovascular disease (coronary heart disease combined with essential hypertension stage II associated with anxiety and depressive disorders. To address these issues, we have formed a group of patients with anxiety and depressive disorders (group 1, n = 40, patients with coronary artery disease and stage II hypertension; group 2 (n = 20 included patients with coronary artery disease; group 3 (n = 25 included patients with hypertension stage II; group 4 (n = 30 represented controls (healthy person. In order to study dysfunction of regulatory neuropeptides at the level of cytokine-mediated immunity in these groups, we have studied diagnostic markers of the suprasegmentary autonomous nervous condition, and cytokine pool of immune system. Immune testing was used to determine β-endorphin, cytokines of pro-inflammatory (TNFα, IL-1β, IL-6 and anti-inflammatory (IL-4, IL-10 spectra in blood serum of patients.In the course of clinical and laboratory examination, the authors found that the patients with polymorbid cardiovascular pathology exhibit regulatory

  7. Echinococcus multilocularis and Its Intermediate Host: A Model of Parasite-Host Interplay

    Directory of Open Access Journals (Sweden)

    Dominique Angèle Vuitton

    2010-01-01

    Full Text Available Host-parasite interactions in the E. multilocularis-intermediate host model depend on a subtle balance between cellular immunity, which is responsible for host's resistance towards the metacestode, the larval stage of the parasite, and tolerance induction and maintenance. The pathological features of alveolar echinococcosis. the disease caused by E. multilocularis, are related both to parasitic growth and to host's immune response, leading to fibrosis and necrosis, The disease spectrum is clearly dependent on the genetic background of the host as well as on acquired disturbances of Th1-related immunity. The laminated layer of the metacestode, and especially its carbohydrate components, plays a major role in tolerance induction. Th2-type and anti-inflammatory cytokines, IL-10 and TGF-β, as well as nitric oxide, are involved in the maintenance of tolerance and partial inhibition of cytotoxic mechanisms. Results of studies in the experimental mouse model and in patients suggest that immune modulation with cytokines, such as interferon-α, or with specific antigens could be used in the future to treat patients with alveolar echinococcosis and/or to prevent this very severe parasitic disease.

  8. Changes in T-cell subpopulations and cytokine network during early period of ibrutinib therapy in chronic lymphocytic leukemia patients: the significant decrease in T regulatory cells number.

    Science.gov (United States)

    Podhorecka, Monika; Goracy, Aneta; Szymczyk, Agnieszka; Kowal, Malgorzata; Ibanez, Blanca; Jankowska-Lecka, Olga; Macheta, Arkadiusz; Nowaczynska, Aleksandra; Drab-Urbanek, Elzbieta; Chocholska, Sylwia; Jawniak, Dariusz; Hus, Marek

    2017-05-23

    B cell receptor (BCR) stimulation signal plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), and kinase inhibitors directed toward the BCR pathway are now the promising anti-leukemic drugs. Ibrutinib, a Bruton tyrosine kinase inhibitor, demonstrates promising clinical activity in CLL. It is reported that ibrutinib, additionally to directly targeting leukemic cells, also inhibits the interactions of these cells with T cells, macrophages and accessory cells. Assessment of these mechanisms is important because of their non -direct anti-leukemic effects and to identify possible side effects connected with long-term drug administration.The aim of this study was to assess the in vivo effects of ibrutinib on T-cell subpopulations and cytokine network in CLL. The analysis was performed on a group of 19 patients during first month of ibrutinib therapy. The standard multicolor flow cytometry and cytometric bead array methods were used for assessment of T-cell subsets and cytokines/chemokines, respectively.The data obtained indicates that Ibrutinib treatment results in changes in T-cell subpopulations and cytokine network in CLL patients. Particularly, a significant reduction of T regulatory cells in peripheral blood was observed. By targeting these populations of T cells Ibrutinib can stimulate rejection of tumor cells by the immune system.

  9. Fatigue in Patients with Multiple Sclerosis: Is It Related to Pro- and Anti-Inflammatory Cytokines?

    Directory of Open Access Journals (Sweden)

    Arjan Malekzadeh

    2015-01-01

    Full Text Available Objective. To investigate the pathophysiological role of pro- and anti-inflammatory cytokines in primary multiple sclerosis-related fatigue. Methods. Fatigued and non-fatigued patients with multiple sclerosis (MS were recruited and their cytokine profiles compared. Patients with secondary fatigue were excluded. Fatigue was assessed with the self-reported Checklist Individual Strength (CIS20r, subscale fatigue. A CIS20r fatigue cut-off score of 35 was applied to differentiate between non-fatigued (CIS20r fatigue ≤34 and fatigued (CIS20r fatigue ≥35 patients with MS. Blood was collected to determine the serum concentrations of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, IL-12p70, IL-17, TNFα, and IFN-γ and anti-inflammatory cytokines (IL-4, IL-5, IL-10, and IL-13. We controlled for the confounding effect of age, gender, duration of MS, disease severity, type of MS, and use of immunomodulatory drugs. Results. Similar cytokine levels were observed between MS patients with (n=21 and without fatigue (n=14. Adjusted multiple regression analyses showed a single significant positive relationship, that of IL-6 with CIS20r fatigue score. The explained variance of the IL-6 model was 21.1%, once adjusted for the confounding effect of age. Conclusion. The pro-inflammatory cytokine interleukin-6 (IL-6 may play a role in the pathophysiology of primary fatigue in patients with MS. Trial Registrations. ISRCTN69520623, ISRCTN58583714, and ISRCTN82353628.

  10. IFNγ signaling endows DCs with the capacity to control type I inflammation during parasitic infection through promoting T-bet+ regulatory T cells.

    Directory of Open Access Journals (Sweden)

    Hyang-Mi Lee

    2015-02-01

    Full Text Available IFNγ signaling drives dendritic cells (DCs to promote type I T cell (Th1 immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population.

  11. Suppressing an anti-inflammatory cytokine reveals a strong age-dependent survival cost in mice.

    Directory of Open Access Journals (Sweden)

    Virginia Belloni

    Full Text Available BACKGROUND: The central paradigm of ecological immunology postulates that selection acts on immunity as to minimize its cost/benefit ratio. Costs of immunity may arise because the energetic requirements of the immune response divert resources that are no longer available for other vital functions. In addition to these resource-based costs, mis-directed or over-reacting immune responses can be particularly harmful for the host. In spite of the potential importance of immunopathology, most studies dealing with the evolution of the immune response have neglected such non resource-based costs. To keep the immune response under control, hosts have evolved regulatory pathways that should be considered when studying the target of the selection pressures acting on immunity. Indeed, variation in regulation may strongly modulate the negative outcome of immune activation, with potentially important fitness consequences. METHODOLOGY/PRINCIPAL FINDINGS: Here, we experimentally assessed the survival costs of reduced immune regulation by inhibiting an anti-inflammatory cytokine (IL-10 with anti-IL-10 receptor antibodies (anti-IL-10R in mice that were either exposed to a mild inflammation or kept as control. The experiment was performed on young (3 months and old (15 months individuals, as to further assess the age-dependent cost of suppressing immune regulation. IL-10 inhibition induced high mortality in old mice exposed to the mild inflammatory insult, whereas no mortality was observed in young mice. However, young mice experienced a transitory lost in body mass when injected with the anti-IL-10R antibodies, showing that the treatment was to a lesser extent also costly for young individuals. CONCLUSIONS: These results suggest a major role of immune regulation that deserves attention when investigating the evolution of immunity, and indicate that the capacity to down-regulate the inflammatory response is crucial for late survival and longevity.

  12. Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites.

    Science.gov (United States)

    Engel, Jessica A; Jones, Amy J; Avery, Vicky M; Sumanadasa, Subathdrage D M; Ng, Susanna S; Fairlie, David P; Skinner-Adams, Tina; Andrews, Katherine T

    2015-12-01

    Histone deacetylase (HDAC) enzymes work together with histone acetyltransferases (HATs) to reversibly acetylate both histone and non-histone proteins. As a result, these enzymes are involved in regulating chromatin structure and gene expression as well as other important cellular processes. HDACs are validated drug targets for some types of cancer, with four HDAC inhibitors clinically approved. However, they are also showing promise as novel drug targets for other indications, including malaria and other parasitic diseases. In this study the in vitro activity of four anti-cancer HDAC inhibitors was examined against parasites that cause malaria and trypanosomiasis. Three of these inhibitors, suberoylanilide hydroxamic acid (SAHA; vorinostat(®)), romidepsin (Istodax(®)) and belinostat (Beleodaq(®)), are clinically approved for the treatment of T-cell lymphoma, while the fourth, panobinostat, has recently been approved for combination therapy use in certain patients with multiple myeloma. All HDAC inhibitors were found to inhibit the growth of asexual-stage Plasmodium falciparum malaria parasites in the nanomolar range (IC50 10-200 nM), while only romidepsin was active at sub-μM concentrations against bloodstream form Trypanosoma brucei brucei parasites (IC50 35 nM). The compounds were found to have some selectivity for malaria parasites compared with mammalian cells, but were not selective for trypanosome parasites versus mammalian cells. All compounds caused hyperacetylation of histone and non-histone proteins in P. falciparum asexual stage parasites and inhibited deacetylase activity in P. falciparum nuclear extracts in addition to recombinant PfHDAC1 activity. P. falciparum histone hyperacetylation data indicate that HDAC inhibitors may differentially affect the acetylation profiles of histone H3 and H4.

  13. Regulatory T cell levels and cytokine production in active non-infectious uveitis: in-vitro effects of pharmacological treatment.

    Science.gov (United States)

    Molins, B; Mesquida, M; Lee, R W J; Llorenç, V; Pelegrín, L; Adán, A

    2015-03-01

    The aim of this study was to quantify the proportion of regulatory T cells (Treg ) and cytokine expression by peripheral blood mononuclear cells (PBMCs) in patients with active non-infectious uveitis, and to evaluate the effect of in-vitro treatment with infliximab, dexamethasone and cyclosporin A on Treg levels and cytokine production in PBMCs from uveitis patients and healthy subjects. We included a group of 21 patients with active non-infectious uveitis and 18 age-matched healthy subjects. The proportion of forkhead box protein 3 (FoxP3)(+) Treg cells and intracellular tumour necrosis factor (TNF)-α expression in CD4(+) T cells was determined by flow cytometry. PBMCs were also either rested or activated with anti-CD3/anti-CD28 and cultured in the presence or absence of dexamethasone, cyclosporin A and infliximab. Supernatants of cultured PBMCs were collected and TNF-α, interleukin (IL)-10, IL-17 and interferon (IFN)-γ levels were measured by enzyme-linked immunosorbent assay (ELISA). No significant differences were observed in nTreg levels between uveitis patients and healthy subjects. However, PBMCs from uveitis patients produced significantly higher amounts of TNF-α and lower amounts of IL-10. Dexamethasone treatment in vitro significantly reduced FoxP3(+) Treg levels in PBMCs from both healthy subjects and uveitis patients, and all tested drugs significantly reduced TNF-α production in PBMCs. Dexamethasone and cyclosporin A significantly reduced IL-17 and IFN-γ production in PBMCs and dexamethasone up-regulated IL-10 production in activated PBMCs from healthy subjects. Our results suggest that PBMCs from patients with uveitis express more TNF-α and less IL-10 than healthy subjects, and this is independent of FoxP3(+) Treg levels. Treatment with infliximab, dexamethasone and cyclosporin A in vitro modulates cytokine production, but does not increase the proportion of FoxP3(+) Treg cells. © 2014 British Society for Immunology.

  14. Investigating anti-parasitic effects of plant secondary metabolites: effects on swine nematodes

    DEFF Research Database (Denmark)

    Williams, Andrew; Pena-Espinoza, Miguel Angel; Fryganas, Christos

    2014-01-01

    Organic and outdoor animal production presents challenges to animal health and productivity. In organic pig production, animals must have access to outdoor pastures which increases exposure to pathogens such as gastrointestinal nematodes. Moreover, the routine use of synthetic anti-parasitic drugs...

  15. Proinflammatory and anti-inflammatory cytokine balance in gasoline exhaust induced pulmonary injury in mice.

    Science.gov (United States)

    Sureshkumar, Veerapandian; Paul, Bholanath; Uthirappan, Mani; Pandey, Renu; Sahu, Anand Prakash; Lal, Kewal; Prasad, Arun Kumar; Srivastava, Suresh; Saxena, Ashok; Mathur, Neeraj; Gupta, Yogendra Kumar

    2005-03-01

    Proinflammatory and anti-inflammatory cytokine balance and associated changes in pulmonary bronchoalveolar lavage fluid (BALF) of unleaded gasoline exhaust (GE) exposed mice were investigated. Animals were exposed to GE (1 L/min of GE mixed with 14 L/min of compressed air) using a flow-past, nose-only, dynamic inhalation exposure chamber for different durations (7, 14, and 21 days). The particulate content of the GE was found to be 0.635, +/-0.10 mg PM/m3. Elevated levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were observed in BALF of GE-exposed mice, but interleukin 1beta(IL-1beta) and the anti-inflammatory cytokine interleukin-10 (IL-10) remained unaffected. GE induced higher activities of alkaline phosphatase (ALP), gamma-glutamyl transferase (gammaGT), and lactate dehydrogenase (LDH) in the BALF, indicating Type II alveolar epithelial cell injury, Clara-cell injury, and general toxicity, respectively. Total protein in the BALF increased after 14 and 21 days of exposure, indicating enhanced alveolar-capillary permeability. However, the difference in the mean was found statistically insignificant in comparison to the compressed air control. Total cell count in the BALF of GE-exposed mice ranged between 0.898 and 0.813x10(6) cells/ml, whereas the compressed air control showed 0.65x10(6) cells/mL. The histopathological changes in GE-exposed lung includes perivascular, and peribronchiolar cuffing of mononuclear cells, migration of polymorphonuclear cells in the alveolar septa, alveolar thickening, and mild alveolar edematous changes indicating inflammation. The shift in pro- and anti-inflammatory cytokine balance and elevation of the pulmonary marker enzymes indicate toxic insult of GE. This study will help in our understanding of the mechanism of pulmonary injury by GE in the light of cytokine profiles, pulmonary marker enzymes, and lung architecture.

  16. CYTOKINES GENETIC POLYMORPHISM: THE PAST AND THE FUTURE

    Directory of Open Access Journals (Sweden)

    L. V. Puzyryova

    2016-01-01

    Full Text Available The molecular genetics opens the new horizons in modern medicine, especially now when many diseases are given huge value in a type of their prevalence among various groups of population. Extremely high interleukin genes polymorphism degrees are studied well especially genetic polymorphism of tumor necrosis factor. Patients with HIV infection in the territory of Russia cause now the highest degree of mortality that is the most actual and socially significant problem of healthcare. This problems studying attracts many researchers. Works in respect of genetic immunity to a virus and influence of cytokines production on the disease forecast are especially interesting. One of the HIV replication influencing factors are cytokines, some of which, including the tumor necrosis factor and interleukin-6 can promote replication of HIV, raising an expression of virus regulatory genes. During disease progress in parallel of anti-inflammatory cytokines level increase (causing in this case rather ineffective antibodies level increase there is an T-helpers suppression stimulating a strong cellular component. Cytokine network functioning during HIV infection depends on many reasons which the individual variation in cytokine production caused by a number of genetic features, as well as an existence of opportunistic infection. Cytokines polymorphism determination in HIV infected patients is necessary in clinical practice for disease progression forecast to adverse fast transition to AIDS that it is important to consider in a choice of tactics of the supporting therapy of HIV-positive patients. Considering insufficient efficiency of modern methods of treatment, restoration and modulation of cytokines balance will increase anti-virus activity of immune system, influencing the factors blocking replication of a HIV.

  17. Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites

    Directory of Open Access Journals (Sweden)

    Jessica A. Engel

    2015-12-01

    Full Text Available Histone deacetylase (HDAC enzymes work together with histone acetyltransferases (HATs to reversibly acetylate both histone and non-histone proteins. As a result, these enzymes are involved in regulating chromatin structure and gene expression as well as other important cellular processes. HDACs are validated drug targets for some types of cancer, with four HDAC inhibitors clinically approved. However, they are also showing promise as novel drug targets for other indications, including malaria and other parasitic diseases. In this study the in vitro activity of four anti-cancer HDAC inhibitors was examined against parasites that cause malaria and trypanosomiasis. Three of these inhibitors, suberoylanilide hydroxamic acid (SAHA; vorinostat®, romidepsin (Istodax® and belinostat (Beleodaq®, are clinically approved for the treatment of T-cell lymphoma, while the fourth, panobinostat, has recently been approved for combination therapy use in certain patients with multiple myeloma. All HDAC inhibitors were found to inhibit the growth of asexual-stage Plasmodium falciparum malaria parasites in the nanomolar range (IC50 10–200 nM, while only romidepsin was active at sub-μM concentrations against bloodstream form Trypanosoma brucei brucei parasites (IC50 35 nM. The compounds were found to have some selectivity for malaria parasites compared with mammalian cells, but were not selective for trypanosome parasites versus mammalian cells. All compounds caused hyperacetylation of histone and non-histone proteins in P. falciparum asexual stage parasites and inhibited deacetylase activity in P. falciparum nuclear extracts in addition to recombinant PfHDAC1 activity. P. falciparum histone hyperacetylation data indicate that HDAC inhibitors may differentially affect the acetylation profiles of histone H3 and H4.

  18. Ex Vivo Host and Parasite Response to Antileishmanial Drugs and Immunomodulators

    Science.gov (United States)

    McMahon-Pratt, Diane; Saravia, Nancy Gore

    2015-01-01

    Background Therapeutic response in infectious disease involves host as well as microbial determinants. Because the immune and inflammatory response to Leishmania (Viannia) species defines the outcome of infection and efficacy of treatment, immunomodulation is considered a promising therapeutic strategy. However, since Leishmania infection and antileishmanial drugs can themselves modulate drug transport, metabolism and/or immune responses, immunotherapeutic approaches require integrated assessment of host and parasite responses. Methodology To achieve an integrated assessment of current and innovative therapeutic strategies, we determined host and parasite responses to miltefosine and meglumine antimoniate alone and in combination with pentoxifylline or CpG 2006 in peripheral blood mononuclear cells (PBMCs) of cutaneous leishmaniasis patients. Parasite survival and secretion of TNF-α, IFN-γ, IL-10 and IL-13 were evaluated concomitantly in PBMCs infected with Luc-L. (V.) panamensis exposed to meglumine antimoniate (4, 8, 16, 32 and 64 μg SbV/mL) or miltefosine (2, 4, 8, 16 and 32 μM HePC). Concentrations of 4 μM of miltefosine and 8 μg SbV/mL were selected for evaluation in combination with immunomodulators based on the high but partial reduction of parasite burden by these antileishmanial concentrations without affecting cytokine secretion of infected PBMCs. Intracellular parasite survival was determined by luminometry and cytokine secretion measured by ELISA and multiplex assays. Principal Findings Anti- and pro-inflammatory cytokines characteristic of L. (V.) panamensis infection were evaluable concomitantly with viability of Leishmania within monocyte-derived macrophages present in PBMC cultures. Both antileishmanial drugs reduced the parasite load of macrophages; miltefosine also suppressed IL-10 and IL-13 secretion in a dose dependent manner. Pentoxifylline did not affect parasite survival or alter antileishmanial effects of miltefosine or meglumine

  19. Serum levels of cytokines in water buffaloes experimentally infected with Fasciola gigantica.

    Science.gov (United States)

    Zhang, Fu-Kai; Guo, Ai-Jiang; Hou, Jun-Ling; Sun, Miao-Miao; Sheng, Zhao-An; Zhang, Xiao-Xuan; Huang, Wei-Yi; Elsheikha, Hany M; Zhu, Xing-Quan

    2017-09-15

    Fasciola gigantica infection in water buffaloes causes significant economic losses especially in developing countries. Although modulation of the host immune response by cytokine neutralization or vaccination is a promising approach to control infection with this parasite, our understanding of cytokine's dynamic during F. gigantica infection is limited. To address this, we quantified the levels of serum cytokines produced in water buffaloes following experimental infection with F. gigantica. Five buffaloes were infected via oral gavage with 500 viable F. gigantica metacercariae and blood samples were collected from buffaloes one week before infection and for 13 consecutive weeks thereafter. The levels of 10 cytokines in serum samples were simultaneously determined using ELISA. F. gigantica failed to elicit the production of various pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-2, IL-6, IL-12, and IFN-γ. On the other hand, evidence of a Th2 type response was detected, but only early in the course of parasite colonization and included modest increase in the levels of IL-10 and IL-13. The results also revealed suppression of the immune responses as a feature of chronic F. gigantica infection in buffaloes. Taken together, F. gigantica seems to elicit a modest Th2 response at early stage of infection in order to downregulate harmful Th1- and Th17-type inflammatory responses in experimentally infected buffaloes. The full extent of anti-F. gigantica immune response and its relation to pathogenesis requires further study. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Citoquinas reguladoras de la respuesta al transplante renal alogénico Regulatory cytokines in the response to the allogeneic renal transplant

    Directory of Open Access Journals (Sweden)

    Rita L. Cardoni

    2005-03-01

    monitoring the transplant rejection and the diagnosis of the associated nephropathies, in spite of the invasiveness of the procedure. Thus, it is of great interest to find alternative tools for diagnosis. The evaluation of regulatory cytokines is a simple procedure of low cost that could be useful to increase the sensitivity of the detection of polymorphic differences, to predict the graft acceptance and for the early detection of rejection. Recent studies suggest that the high production of pro-inflammatory mediators, such as Th1 cytokines, could be detrimental, whereas the production of anti-inflammatory regulatory cytokines, such as interleukin (IL-10 and tumor necrosis factor (TGF-b, could be beneficial for graft survival. In the early stages, the cellular cytotoxicity is activated by the Th1 response and the detection of cytotoxic molecules is associated to the acute rejection. Later, the balance between pro and anti-inflammatory mediators and the regulation of their levels could be more important. In this regard, TGF-b is also fibrogenic and a high local production can contribute to kidney damage. On the other hand, the increased production of IL-10 in response to the allogeneic stimuli could be, in most cases, an important marker of long-term acceptance.

  1. Adipose Tissue-Derived Mesenchymal Stromal Cells Protect Mice Infected with Trypanosoma cruzi from Cardiac Damage through Modulation of Anti-parasite Immunity.

    Science.gov (United States)

    Mello, Debora B; Ramos, Isalira P; Mesquita, Fernanda C P; Brasil, Guilherme V; Rocha, Nazareth N; Takiya, Christina M; Lima, Ana Paula C A; Campos de Carvalho, Antonio C; Goldenberg, Regina S; Carvalho, Adriana B

    2015-01-01

    Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), is a complex disease endemic in Central and South America. It has been gathering interest due to increases in non-vectorial forms of transmission, especially in developed countries. The objective of this work was to investigate if adipose tissue-derived mesenchymal stromal cells (ASC) can alter the course of the disease and attenuate pathology in a mouse model of chagasic cardiomyopathy. ASC were injected intraperitoneally at 3 days post-infection (dpi). Tracking by bioluminescence showed that cells remained in the abdominal cavity for up to 9 days after injection and most of them migrated to the abdominal or subcutaneous fat, an early parasite reservoir. ASC injection resulted in a significant reduction in blood parasitemia, which was followed by a decrease in cardiac tissue inflammation, parasitism and fibrosis at 30 dpi. At the same time point, analyses of cytokine release in cells isolated from the heart and exposed to T. cruzi antigens indicated an anti-inflammatory response in ASC-treated animals. In parallel, splenocytes exposed to the same antigens produced a pro-inflammatory response, which is important for the control of parasite replication, in placebo and ASC-treated groups. However, splenocytes from the ASC group released higher levels of IL-10. At 60 dpi, magnetic resonance imaging revealed that right ventricular (RV) dilation was prevented in ASC-treated mice. In conclusion, the injection of ASC early after T. cruzi infection prevents RV remodeling through the modulation of immune responses. Lymphoid organ response to the parasite promoted the control of parasite burden, while the heart, a target organ of Chagas disease, was protected from damage due to an improved control of inflammation in ASC-treated mice.

  2. Adipose Tissue-Derived Mesenchymal Stromal Cells Protect Mice Infected with Trypanosoma cruzi from Cardiac Damage through Modulation of Anti-parasite Immunity.

    Directory of Open Access Journals (Sweden)

    Debora B Mello

    Full Text Available Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi, is a complex disease endemic in Central and South America. It has been gathering interest due to increases in non-vectorial forms of transmission, especially in developed countries. The objective of this work was to investigate if adipose tissue-derived mesenchymal stromal cells (ASC can alter the course of the disease and attenuate pathology in a mouse model of chagasic cardiomyopathy.ASC were injected intraperitoneally at 3 days post-infection (dpi. Tracking by bioluminescence showed that cells remained in the abdominal cavity for up to 9 days after injection and most of them migrated to the abdominal or subcutaneous fat, an early parasite reservoir. ASC injection resulted in a significant reduction in blood parasitemia, which was followed by a decrease in cardiac tissue inflammation, parasitism and fibrosis at 30 dpi. At the same time point, analyses of cytokine release in cells isolated from the heart and exposed to T. cruzi antigens indicated an anti-inflammatory response in ASC-treated animals. In parallel, splenocytes exposed to the same antigens produced a pro-inflammatory response, which is important for the control of parasite replication, in placebo and ASC-treated groups. However, splenocytes from the ASC group released higher levels of IL-10. At 60 dpi, magnetic resonance imaging revealed that right ventricular (RV dilation was prevented in ASC-treated mice.In conclusion, the injection of ASC early after T. cruzi infection prevents RV remodeling through the modulation of immune responses. Lymphoid organ response to the parasite promoted the control of parasite burden, while the heart, a target organ of Chagas disease, was protected from damage due to an improved control of inflammation in ASC-treated mice.

  3. Counter-conditioning as an intervention to modify anti-fat attitudes

    Directory of Open Access Journals (Sweden)

    Stuart W. Flint

    2013-07-01

    Full Text Available This study examined the effect of anti-fat attitude counter-conditioning using positive images of obese individuals participants completed implicit and explicit measures of attitudes towards fatness on three occasions: no intervention; following exposure to positive images of obese members of the general public; and to images of obese celebrities. Contrary to expectations, positive images of obese individuals did not result in more positive attitudes towards fatness as expected and, in some cases, indices of these attitudes worsened. Results suggest that attitudes towards obesity and fatness may be somewhat robust and resistant to change, possibly suggesting a central and not peripheral processing route for their formation.

  4. Regulatory T Cells and Host Anti-CML Responses

    National Research Council Canada - National Science Library

    Wong, Jr, K. K

    2008-01-01

    CD4+CD25+FoxP-3+ regulatory T-cells (Tregs) suppress immune responses to "self" antigens, but also have been shown to suppress host anti-tumor responses in several human malignancies, including breast, gastrointestinal, and ovarian cancer...

  5. A cytokine axis regulates elastin formation and degradation

    Science.gov (United States)

    Sproul, Erin P.; Argraves, W. Scott

    2013-01-01

    Underlying the dynamic regulation of tropoelastin expression and elastin formation in development and disease are transcriptional and post-transcriptional mechanisms that have been the focus of much research. Of particular importance is the cytokine–governed elastin regulatory axis in which the pro-elastogenic activities of transforming growth factor β-1 (TGFβ1) and insulin-like growth factor-I (IGF-I) are opposed by anti-elastogenic activities of basic fibroblast growth factor (bFGF/FGF-2), heparin-binding epidermal growth factor-like growth factor (HB-EGF), EGF, PDGF-BB, TGFα, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and noncanonical TGFβ1 signaling. A key mechanistic feature of the regulatory axis is that cytokines influence elastin formation through effects on the cell cycle involving control of cyclin–cyclin dependent kinase complexes and activation of the Ras/MEK/ERK signaling pathway. In this article we provide an overview of the major cytokines/growth factors that modulate elastogenesis and describe the underlying molecular mechanisms for their action on elastin production. PMID:23160093

  6. Transgenic Expression of the Anti-parasitic Factor TEP1 in the Malaria Mosquito Anopheles gambiae.

    Directory of Open Access Journals (Sweden)

    Gloria Volohonsky

    2017-01-01

    Full Text Available Mosquitoes genetically engineered to be resistant to Plasmodium parasites represent a promising novel approach in the fight against malaria. The insect immune system itself is a source of anti-parasitic genes potentially exploitable for transgenic designs. The Anopheles gambiae thioester containing protein 1 (TEP1 is a potent anti-parasitic protein. TEP1 is secreted and circulates in the mosquito hemolymph, where its activated cleaved form binds and eliminates malaria parasites. Here we investigated whether TEP1 can be used to create malaria resistant mosquitoes. Using a GFP reporter transgene, we determined that the fat body is the main site of TEP1 expression. We generated transgenic mosquitoes that express TEP1r, a potent refractory allele of TEP1, in the fat body and examined the activity of the transgenic protein in wild-type or TEP1 mutant genetic backgrounds. Transgenic TEP1r rescued loss-of-function mutations, but did not increase parasite resistance in the presence of a wild-type susceptible allele. Consistent with previous reports, TEP1 protein expressed from the transgene in the fat body was taken up by hemocytes upon a challenge with injected bacteria. Furthermore, although maturation of transgenic TEP1 into the cleaved form was impaired in one of the TEP1 mutant lines, it was still sufficient to reduce parasite numbers and induce parasite melanization. We also report here the first use of Transcription Activator Like Effectors (TALEs in Anopheles gambiae to stimulate expression of endogenous TEP1. We found that artificial elevation of TEP1 expression remains moderate in vivo and that enhancement of endogenous TEP1 expression did not result in increased resistance to Plasmodium. Taken together, our results reveal the difficulty of artificially influencing TEP1-mediated Plasmodium resistance, and contribute to further our understanding of the molecular mechanisms underlying mosquito resistance to Plasmodium parasites.

  7. Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes.

    Science.gov (United States)

    Alnek, Kristi; Kisand, Kalle; Heilman, Kaire; Peet, Aleksandr; Varik, Karin; Uibo, Raivo

    2015-01-01

    The production of several cytokines could be dysregulated in type 1 diabetes (T1D). In particular, the activation of T helper (Th) type 1 (Th1) cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α), Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8), but not human leukocyte antigen (HLA) genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.

  8. Imagining Another Europe: Building a Pan-European Counter-Hegemonic Bloc Around an Anti-Austerity Master Frame

    NARCIS (Netherlands)

    Scholl, C.; Freyberg-Inan, A.

    Going beyond the local and national scopes of anti-austerity mobilizations, we contribute to this special issue by focusing on counter-hegemonic protest at the pan-European level. In the context of the current austerity regimes, this emerging and precarious social formation enacts resistance against

  9. Occurrence of anti-Toxoplasma gondii antibodies and parasite DNA in backyard chicken breeding in Northeast, Brazil

    Directory of Open Access Journals (Sweden)

    Marcela Fernanda Torres Samico Fernandes

    2016-03-01

    Full Text Available Abstract The aim of the present study was to investigate the occurrence of anti-Toxoplasma gondii antibodies and parasite DNA in backyard chickens bred in the metropolitan area of Recife, Brazil. In total, 212 serum samples were collected from 16 properties, and 12 backyard chickens were collected in the six sanitary districts of Recife. An indirect immunofluorescence assay (IFA was used to investigate the occurrence of anti-Toxoplasma gondii antibodies. Polymerase chain reaction (PCR was used to detect T. gondii DNA in brain, heart, liver and lung specimens. Of the samples analyzed by serology, 86/212 (40.56% were positive; of the samples analyzed by PCR, 2/12 (16.7% were positive, with both samples positive by both tests (serological and molecular. The presence of antibody anti-T. gondii and parasite DNA in tissues of these animals are worrying aspects for public health because there is a risk of transmission of the parasite to humans through eating undercooked or raw meat. Based on the results, the adoption of preventive measures to prevent the cats access to the chickens creations should be encouraged, since these animals were identified in most of the studied properties.

  10. Tulbaghia violacea and Allium ursinum Extracts Exhibit Anti-Parasitic and Antimicrobial Activities.

    Science.gov (United States)

    Krstin, Sonja; Sobeh, Mansour; Braun, Markus Santhosh; Wink, Michael

    2018-02-02

    Garlic has played an important role in culinary arts and remedies in the traditional medicine throughout human history. Parasitic infections represent a burden in the society of especially poor countries, causing more than 1 billion infections every year and leading to around one million deaths. In this study, we investigated the mode of anti-parasitic activity of "wild garlics" Tulbaghia violacea and Allium ursinum dichloromethane extracts against parasites Trypanosoma brucei brucei and Leishmania tarentolae with regard to their already known antimicrobial activity. We also evaluated their cytotoxic potential against human cells. Both extracts showed a relevant trypanocidal and leishmanicidal activity, although L. tarentolae was less sensitive. We determined that the probable mode of action of both extracts is the irreversible inhibition of the activity of Trypanosoma brucei trypanothione reductase enzyme. The extracts showed a mild cytotoxic activity against human keratinocytes. They also exhibited weak-in most cases comparable-antibacterial and antifungal activity. HPLC-MS/MS analysis showed that both extracts are abundant in sulfur compounds. Thus, for the first time, the ability of Allium ursinum and Tulbaghia violacea to kill Trypanosoma sp. and Leishmania sp. parasites, probably by binding to and inactivating sulfur-containing compounds essential for the survival of the parasite, is shown.

  11. Tulbaghia violacea and Allium ursinum Extracts Exhibit Anti-Parasitic and Antimicrobial Activities

    Directory of Open Access Journals (Sweden)

    Sonja Krstin

    2018-02-01

    Full Text Available Garlic has played an important role in culinary arts and remedies in the traditional medicine throughout human history. Parasitic infections represent a burden in the society of especially poor countries, causing more than 1 billion infections every year and leading to around one million deaths. In this study, we investigated the mode of anti-parasitic activity of “wild garlics” Tulbaghia violacea and Allium ursinum dichloromethane extracts against parasites Trypanosoma brucei brucei and Leishmania tarentolae with regard to their already known antimicrobial activity. We also evaluated their cytotoxic potential against human cells. Both extracts showed a relevant trypanocidal and leishmanicidal activity, although L. tarentolae was less sensitive. We determined that the probable mode of action of both extracts is the irreversible inhibition of the activity of Trypanosoma brucei trypanothione reductase enzyme. The extracts showed a mild cytotoxic activity against human keratinocytes. They also exhibited weak—in most cases comparable—antibacterial and antifungal activity. HPLC-MS/MS analysis showed that both extracts are abundant in sulfur compounds. Thus, for the first time, the ability of Allium ursinum and Tulbaghia violacea to kill Trypanosoma sp. and Leishmania sp. parasites, probably by binding to and inactivating sulfur-containing compounds essential for the survival of the parasite, is shown.

  12. The effectiveness of empirical anti-parasitic treatment in returning travellers with persistent abdominal symptoms.

    Science.gov (United States)

    Nissan, Batel; Lachish, Tamar; Schwartz, Eli

    2018-01-01

    Persistent abdominal symptoms (PAS) are common among returning-travellers. In the absence of sensitive tests to identify intestinal parasites, gastrointestinal (GI) symptoms often remain a diagnostic challenge. In this study we examined the effectiveness of empirical anti-parasitic treatment in returning-travellers with PAS despite no positive stool-test. A retrospective study among returning travellers who approached the clinic between the years 2014 and 2016 with GI complaints without a positive stool-test. The empirical treatment included broad-spectrum anti-parasitic agents-oral Tinidazole and Albendazole. A follow-up questionnaire was performed at least 6 months post-treatment. A total of 102 patients responded the questionnaire-50% women; average age 31.14 (±12.20) years. The average duration of complaints before treatment was 16.52 (±30.06) months. Common GI symptoms included abdominal pain (83.3%) and diarrhoea (78.4%); 67.6% of the patients complained of extreme fatigue. Overall, 69% of the patients reported an improvement in GI symptoms, 37% of them reported full recovery within a few weeks post-treatment. Furthermore, there was an improvement in the energy level and general well-being in 68% and 70% of the patients, respectively. Only 33% of the patients reported minor side effects related to the treatment. The improvement in GI symptoms, energy level and general well-being shortly after anti-parasitic treatment justifies this empirical approach in returning-travellers with PAS despite negative stool-tests. The association between fatigue and PAS post-travel and the improvement in both as a response to treatment defines fatigue as part of a new syndrome-'Post-travel fatigue and abdominal symptoms'. © International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

  13. Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes.

    Directory of Open Access Journals (Sweden)

    Kristi Alnek

    Full Text Available The production of several cytokines could be dysregulated in type 1 diabetes (T1D. In particular, the activation of T helper (Th type 1 (Th1 cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF and interleukin (IL-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α, Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8, but not human leukocyte antigen (HLA genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.

  14. Irradiation-atenuated anti-parasitic vaccines against helminthic infections in ruminants

    International Nuclear Information System (INIS)

    Alabay, M.

    1986-01-01

    The only commercially available irradiated vaccine is Dictol, the anti-Dictiyocaulus viviparus vaccine used in cattle. This succesful product has been in use for over 20 years. Irradiated vaccines have been applied to a number of different host-parasite systems and it has been shown that a high degree of protection can be conferred on the host by administration of radiation-attenuated larvae. In this paper, present situation of radiation attenuated vaccines against helminthic diseases of ruminants is reviewed. (author)

  15. Pro-/anti-inflammatory cytokine gene polymorphisms and chronic kidney disease: a cross-sectional study

    Directory of Open Access Journals (Sweden)

    Okada Rieko

    2012-01-01

    Full Text Available Abstract Background The aim of this study was to explore the associations between common potential functional promoter polymorphisms in pro-/anti-inflammatory cytokine genes and kidney function/chronic kidney disease (CKD prevalence in a large Japanese population. Methods A total of 3,323 subjects aged 35-69 were genotyped for all 10 single nucleotide polymorphisms (SNPs in the promoter regions of candidate genes with minor allele frequencies of > 0.100 in Japanese populations. The estimated glomerular filtration rate (eGFR and CKD prevalence (eGFR 2 of the subjects were compared among the genotypes. Results A higher eGFR and lower prevalence of CKD were observed for the homozygous variants of IL4 -33CC (high IL-4 [anti-inflammatory cytokine]-producing genotype and IL6 -572GG (low IL-6 [pro-inflammatory cytokine]-producing genotype. Subjects with IL4 CC + IL6 GG showed the highest mean eGFR (79.1 ml/min/1.73 m2 and lowest CKD prevalence (0.0%, while subjects carrying IL4 TT + IL6 CC showed the lowest mean eGFR (73.4 ml/min/1.73 m2 and highest CKD prevalence (17.9%. Conclusions The functional promoter polymorphisms IL4 T-33C (rs2070874 and IL6 C-572G (rs1800796, which are the only SNPs that affect the IL-4 and IL-6 levels in Japanese subjects, were associated with kidney function and CKD prevalence in a large Japanese population.

  16. A Plasmodium falciparum screening assay for anti-gametocyte drugs based on parasite lactate dehydrogenase detection

    NARCIS (Netherlands)

    D'Alessandro, S.; Silvestrini, F.; Dechering, K.; Corbett, Y.; Parapini, S.; Timmerman, M.; Galastri, L.; Basilico, N.; Sauerwein, R.; Alano, P.; Taramelli, D.

    2013-01-01

    OBJECTIVES: Plasmodium gametocytes, responsible for malaria parasite transmission from humans to mosquitoes, represent a crucial target for new antimalarial drugs to achieve malaria elimination/eradication. We developed a novel colorimetric screening method for anti-gametocyte compounds based on the

  17. The Regulatory Function of Eosinophils.

    Science.gov (United States)

    Wen, Ting; Rothenberg, Marc E

    2016-10-01

    Eosinophils are a minority circulating granulocyte classically viewed as being involved in host defense against parasites and promoting allergic reactions. However, a series of new regulatory functions for these cells have been identified in the past decade. During homeostasis, eosinophils develop in the bone marrow and migrate from the blood into target tissues following an eotaxin gradient, with interleukin-5 being a key cytokine for eosinophil proliferation, survival, and priming. In multiple target tissues, eosinophils actively regulate a variety of immune functions through their vast arsenal of granule products and cytokines, as well as direct cellular interaction with cells in proximity. The immunologic regulation of eosinophils extends from innate immunity to adaptive immunity and also involves non-immune cells. Herein, we summarize recent findings regarding novel roles of murine and human eosinophils, focusing on interactions with other hematopoietic cells. We also review new experimental tools available and remaining questions to uncover a greater understanding of this enigmatic cell.

  18. Unexpected T cell regulatory activity of anti-histone H1 autoantibody: Its mode of action in regulatory T cell-dependent and -independent manners

    Energy Technology Data Exchange (ETDEWEB)

    Takaoka, Yuki [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima (Japan); Kawamoto, Seiji, E-mail: skawa@hiroshima-u.ac.jp [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima (Japan); Katayama, Akiko [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima (Japan); Nakano, Toshiaki [Liver Transplantation Program, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan (China); Yamanaka, Yasushi; Takahashi, Miki [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima (Japan); Shimada, Yayoi; Chiang, Kuei-Chen [Kazusa Institute for Drug Discovery, Josai International University, Kisarazu (Japan); Ohmori, Naoya [Kazusa Institute for Drug Discovery, Josai International University, Kisarazu (Japan); Faculty of Nursing, Josai International University, Togane (Japan); Aki, Tsunehiro [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima (Japan); Goto, Takeshi; Sato, Shuji [Kazusa Institute for Drug Discovery, Josai International University, Kisarazu (Japan); Faculty of Nursing, Josai International University, Togane (Japan); Goto, Shigeru [Liver Transplantation Program, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan (China); Iwao Hospital, Yufuin (Japan); Chen, Chao-Long [Liver Transplantation Program, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan (China); Ono, Kazuhisa [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima (Japan)

    2013-02-08

    Highlights: ► Anti-histone H1 autoantibody (anti-H1) acts on T cells to inhibit their activation. ► Anti-H1 suppresses T cell activation in Treg cell-dependent and -independent manners. ► Suboptimal dose of anti-H1 enhances suppressor function of Treg cells. ► High dose of anti-H1 directly inhibits T cell receptor signaling. -- Abstract: Induction of anti-nuclear antibodies against DNA or histones is a hallmark of autoimmune disorders, but their actual contribution to disease predisposition remains to be clarified. We have previously reported that autoantibodies against histone H1 work as a critical graft survival factor in a rat model of tolerogeneic liver transplantation. Here we show that an immunosuppressive anti-histone H1 monoclonal antibody (anti-H1 mAb) acts directly on T cells to inhibit their activation in response to T cell receptor (TCR) ligation. Intriguingly, the T cell activation inhibitory activity of anti-H1 mAb under suboptimal dosages required regulatory T (Treg) cells, while high dose stimulation with anti-H1 mAb triggered a Treg cell-independent, direct negative regulation of T cell activation upon TCR cross-linking. In the Treg cell-dependent mode of immunosuppressive action, anti-H1 mAb did not induce the expansion of CD4{sup +}Foxp3{sup +} Treg cells, but rather potentiated their regulatory capacity. These results reveal a previously unappreciated T cell regulatory role of anti-H1 autoantibody, whose overproduction is generally thought to be pathogenic in the autoimmune settings.

  19. Unexpected T cell regulatory activity of anti-histone H1 autoantibody: Its mode of action in regulatory T cell-dependent and -independent manners

    International Nuclear Information System (INIS)

    Takaoka, Yuki; Kawamoto, Seiji; Katayama, Akiko; Nakano, Toshiaki; Yamanaka, Yasushi; Takahashi, Miki; Shimada, Yayoi; Chiang, Kuei-Chen; Ohmori, Naoya; Aki, Tsunehiro; Goto, Takeshi; Sato, Shuji; Goto, Shigeru; Chen, Chao-Long; Ono, Kazuhisa

    2013-01-01

    Highlights: ► Anti-histone H1 autoantibody (anti-H1) acts on T cells to inhibit their activation. ► Anti-H1 suppresses T cell activation in Treg cell-dependent and -independent manners. ► Suboptimal dose of anti-H1 enhances suppressor function of Treg cells. ► High dose of anti-H1 directly inhibits T cell receptor signaling. -- Abstract: Induction of anti-nuclear antibodies against DNA or histones is a hallmark of autoimmune disorders, but their actual contribution to disease predisposition remains to be clarified. We have previously reported that autoantibodies against histone H1 work as a critical graft survival factor in a rat model of tolerogeneic liver transplantation. Here we show that an immunosuppressive anti-histone H1 monoclonal antibody (anti-H1 mAb) acts directly on T cells to inhibit their activation in response to T cell receptor (TCR) ligation. Intriguingly, the T cell activation inhibitory activity of anti-H1 mAb under suboptimal dosages required regulatory T (Treg) cells, while high dose stimulation with anti-H1 mAb triggered a Treg cell-independent, direct negative regulation of T cell activation upon TCR cross-linking. In the Treg cell-dependent mode of immunosuppressive action, anti-H1 mAb did not induce the expansion of CD4 + Foxp3 + Treg cells, but rather potentiated their regulatory capacity. These results reveal a previously unappreciated T cell regulatory role of anti-H1 autoantibody, whose overproduction is generally thought to be pathogenic in the autoimmune settings

  20. Involvement of regulatory T cells and selected cytokines in the pathogenesis of bronchial asthma

    Directory of Open Access Journals (Sweden)

    Monika Zuśka-Prot

    2016-06-01

    Full Text Available Asthma pathogenesis is complex and involves the interplay of many factors and actions. Airway inflammation in allergic asthma is characterized by an exaggerated activation of T helper type 2 cells, IgE production and infiltration and activation of eosinophils. The results of studies conducted in recent years indicate that the deficit of naturally occurring Foxp3+CD25+CD4+ and Foxp3+CD25+CD8+ regulatory T cells and type 1 regulatory T cells plays a pivotal role in the development of this disease. Moreover, numerous studies have provided convincing evidence that a decrease in IL-10 production and an increase in IL-17 production have an important place in the pathophysiology of asthma. TGF-β is another important cytokine involved in this disease. TGF-β has a paradoxical status in relation to asthma pathogenesis because it seems to play a role in both suppressing and promoting asthma development. This review discusses briefly clinical and experimental data concerning the involvement of T regulatory cells and IL-10, IL-17 and TGF-β in the pathogenesis of asthma.

  1. Anti-inflammatory homoeopathic drug dilutions restrain lipopolysaccharide-induced release of pro-inflammatory cytokines: In vitro and in vivo evidence

    Directory of Open Access Journals (Sweden)

    Umesh B Mahajan

    2017-01-01

    Full Text Available Context: The lipopolysaccharide (LPS-induced cytokine release and oxidative stress are validated experimental parameters used to test anti-inflammatory activity. We investigated the effects of homoeopathic mother tinctures, 6 CH, 30 CH and 200 CH dilutions of Arnica montana, Thuja occidentalis and Bryonia alba against LPS (1 μg/ml-induced cytokine release from RAW-264.7 cells and human whole-blood culture. Materials and Methods: For in vivo evaluations, mice were orally treated with 0.1 ml drug dilutions twice a day for 5 days followed by an intraperitoneal injection of 0.5 mg/kg LPS. After 24 h, the mice were sacrificed and serum levels of pro-inflammatory cytokines and nitric oxide were determined. The extent of oxidative stress was determined in the liver homogenates as contents of reduced glutathione, malondialdehyde, superoxide dismutase and catalase. Results: The tested drug dilutions significantly reduced in vitro LPS-induced release of tumour necrosis factor-α, interleukin-1 (IL-1 and IL-6 from the RAW-264.7 cells and human whole blood culture. Similar suppression of cytokines was evident in mice serum samples. These drugs also protected mice from the LPS-induced oxidative stress in liver tissue. Conclusions: Our findings substantiate the protective effects of Arnica, Thuja and Bryonia homoeopathic dilutions against LPS-induced cytokine elevations and oxidative stress. This study authenticates the claims of anti-inflammatory efficacy of these homoeopathic drugs.

  2. Antibody-cytokine fusion proteins for treatment of cancer: engineering cytokines for improved efficacy and safety.

    Science.gov (United States)

    Young, Patricia A; Morrison, Sherie L; Timmerman, John M

    2014-10-01

    The true potential of cytokine therapies in cancer treatment is limited by the inability to deliver optimal concentrations into tumor sites due to dose-limiting systemic toxicities. To maximize the efficacy of cytokine therapy, recombinant antibody-cytokine fusion proteins have been constructed by a number of groups to harness the tumor-targeting ability of monoclonal antibodies. The aim is to guide cytokines specifically to tumor sites where they might stimulate more optimal anti-tumor immune responses while avoiding the systemic toxicities of free cytokine therapy. Antibody-cytokine fusion proteins containing interleukin (IL)-2, IL-12, IL-21, tumor necrosis factor (TNF)α, and interferons (IFNs) α, β, and γ have been constructed and have shown anti-tumor activity in preclinical and early-phase clinical studies. Future priorities for development of this technology include optimization of tumor targeting, bioactivity of the fused cytokine, and choice of appropriate agents for combination therapies. This review is intended to serve as a framework for engineering an ideal antibody-cytokine fusion protein, focusing on previously developed constructs and their clinical trial results. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. In silico discovery of transcription regulatory elements in Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Le Roch Karine G

    2008-02-01

    Full Text Available Abstract Background With the sequence of the Plasmodium falciparum genome and several global mRNA and protein life cycle expression profiling projects now completed, elucidating the underlying networks of transcriptional control important for the progression of the parasite life cycle is highly pertinent to the development of new anti-malarials. To date, relatively little is known regarding the specific mechanisms the parasite employs to regulate gene expression at the mRNA level, with studies of the P. falciparum genome sequence having revealed few cis-regulatory elements and associated transcription factors. Although it is possible the parasite may evoke mechanisms of transcriptional control drastically different from those used by other eukaryotic organisms, the extreme AT-rich nature of P. falciparum intergenic regions (~90% AT presents significant challenges to in silico cis-regulatory element discovery. Results We have developed an algorithm called Gene Enrichment Motif Searching (GEMS that uses a hypergeometric-based scoring function and a position-weight matrix optimization routine to identify with high-confidence regulatory elements in the nucleotide-biased and repeat sequence-rich P. falciparum genome. When applied to promoter regions of genes contained within 21 co-expression gene clusters generated from P. falciparum life cycle microarray data using the semi-supervised clustering algorithm Ontology-based Pattern Identification, GEMS identified 34 putative cis-regulatory elements associated with a variety of parasite processes including sexual development, cell invasion, antigenic variation and protein biosynthesis. Among these candidates were novel motifs, as well as many of the elements for which biological experimental evidence already exists in the Plasmodium literature. To provide evidence for the biological relevance of a cell invasion-related element predicted by GEMS, reporter gene and electrophoretic mobility shift assays

  4. Modulation of Cytokine Production by Drugs with Antiepileptic or Mood Stabilizer Properties in Anti-CD3- and Anti-CD40-Stimulated Blood In Vitro

    Directory of Open Access Journals (Sweden)

    Hubertus Himmerich

    2014-01-01

    Full Text Available Increased cytokine production possibly due to oxidative stress has repeatedly been shown to play a pivotal role in the pathophysiology of epilepsy and bipolar disorder. Recent in vitro and animal studies of valproic acid (VPA report antioxidative and anti-inflammatory properties, and suppression of interleukin (IL-6 and tumor necrosis factor (TNF-α. We tested the effect of drugs with antiepileptic or mood stabilizer properties, namely, primidone (PRM, carbamazepine (CBZ, levetiracetam (LEV, lamotrigine (LTG, VPA, oxcarbazepine (OXC, topiramate (TPM, phenobarbital (PB, and lithium on the production of the following cytokines in vitro: interleukin (IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22, and TNF-α. We performed a whole blood assay with stimulated blood of 14 healthy female subjects. Anti-human CD3 monoclonal antibody OKT3, combined with 5C3 antibody against CD40, was used as stimulant. We found a significant reduction of IL-1 and IL-2 levels with all tested drugs other than lithium in the CD3/5C3-stimulated blood; VPA led to a decrease in IL-1β, IL-2, IL-4, IL-6, IL-17, and TNF-α production, which substantiates and adds knowledge to current hypotheses on VPA’s anti-inflammatory properties.

  5. Deficient regulatory T cell activity and low frequency of IL-17-producing T cells correlate with the extent of cardiomyopathy in human Chagas' disease.

    Directory of Open Access Journals (Sweden)

    Paulo Marcos Matta Guedes

    Full Text Available BACKGROUND: Myocardium damage during Chagas' disease results from the immunological imbalance between pro- and production of anti-inflammatory cytokines and has been explained based on the Th1-Th2 dichotomy and regulatory T cell activity. Recently, we demonstrated that IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite induced myocarditis. Here, we investigated the role of IL-17 and regulatory T cell during human Chagas' disease. METHODOLOGY/PRINCIPAL FINDINGS: First, we observed CD4(+IL-17(+ T cells in culture of peripheral blood mononuclear cells (PBMC from Chagas' disease patients and we evaluated Th1, Th2, Th17 cytokine profile production in the PBMC cells from Chagas' disease patients (cardiomyopathy-free, and with mild, moderate or severe cardiomyopathy cultured with T. cruzi antigen. Cultures of PBMC from patients with moderate and severe cardiomyopathy produced high levels of TNF-α, IFN-γ and low levels of IL-10, when compared to mild cardiomyopathy or cardiomyopathy-free patients. Flow cytometry analysis showed higher CD4(+IL-17(+ cells in PBMC cultured from patients without or with mild cardiomyopathy, in comparison to patients with moderate or severe cardiomyopathy. We then analyzed the presence and function of regulatory T cells in all patients. All groups of Chagas' disease patients presented the same frequency of CD4(+CD25(+ regulatory T cells. However, CD4(+CD25(+ T cells from patients with mild cardiomyopathy or cardiomyopathy-free showed higher suppressive activity than those with moderate and severe cardiomyopathy. IFN-γ levels during chronic Chagas' disease are inversely correlated to the LVEF (P = 0.007, r = -0.614, while regulatory T cell activity is directly correlated with LVEF (P = 0.022, r = 0.500. CONCLUSION/SIGNIFICANCE: These results indicate that reduced production of the cytokines IL-10 and IL-17 in association with high levels of IFN-γ and TNF

  6. Anti-cytokine therapies in T1D

    DEFF Research Database (Denmark)

    Nepom, Gerald T; Ehlers, Mario; Mandrup-Poulsen, Thomas

    2013-01-01

    Therapeutic targeting of proinflammatory cytokines is clinically beneficial in several autoimmune disorders. Several of these cytokines are directly implicated in the pathogenesis of type 1 diabetes, suggesting opportunities for design of clinical trials in type 1 diabetes that incorporate select...... suitable for modulating the immune response in T1D....

  7. Peripheral parasitaemia and its association with plasma cytokines ...

    African Journals Online (AJOL)

    Also, plasma levels of cytokines were measured using Th1/Th2 human cytokine ELISA kits (Abcam, UK). Analysis of Variance and Student's t-test were used for Comparison of groups while Pearson's Correlation Coefficient was used for tests of association. Results: The results revealed a mean parasite density of ...

  8. Variable transcription of pro- and anti-inflammatory cytokines in phocine lymphocytes following canine distemper virus infection.

    Science.gov (United States)

    Seibel, H; Siebert, U; Rosenberger, T; Baumgärtner, W

    2014-10-15

    Canine distemper virus (CDV) is a highly contagious viral pathogen. Domesticated dogs are the main reservoir of CDV. Although phocine distemper virus was responsible for the recent epidemics in seals in the North and Baltic Seas, most devastating epidemics in seals were also caused by CDV. To further study the pathogenesis of CDV infection in seals, it was the aim of the present study to investigate the mechanisms of CDV induced immunosuppression in seals by analyzing the gene transcription of different pro- and anti-inflammatory cytokines in Concanavalin A (Con A) stimulated and non-stimulated phocine lymphocytes in vitro following infection with the CDV Onderstepoort (CDV-OND) strain. Phocine lymphocytes were isolated via density gradient centrifugation. The addition of 1 μg/ml Con A and virus was either performed simultaneously or lymphocytes were stimulated for 48 h with Con A prior to virus infection. Gene transcription of interleukin (IL)-6, IL-12 and tumor necrosis factor alpha (TNFα) as pro-inflammatory cytokines and IL-4, IL-10 and transforming growth factor beta (TGFβ) as anti-inflammatory cytokines were determined by using RT-qPCR. CDV-OND infection caused an initial increase of pro-inflammatory phocine cytokines mRNA 24h after infection, followed by a decrease in gene transcription after 48 h. A strong increase in the transcription of IL-4 and TGFβ was detected after 48 h when virus and mitogen were added simultaneously. An increased IL-10 production occurred only when stimulation and infection were performed simultaneously. Furthermore, an inhibition of IL-12 on IL-4 was noticed in phocine lymphocytes which were stimulated for 48 h prior to infection. In summary, the duration of the stimulation or the lymphocytes seem to have an important influence on the cytokine transcription and indicates that the outcome of CDV infection is dependent on various factors that might sensitize lymphocytes or make them more susceptible or reactive to CDV infection

  9. Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations

    Directory of Open Access Journals (Sweden)

    Peleg Rider

    2016-01-01

    Full Text Available Proinflammatory cytokines are potent mediators of numerous biological processes and are tightly regulated in the body. Chronic uncontrolled levels of such cytokines can initiate and derive many pathologies, including incidences of autoimmunity and cancer. Therefore, therapies that regulate the activity of inflammatory cytokines, either by supplementation of anti-inflammatory recombinant cytokines or by neutralizing them by using blocking antibodies, have been extensively used over the past decades. Over the past few years, new innovative biological agents for blocking and regulating cytokine activities have emerged. Here, we review some of the most recent approaches of cytokine targeting, focusing on anti-TNF antibodies or recombinant TNF decoy receptor, recombinant IL-1 receptor antagonist (IL-1Ra and anti-IL-1 antibodies, anti-IL-6 receptor antibodies, and TH17 targeting antibodies. We discuss their effects as biologic drugs, as evaluated in numerous clinical trials, and highlight their therapeutic potential as well as emphasize their inherent limitations and clinical risks. We suggest that while systemic blocking of proinflammatory cytokines using biological agents can ameliorate disease pathogenesis and progression, it may also abrogate the hosts defense against infections. Moreover, we outline the rational need to develop new therapies, which block inflammatory cytokines only at sites of inflammation, while enabling their function systemically.

  10. Sunitinib indirectly enhanced anti-tumor cytotoxicity of cytokine-induced killer cells and CD3⁺CD56⁺ subset through the co-culturing dendritic cells.

    Directory of Open Access Journals (Sweden)

    Adisak Wongkajornsilp

    Full Text Available Cytokine-induced killer (CIK cells have reached clinical trials for leukemia and solid tumors. Their anti-tumor cytotoxicity had earlier been shown to be intensified after the co-culture with dendritic cells (DCs. We observed markedly enhanced anti-tumor cytotoxicity activity of CIK cells after the co-culture with sunitinib-pretreated DCs over that of untreated DCs. This cytotoxicity was reliant upon DC modulation by sunitinib because the direct exposure of CIK cells to sunitinib had no significant effect. Sunitinib promoted Th1-inducing and pro-inflammatory phenotypes (IL-12, IFN-γ and IL-6 in DCs at the expense of Th2 inducing phenotype (IL-13 and regulatory phenotype (PD-L1, IDO. Sunitinib-treated DCs subsequently induced the upregulation of Th1 phenotypic markers (IFN-γ and T-bet and the downregulation of the Th2 signature (GATA-3 and the Th17 marker (RORC on the CD3⁺CD56⁺ subset of CIK cells. It concluded that sunitinib-pretreated DCs drove the CD3⁺CD56⁺ subset toward Th1 phenotype with increased anti-tumor cytotoxicity.

  11. Direct and indirect effects of retinoic acid on human Th2 cytokine and chemokine expression by human T lymphocytes

    Directory of Open Access Journals (Sweden)

    Deep-Dixit Vishwa

    2006-11-01

    Full Text Available Abstract Background Vitamin A (VA deficiency induces a type 1 cytokine response and exogenously provided retinoids can induce a type 2 cytokine response both in vitro and in vivo. The precise mechanism(s involved in this phenotypic switch are inconsistent and have been poorly characterized in humans. In an effort to determine if retinoids are capable of inducing Th2 cytokine responses in human T cell cultures, we stimulated human PBMCs with immobilized anti-CD3 mAb in the presence or absence of all-trans retinoic acid (ATRA or 9-cis-RA. Results Stimulation of human PBMCs and purified T cells with ATRA and 9-cis-RA increased mRNA and protein levels of IL-4, IL-5, and IL-13 and decreased levels of IFN-γ, IL-2, IL-12p70 and TNF-α upon activation with anti-CD3 and/or anti-CD28 mAbs. These effects were dose-dependent and evident as early as 12 hr post stimulation. Real time RT-PCR analysis revealed a dampened expression of the Th1-associated gene, T-bet, and a time-dependent increase in the mRNA for the Th2-associated genes, GATA-3, c-MAF and STAT6, upon treatment with ATRA. Besides Th1 and Th2 cytokines, a number of additional proinflammatory and regulatory cytokines including several chemokines were also differentially regulated by ATRA treatment. Conclusion These data provide strong evidence for multiple inductive roles for retinoids in the development of human type-2 cytokine responses.

  12. Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies.

    Science.gov (United States)

    Brattsand, R; Linden, M

    1996-01-01

    Glucocorticoids inhibit the expression and action of most cytokines. This is part of the in vivo feed-back system between inflammation-derived cytokines and CNS-adrenal produced corticosteroids with the probable physiological relevance to balance parts of the host defence and anti-inflammatory systems of the body. Glucocorticoids modulate cytokine expression by a combination of genomic mechanisms. The activated glucocorticoid-receptor complex can (i) bind to and inactivate key proinflammatory transcription factors (e.g. AP-1, NF kappa B). This takes place at the promotor responsive elements of these factors, but has also been reported without the presence of DNA; (ii) via glucocorticoid responsive elements (GRE), upregulate the expression of cytokine inhibitory proteins, e.g. I kappa B, which inactivates the transcription factor NF kappa B and thereby the secondary expression of a series of cytokines; (iii) reduce the half-life time and utility of cytokine mRNAs. In studies with triggered human blood mononuclear cells in culture, glucocorticoids strongly diminish the production of the 'initial phase' cytokines IL-1 beta and TNF-alpha and the 'immunomodulatory' cytokines IL-2, IL-3, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, as well as of IL-6, IL-8 and the growth factor GM-CSF. While steroid treatment broadly attenuates cytokine production, it cannot modulate it selectively, e.g. just the TH0, the TH1 or the TH2 pathways. The production of the 'anti-inflammatory' IL-10 is also inhibited. The exceptions of steroid down-regulatory activity on cytokine expression seem to affect 'repair phase' cytokines like TGF-beta and PDGF. These are even reported to be upregulated, which may explain the rather weak steroid dampening action on healing and fibrotic processes. Some growth factors, e.g. G-CSF and M-CSF, are only weakly affected. In addition to diminishing the production of a cytokine, steroids can also often inhibit its subsequent actions. Because cytokines work in

  13. Octopamine and Tyramine Contribute Separately to the Counter-Regulatory Response to Sugar Deficit in Drosophila

    Directory of Open Access Journals (Sweden)

    Christine Damrau

    2018-01-01

    Full Text Available All animals constantly negotiate external with internal demands before and during action selection. Energy homeostasis is a major internal factor biasing action selection. For instance, in addition to physiologically regulating carbohydrate mobilization, starvation-induced sugar shortage also biases action selection toward food-seeking and food consumption behaviors (the counter-regulatory response. Biogenic amines are often involved when such widespread behavioral biases need to be orchestrated. In mammals, norepinephrine (noradrenalin is involved in the counterregulatory response to starvation-induced drops in glucose levels. The invertebrate homolog of noradrenalin, octopamine (OA and its precursor tyramine (TA are neuromodulators operating in many different neuronal and physiological processes. Tyrosine-ß-hydroxylase (tßh mutants are unable to convert TA into OA. We hypothesized that tßh mutant flies may be aberrant in some or all of the counter-regulatory responses to starvation and that techniques restoring gene function or amine signaling may elucidate potential mechanisms and sites of action. Corroborating our hypothesis, starved mutants show a reduced sugar response and their hemolymph sugar concentration is elevated compared to control flies. When starved, they survive longer. Temporally controlled rescue experiments revealed an action of the OA/TA-system during the sugar response, while spatially controlled rescue experiments suggest actions also outside of the nervous system. Additionally, the analysis of two OA- and four TA-receptor mutants suggests an involvement of both receptor types in the animals' physiological and neuronal response to starvation. These results complement the investigations in Apis mellifera described in our companion paper (Buckemüller et al., 2017.

  14. Strategic variation in mobbing as a front line of defense against brood parasitism.

    Science.gov (United States)

    Welbergen, Justin A; Davies, Nicholas B

    2009-02-10

    Coevolutionary arms races, where adaptations in one party select for counter-adaptations in another and vice versa, are fundamental to interactions between organisms and their predators, pathogens, and parasites [1]. Avian brood parasites and their hosts have emerged as model systems for studying such reciprocal coevolutionary processes [2, 3]. For example, hosts have evolved changes in egg appearance and rejection of foreign eggs in response to brood parasitism from cuckoos, and cuckoos have evolved host-egg mimicry as a counter-response [4-6]. However, the host's front line of defense is protecting the nest from being parasitized in the first place [7-10], yet little is known about the effectiveness of nest defense as an antiparasite adaptation, and its coevolutionary significance remains poorly understood [10]. Here we show first that mobbing of common cuckoos Cuculus canorus by reed warblers Acrocephalus scirpaceus is an effective defense against parasitism. Second, mobbing of cuckoos is a phenotypically plastic trait that is modified strategically according to local parasitism risk. This supports the view that hosts use a "defense in-depth strategy," with successive flexible lines of defense that coevolve with corresponding offensive lines of the parasite. This highlights the need for more holistic research into the coevolutionary consequences when multiple adaptations and counter-adaptations evolve in concert [11].

  15. Supercritical fluid extraction of oregano (Origanum vulgare) essentials oils: anti-inflammatory properties based on cytokine response on THP-1 macrophages.

    Science.gov (United States)

    Ocaña-Fuentes, A; Arranz-Gutiérrez, E; Señorans, F J; Reglero, G

    2010-06-01

    Two fractions (S1 and S2) of an oregano (Origanum vulgare) extract obtained by supercritical fluid extraction have been used to test anti-inflammatory effects on activated human THP-1 cells. The main compounds present in the supercritical extract fractions of oregano were trans-sabinene hydrate, thymol and carvacrol. Fractions toxicity was assessed using the mitochondrial-respiration-dependent 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) reduction method for several concentrations during 24 and 48 h of incubation. Concentrations higher than 30 microg/mL of both supercritical S1 and S2 oregano fractions caused a reduction in cell viability in a dose-dependent manner. Oxidized-LDLs (oxLDLs) activated THP-1 macrophages were used as cellular model of atherogenesis and the release/secretion of cytokines (TNT-alpha, IL-1beta, IL-6 and IL-10) and their respective mRNA expressions were quantified both in presence or absence of supercritical oregano extracts. The results showed a decrease in pro-inflammatory TNF-alpha, IL-1beta and IL-6 cytokines synthesis, as well as an increase in the production of anti-inflammatory cytokine IL-10. These results may suggest an anti-inflammatory effect of oregano extracts and their compounds in a cellular model of atherosclerosis. Copyright 2010 Elsevier Ltd. All rights reserved.

  16. Serum levels of inflammatory and regulatory cytokines in patients with hemorrhagic fever with renal syndrome

    Directory of Open Access Journals (Sweden)

    Avšič-Županc Tatjana

    2011-05-01

    Full Text Available Abstract Background Hantaviruses are the causative agents of two zoonotic diseases: hemorrhagic fever with renal syndrome (HFRS and hantavirus cardiopulmonary syndrome (HCPS. The pathogenesis of HFRS is poorly understood. However, it has been suggested that immune mechanisms, including cytokines, might have an important role in HFRS pathogenesis. Thus, the aim of our study was to investigate cytokine profiles in serum samples of HFRS patients from Slovenia and explore a possible correlation between cytokine levels and disease severity. Methods Acute-phase serum samples from 52 patients, diagnosed with DOBV infection, and 61 patients, diagnosed with PUUV infection, were included in this study. Patients were divided into two groups - severe or mild - based on disease severity. Levels of IL-10, IL-12, INF-γ and TNF-α were measured in the serum samples with commercial ELISA tests. Results Increased levels of IL-10, INF-γ, and TNF-α were found in almost all the serum samples tested. On average, higher concentrations were detected in patients infected with DOBV than PUUV. Furthermore, significantly higher levels of IL-10 (P = 0.001 and TNF-α (P = 0.003 were found in patients with a more severe clinical course of disease. The same association between IL-10 (P P = 0.021, and the severity of the disease was observed also when only patients infected with DOBV were considered. No differences in cytokine concentrations according to disease severity were observed in patients infected with PUUV. Concentrations of serum IL-12 in HFRS patients were in the normal range, however, higher levels were detected in patients infected with PUUV than in patients infected with DOBV. Conclusions We suggest that imbalance in production of proinflammatory and regulatory cytokines might be in part responsible for a more severe course of HFRS.

  17. Regulatory T Cells Contribute to the Inhibition of Radiation-Induced Acute Lung Inflammation via Bee Venom Phospholipase A₂ in Mice.

    Science.gov (United States)

    Shin, Dasom; Lee, Gihyun; Sohn, Sung-Hwa; Park, Soojin; Jung, Kyung-Hwa; Lee, Ji Min; Yang, Jieun; Cho, Jaeho; Bae, Hyunsu

    2016-04-30

    Bee venom has long been used to treat various inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Previously, we reported that bee venom phospholipase A₂ (bvPLA₂) has an anti-inflammatory effect through the induction of regulatory T cells. Radiotherapy is a common anti-cancer method, but often causes adverse effects, such as inflammation. This study was conducted to evaluate the protective effects of bvPLA₂ in radiation-induced acute lung inflammation. Mice were focally irradiated with 75 Gy of X-rays in the lung and administered bvPLA₂ six times after radiation. To evaluate the level of inflammation, the number of immune cells, mRNA level of inflammatory cytokine, and histological changes in the lung were measured. BvPLA₂ treatment reduced the accumulation of immune cells, such as macrophages, neutrophils, lymphocytes, and eosinophils. In addition, bvPLA₂ treatment decreased inflammasome-, chemokine-, cytokine- and fibrosis-related genes' mRNA expression. The histological results also demonstrated the attenuating effect of bvPLA₂ on radiation-induced lung inflammation. Furthermore, regulatory T cell depletion abolished the therapeutic effects of bvPLA₂ in radiation-induced pneumonitis, implicating the anti-inflammatory effects of bvPLA₂ are dependent upon regulatory T cells. These results support the therapeutic potential of bvPLA₂ in radiation pneumonitis and fibrosis treatments.

  18. HMGB in mollusk Crassostrea ariakensis Gould: structure, pro-inflammatory cytokine function characterization and anti-infection role of its antibody.

    Directory of Open Access Journals (Sweden)

    Ting Xu

    Full Text Available BACKGROUND: Crassostrea ariakensis Gould is a representative bivalve species and an economically important oyster in China, but suffers severe mortalities in recent years that are caused by rickettsia-like organism (RLO. Prevention and control of this disease is a priority for the development of oyster aquaculture. It has been proven that mammalian HMGB (high mobility group box can be released extracellularly and acts as an important pro-inflammatory cytokine and late mediator of inflammatory reactions. In vertebrates, HMGB's antibody (anti-HMGB has been shown to confer significant protection against certain local and systemic inflammatory diseases. Therefore, we investigated the functions of Ca-HMGB (oyster HMGB and anti-CaHMGB (Ca-HMGB's antibody in oyster RLO/LPS (RLO or LPS-induced disease or inflammation. METHODOLOGY/PRINCIPAL FINDINGS: Sequencing analysis revealed Ca-HMGB shares conserved structures with mammalians. Tissue-specific expression indicates that Ca-HMGB has higher relative expression in hemocytes. Significant continuous up-regulation of Ca-HMGB was detected when the hemocytes were stimulated with RLO/LPS. Recombinant Ca-HMGB protein significantly up-regulated the expression levels of some cytokines. Indirect immunofluorescence study revealed that Ca-HMGB localized both in the hemocyte nucleus and cytoplasm before RLO challenge, but mainly in the cytoplasm 12 h after challenge. Western blot analysis demonstrated Ca-HMGB was released extracellularly 4-12 h after RLO challenge. Anti-CaHMGB was added to the RLO/LPS-challenged hemocyte monolayer and real-time RT-PCR showed that administration of anti-CaHMGB dramatically reduced the rate of RLO/LPS-induced up-regulation of LITAF at 4-12 h after treatment. Flow cytometry analysis indicated that administration of anti-CaHMGB reduced RLO/LPS-induced hemocyte apoptosis and necrosis rates. CONCLUSIONS/SIGNIFICANCE: Ca-HMGB can be released extracellularly and its subcellular localization

  19. Anti-inflammatory effects of phytochemicals from fruits, vegetables, and food legumes: A review.

    Science.gov (United States)

    Zhu, Fengmei; Du, Bin; Xu, Baojun

    2018-05-24

    Inflammation is the first biological response of the immune system to infection, injury or irritation. Evidence suggests that the anti-inflammatory effect is mediated through the regulation of various inflammatory cytokines, such as nitric oxide, interleukins, tumor necrosis factor alpha-α, interferon gamma-γ as well as noncytokine mediator, prostaglandin E 2 . Fruits, vegetables, and food legumes contain high levels of phytochemicals that show anti-inflammatory effect, but their mechanisms of actions have not been completely identified. The aim of this paper was to summarize the recent investigations and findings regarding in vitro and animal model studies on the anti-inflammatory effects of fruits, vegetables, and food legumes. Specific cytokines released for specific type of physiological event might shed some light on the specific use of each source of phytochemicals that can benefit to counter the inflammatory response. As natural modulators of proinflammatory gene expressions, phytochemical from fruits, vegetables, and food legumes could be incorporated into novel bioactive anti-inflammatory formulations of various nutraceuticals and pharmaceuticals. Finally, these phytochemicals are discussed as the natural promotion strategy for the improvement of human health status. The phenolics and triterpenoids in fruits and vegetables showed higher anti-inflammatory activity than other compounds. In food legumes, lectins and peptides had anti-inflammatory activity in most cases. However, there are lack of human study data on the anti-inflammatory activity of phytochemicals from fruits, vegetables, and food legumes.

  20. Proinflammatory and anti-inflammatory cytokines present in the acute phase of experimental colitis treated with Saccharomyces boulardii.

    Science.gov (United States)

    Grijó, Nathália Nahas; Borra, Ricardo Carneiro; Sdepanian, Vera Lucia

    2010-09-01

    To study the proinflammatory and anti-inflammatory cytokines present in the acute phase of trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis treated with Saccharomyces boulardii. Thirty male Wistar rats were divided into three groups: (1) treated group--received Saccharomyces boulardii for 14 days; (2) non-treated group--received sodium chloride solution for 14 days; (3) control group. Colitis was induced on the seventh day of the study in the treated and the non-treated groups using TNBS (10 mg) dissolved in 50% ethanol. Quantification of cytokines, including interleukin (IL)-1beta (IL-1beta), IL-6, transforming growth factor-beta (TGF-beta), IL-10 and tumor necrosis factor-alpha (TNF-alpha), in the serum and colonic tissue collected on day 14 were carried out using an enzyme-linked immunosorbent assay (ELISA). The mean concentrations of TGF-beta in both the serum and the colonic tissue of the treated group were statistically higher than that of the control group. The mean concentration of TGF-beta in the colonic tissue of the non-treated group was also statistically higher than the control group. The group treated with Saccharomyces boulardii showed increased amounts of TGF-beta, an anti-inflammatory cytokine, during the acute phase of colitis. There were no differences in the amount of TNF-alpha, IL-1beta, IL-6, and IL-10 between the treated and the non-treated or the control groups during the acute phase of experimental colitis induced by TNBS.

  1. Cytokine regulation of immune tolerance

    OpenAIRE

    Wu, Jie; Xie, Aini; Chen, Wenhao

    2014-01-01

    The immune system provides defenses against invading pathogens while maintaining immune tolerance to self-antigens. This immune homeostasis is harmonized by the direct interactions between immune cells and the cytokine environment in which immune cells develop and function. Herein, we discuss three non-redundant paradigms by which cytokines maintain or break immune tolerance. We firstly describe how anti-inflammatory cytokines exert direct inhibitory effects on immune cells to enforce immune ...

  2. Beneficial effects of cytokine induced hyperlipidemia.

    Science.gov (United States)

    Feingold, K R; Hardardóttir, I; Grunfeld, C

    1998-01-01

    Infection, inflammation and trauma induce marked changes in the plasma levels of a wide variety of proteins (acute phase response), and these changes are mediated by cytokines. The acute phase response is thought to be beneficial to the host. The host's response to injury also results in dramatic alterations in lipid metabolism and circulating lipoprotein levels which are mediated by cytokines. A large number of cytokines including TNF, the interleukins, and the interferons increase serum triglyceride levels. This rapid increase (1-2 h) is predominantly due to an increase in hepatic VLDL secretion while the late increase may be due to a variety of factors including increased hepatic production of VLDL or delayed clearance secondary to a decrease in lipoprotein lipase activity and/or apolipoprotein E levels on VLDL. In animals other than primates, cytokines also increase serum cholesterol levels, most likely by increasing hepatic cholesterol. Cytokines increase hepatic cholesterol synthesis by stimulating HMG CoA reductase gene expression and decrease hepatic cholesterol catabolism by inhibiting cholesterol 7 alpha-hydroxylase, the key enzyme in bile acid synthesis. Injury and/or cytokines also decrease HDL cholesterol levels and induce alterations in the composition of HDL. The content of SAA and apolipoprotein J increase, apolipoprotein A1 may decrease, and the cholesterol ester content decreases while free cholesterol increases. Additionally, key proteins involved in HDL metabolism are altered by cytokines; LCAT activity, hepatic lipase activity, and CETP levels decrease. These changes in lipid and lipoprotein metabolism may be beneficial in a number of ways including: lipoproteins competing with viruses for cellular receptors, apolipoproteins neutralizing viruses, lipoproteins binding and targeting parasites for destruction, apolipoproteins lysing parasites, redistribution of nutrients to cells involved in the immune response and/or tissue repair, and

  3. Killing of trypanosomatid parasites by a modified bovine host defense peptide, BMAP-18.

    Directory of Open Access Journals (Sweden)

    Lee R Haines

    Full Text Available BACKGROUND: Tropical diseases caused by parasites continue to cause socioeconomic devastation that reverberates worldwide. There is a growing need for new control measures for many of these diseases due to increasing drug resistance exhibited by the parasites and problems with drug toxicity. One new approach is to apply host defense peptides (HDP; formerly called antimicrobial peptides to disease control, either to treat infected hosts, or to prevent disease transmission by interfering with parasites in their insect vectors. A potent anti-parasite effector is bovine myeloid antimicrobial peptide-27 (BMAP-27, a member of the cathelicidin family. Although BMAP-27 is a potent inhibitor of microbial growth, at higher concentrations it also exhibits cytotoxicity to mammalian cells. We tested the anti-parasite activity of BMAP-18, a truncated peptide that lacks the hydrophobic C-terminal sequence of the BMAP-27 parent molecule, an alteration that confers reduced toxicity to mammalian cells. METHODOLOGY/PRINCIPAL FINDINGS: BMAP-18 showed strong growth inhibitory activity against several species and life cycle stages of African trypanosomes, fish trypanosomes and Leishmania parasites in vitro. When compared to native BMAP-27, the truncated BMAP-18 peptide showed reduced cytotoxicity on a wide variety of mammalian and insect cells and on Sodalis glossindius, a bacterial symbiont of the tsetse vector. The fluorescent stain rhodamine 123 was used in immunofluorescence microscopy and flow cytometry experiments to show that BMAP-18 at low concentrations rapidly disrupted mitochondrial potential without obvious alteration of parasite plasma membranes, thus inducing death by apoptosis. Scanning electron microscopy revealed that higher concentrations of BMAP-18 induced membrane lesions in the parasites as early as 15 minutes after exposure, thus killing them by necrosis. In addition to direct killing of parasites, BMAP-18 was shown to inhibit LPS

  4. The counter ion: expanding excipient functionality

    Directory of Open Access Journals (Sweden)

    Shireesh Apte

    2011-06-01

    Full Text Available Excipients have increasingly become 'enablers' of drug delivery and efficacy rather than passive bystanders. Advances in pharmaceutical technology have enabled the ability to deliver specific counter ions (in the form of the counter ion containing excipient and the API simultaneously to preselected targets in the body. This, coupled with a near universal mechanism of columbic interactions that determine the [API- counter ion] efficacy, can be harnessed to exploit this hitherto unavailable or unrecognized enabling mechanism. New excipients may be assembled by a near inexhaustible supply of different permutations of counter ions and their judicious use in specific situations could potentially drive a renaissance in excipient innovation (and drug delivery and efficacy despite regulatory stagnation.

  5. Effects of helminth co-infections on atopy, asthma and cytokine production in children living in a poor urban area in Latin America.

    Science.gov (United States)

    Alcântara-Neves, Neuza Maria; de S G Britto, Gabriela; Veiga, Rafael Valente; Figueiredo, Camila A; Fiaccone, Rosimeire Leovigildo; da Conceição, Jackson S; Cruz, Álvaro Augusto; Rodrigues, Laura Cunha; Cooper, Philip John; Pontes-de-Carvalho, Lain C; Barreto, Maurício Lima

    2014-11-19

    Helminths are modulators of the host immune system, and infections with these parasites have been associated with protection against allergies and autoimmune diseases. The human host is often infected with multiple helminth parasites and most studies to date have investigated the effects of helminths in the context of infections with single parasite or types of parasites (e.g. geohelminths). In this study, we investigated how co-infections with three nematodes affect markers of allergic inflammation and asthma in children. We selected Ascaris lumbricoides and Trichuris trichiura, two parasites that inhabit the human intestine and Toxocara spp (Toxocara canis and/or T. cati), intestinal roundworms of dogs and cats that cause systemic larval infection in humans. These parasites were selected as the most prevalent helminth parasites in our study population. 36.4% of children were infected with one parasite; 12.7% with 2 and 5.2% with 3. Eosinophilia>4% and >10% was present in 74.3% and 25.5% of the children, respectively. Total IgE>200 IU/mL, sIgE≥0.70 kU/L and SPT positivity were present in 59.7%, 37.1% and 30% of the children, respectively. 22.7% had recent asthma (12.0% non-atopic and 10.7% atopic). Helminth infections were associated in a dose-dependent way to decrease in the prevalence of SPT and increase in eosinophilia, total IgE, and the production of the regulatory cytokine IL-10 by unstimulated peripheral blood leukocytes. No association with asthma was observed. Helminth co-infections in this population were associated with increased markers of the Th2 immune response, and with a host immune regulatory phenotype that may suppress allergic effector responses such as immediate hypersensitivity reactions in the skin.

  6. Potent neutralizing anti-CD1d antibody reduces lung cytokine release in primate asthma model.

    Science.gov (United States)

    Nambiar, Jonathan; Clarke, Adam W; Shim, Doris; Mabon, David; Tian, Chen; Windloch, Karolina; Buhmann, Chris; Corazon, Beau; Lindgren, Matilda; Pollard, Matthew; Domagala, Teresa; Poulton, Lynn; Doyle, Anthony G

    2015-01-01

    CD1d is a receptor on antigen-presenting cells involved in triggering cell populations, particularly natural killer T (NKT) cells, to release high levels of cytokines. NKT cells are implicated in asthma pathology and blockade of the CD1d/NKT cell pathway may have therapeutic potential. We developed a potent anti-human CD1d antibody (NIB.2) that possesses high affinity for human and cynomolgus macaque CD1d (KD ∼100 pM) and strong neutralizing activity in human primary cell-based assays (IC50 typically <100 pM). By epitope mapping experiments, we showed that NIB.2 binds to CD1d in close proximity to the interface of CD1d and the Type 1 NKT cell receptor β-chain. Together with data showing that NIB.2 inhibited stimulation via CD1d loaded with different glycolipids, this supports a mechanism whereby NIB.2 inhibits NKT cell activation by inhibiting Type 1 NKT cell receptor β-chain interactions with CD1d, independent of the lipid antigen in the CD1d antigen-binding cleft. The strong in vitro potency of NIB.2 was reflected in vivo in an Ascaris suum cynomolgus macaque asthma model. Compared with vehicle control, NIB.2 treatment significantly reduced bronchoalveolar lavage (BAL) levels of Ascaris-induced cytokines IL-5, IL-8 and IL-1 receptor antagonist, and significantly reduced baseline levels of GM-CSF, IL-6, IL-15, IL-12/23p40, MIP-1α, MIP-1β, and VEGF. At a cellular population level NIB.2 also reduced numbers of BAL lymphocytes and macrophages, and blood eosinophils and basophils. We demonstrate that anti-CD1d antibody blockade of the CD1d/NKT pathway modulates inflammatory parameters in vivo in a primate inflammation model, with therapeutic potential for diseases where the local cytokine milieu is critical.

  7. The landscape of human genes involved in the immune response to parasitic worms

    Directory of Open Access Journals (Sweden)

    Fumagalli Matteo

    2010-08-01

    Full Text Available Abstract Background More than 2 billion individuals worldwide suffer from helminth infections. The highest parasite burdens occur in children and helminth infection during pregnancy is a risk factor for preterm delivery and reduced birth weight. Therefore, helminth infections can be regarded as a strong selective pressure. Results Here we propose that candidate susceptibility genes for parasitic worm infections can be identified by searching for SNPs that display a strong correlation with the diversity of helminth species/genera transmitted in different geographic areas. By a genome-wide search we identified 3478 variants that correlate with helminth diversity. These SNPs map to 810 distinct human genes including loci involved in regulatory T cell function and in macrophage activation, as well as leukocyte integrins and co-inhibitory molecules. Analysis of functional relationships among these genes identified complex interaction networks centred around Th2 cytokines. Finally, several genes carrying candidate targets for helminth-driven selective pressure also harbour susceptibility alleles for asthma/allergy or are involved in airway hyper-responsiveness, therefore expanding the known parallelism between these conditions and parasitic infections. Conclusions Our data provide a landscape of human genes that modulate susceptibility to helminths and indicate parasitic worms as one of the major selective forces in humans.

  8. Irradiation-attenuated anti-parasite vaccines in ruminants. Present status and future prospects

    International Nuclear Information System (INIS)

    Taylor, M.G.

    1981-01-01

    The only commercially available irradiated anti-parasite vaccine is Dictol, the anti-Dictyocaulus viviparus vaccine, which is still being widely used in cattle 20 years after its introduction. Several other similar helminth vaccines which showed promise early in their development or use have now been abandoned for reasons both scientific and commercial. Nevertheless, there is still active interest in the development of irradiated vaccines for fascioliasis and schistosomiasis, as recent field trials have shown that irradiated metacercarial and schistosomular vaccines are effective against F. hepatica and S. bovis in cattle. There are no commercially available irradiated vaccines against protozoal diseases. Although experiments showed that irradiated vaccines were effective against Babesia bigemina and Theileria parva in cattle, interest in these has waned as other forms of live vaccines have been introduced. Vaccination against African trypanosomiasis remains an intractable problem, because of the multiplicity of naturally occurring antigenically distinct strains. (author)

  9. The SaeR/S gene regulatory system induces a pro-inflammatory cytokine response during Staphylococcus aureus infection.

    Directory of Open Access Journals (Sweden)

    Robert L Watkins

    Full Text Available Community-associated methicillin-resistant Staphylococcus aureus accounts for a large portion of the increased staphylococcal disease incidence and can cause illness ranging from mild skin infections to rapidly fatal sepsis syndromes. Currently, we have limited understanding of S. aureus-derived mechanisms contributing to bacterial pathogenesis and host inflammation during staphylococcal disease. Herein, we characterize an influential role for the saeR/S two-component gene regulatory system in mediating cytokine induction using mouse models of S. aureus pathogenesis. Invasive S. aureus infection induced the production of localized and systemic pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α, interferon gamma (IFN-γ, interleukin (IL-6 and IL-2. In contrast, mice infected with an isogenic saeR/S deletion mutant demonstrated significantly reduced pro-inflammatory cytokine levels. Additionally, secreted factors influenced by saeR/S elicited pro-inflammatory cytokines in human blood ex vivo. Our study further demonstrated robust saeR/S-mediated IFN-γ production during both invasive and subcutaneous skin infections. Results also indicated a critical role for saeR/S in promoting bacterial survival and enhancing host mortality during S. aureus peritonitis. Taken together, this study provides insight into specific mechanisms used by S. aureus during staphylococcal disease and characterizes a relationship between a bacterial global regulator of virulence and the production of pro-inflammatory mediators.

  10. MicroRNA-302a suppresses influenza A virus-stimulated interferon regulatory factor-5 expression and cytokine storm induction.

    Science.gov (United States)

    Chen, Xueyuan; Zhou, Li; Peng, Nanfang; Yu, Haisheng; Li, Mengqi; Cao, Zhongying; Lin, Yong; Wang, Xueyu; Li, Qian; Wang, Jun; She, Yinglong; Zhu, Chengliang; Lu, Mengji; Zhu, Ying; Liu, Shi

    2017-12-29

    During influenza A virus (IAV) infection, cytokine storms play a vital and critical role in clinical outcomes. We have previously reported that microRNA (miR)-302c regulates IAV-induced IFN expression by targeting the 3'-UTR of nuclear factor κB (NF-κB)-inducing kinase. In the current study, we found that miR-302a, another member of the miR-302 cluster, controls the IAV-induced cytokine storm. According to results from cell-based and knockout mouse models, IAV induces a cytokine storm via interferon regulatory factor-5 (IRF-5). We also found that IAV infection up-regulates IRF-5 expression and that IRF-5 in turn promotes IAV replication. Furthermore, we observed that IRF-5 is a direct target of miR-302a, which down-regulated IRF-5 expression by binding its 3'-UTR. Moreover, IAV increased IRF-5 expression by down-regulating miR-302a expression. Interestingly, miR-302a inhibited IAV replication. In IAV-infected patients, miR-302a expression was down-regulated, whereas IRF-5 expression was up-regulated. Taken together, our work uncovers and defines a signaling pathway implicated in an IAV-induced cytokine storm. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Inflammatory gene regulatory networks in amnion cells following cytokine stimulation: translational systems approach to modeling human parturition.

    Directory of Open Access Journals (Sweden)

    Ruth Li

    Full Text Available A majority of the studies examining the molecular regulation of human labor have been conducted using single gene approaches. While the technology to produce multi-dimensional datasets is readily available, the means for facile analysis of such data are limited. The objective of this study was to develop a systems approach to infer regulatory mechanisms governing global gene expression in cytokine-challenged cells in vitro, and to apply these methods to predict gene regulatory networks (GRNs in intrauterine tissues during term parturition. To this end, microarray analysis was applied to human amnion mesenchymal cells (AMCs stimulated with interleukin-1β, and differentially expressed transcripts were subjected to hierarchical clustering, temporal expression profiling, and motif enrichment analysis, from which a GRN was constructed. These methods were then applied to fetal membrane specimens collected in the absence or presence of spontaneous term labor. Analysis of cytokine-responsive genes in AMCs revealed a sterile immune response signature, with promoters enriched in response elements for several inflammation-associated transcription factors. In comparison to the fetal membrane dataset, there were 34 genes commonly upregulated, many of which were part of an acute inflammation gene expression signature. Binding motifs for nuclear factor-κB were prominent in the gene interaction and regulatory networks for both datasets; however, we found little evidence to support the utilization of pathogen-associated molecular pattern (PAMP signaling. The tissue specimens were also enriched for transcripts governed by hypoxia-inducible factor. The approach presented here provides an uncomplicated means to infer global relationships among gene clusters involved in cellular responses to labor-associated signals.

  12. Anti-Leishmania activity of new ruthenium(II) complexes: Effect on parasite-host interaction.

    Science.gov (United States)

    Costa, Mônica S; Gonçalves, Yasmim G; Nunes, Débora C O; Napolitano, Danielle R; Maia, Pedro I S; Rodrigues, Renata S; Rodrigues, Veridiana M; Von Poelhsitz, Gustavo; Yoneyama, Kelly A G

    2017-10-01

    Leishmaniasis is a parasitic disease caused by protozoa of the genus Leishmania. The many complications presented by the current treatment - including high toxicity, high cost and parasite resistance - make the development of new therapeutic agents indispensable. The present study aims to evaluate the anti-Leishmania potential of new ruthenium(II) complexes, cis‑[Ru II (η 2 -O 2 CR)(dppm) 2 ]PF 6 , with dppm=bis(diphenylphosphino)methane and R=4-butylbenzoate (bbato) 1, 4-(methylthio)benzoate (mtbato) 2 and 3-hydroxy-4-methoxybenzoate (hmxbato) 3, in promastigote cytotoxicity and their effect on parasite-host interaction. The cytotoxicity of complexes was analyzed by MTT assay against Leishmania (Leishmania) amazonensis, Leishmania (Viannia) braziliensis, Leishmania (Leishmania) infantum promastigotes and the murine macrophage (RAW 264.7). The effect of complexes on parasite-host interaction was evaluated by in vitro infectivity assay performed in the presence of two different concentrations of each complex: the promastigote IC 50 value and the concentration nontoxic to 90% of RAW 264.7 macrophages. Complexes 1-3 exhibited potent cytotoxic activity against all Leishmania species assayed. The IC 50 values ranged from 7.52-12.59μM (complex 1); 0.70-3.28μM (complex 2) and 0.52-1.75μM (complex 3). All complexes significantly inhibited the infectivity index at both tested concentrations. The infectivity inhibitions ranged from 37 to 85%. Interestingly, the infectivity inhibitions due to complex action did not differ significantly at either of the tested concentrations, except for the complex 1 against Leishmania (Leishmania) infantum. The infectivity inhibitions resulted from reductions in both percentage of infected macrophages and number of parasites per macrophage. Taken together the results suggest remarkable leishmanicidal activity in vitro by these new ruthenium(II) complexes. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Small P Systems with Catalysts or Anti-Matter Simulating Generalized Register Machines and Generalized Counter Automata

    Directory of Open Access Journals (Sweden)

    Artiom Alhazov

    2015-11-01

    Full Text Available In this paper we focus on two weak forms of cooperation in P systems, namely, catalytic rules and matter/anti-matter annihilation rules. These variants of P systems both are computationally complete, while the corresponding rule complexity turns out to be of special interest. For establishing considerably small universal P systems in both cases, we found two suitable tools: generalized register machines and generalized counter automata. Depending on the features used in the different variants, we construct several small universal P systems.

  14. Regulatory Effect of Melatonin on Cytokine Disturbances in the Pristane-Induced Lupus Mice

    Directory of Open Access Journals (Sweden)

    Ling-ling Zhou

    2010-01-01

    Full Text Available Systemic lupus erythematosus (SLE develops in relation to many environmental factors. In our opinion, it is more important to investigate the effect of melatonin on the environmental- related SLE. In the present study, 0.5 ml pristane were used to induce SLE in female BALB/c mice. Melatonin (0.01, 0.1, 1.0 mg/kg was orally administered immediately after pristane-injection for 24 weeks. IgM anti ssDNA and histone antibodies were detected after 0, 1, 2, 4, 8 weeks pristane injection. The levels of IL-2, IL-6 and IL-13 were detected after 24 weeks. Renal lesions were also observed. The results showed that melatonin antagonized the increasing levels of IgM anti ssDNA and histone autoantibodies. Melatonin could also decrease the IL-6 and IL-13 production and increase the IL-2 production. Besides, melatonin could lessen the renal lesions caused by pristane. These results suggested that melatonin has a beneficial effect on pristane-induced lupus through regulating the cytokines disturbances.

  15. Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4+ T cell subsets in multiple sclerosis patients.

    Science.gov (United States)

    Sacramento, Priscila M; Monteiro, Clarice; Dias, Aleida S O; Kasahara, Taissa M; Ferreira, Thaís B; Hygino, Joana; Wing, Ana Cristina; Andrade, Regis M; Rueda, Fernanda; Sales, Marisa C; Vasconcelos, Claudia Cristina; Bento, Cleonice A M

    2018-05-02

    Excessive levels of pro-inflammatory cytokines in the central nervous system (CNS) are associated with reduced serotonin (5-HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5-HT to modulate the T-cell behavior of patients with multiple sclerosis (MS), a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5-HT attenuated, in vitro, T-cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients. Additionally, 5-HT reduced IFN-γ and IL-17 release by CD8 + T-cells. By contrast, 5-HT increased IL-10 production by CD4 + T-cells from MS patients. A more accurate analysis of these IL-10-secreting CD4 + T-cells revealed that 5-HT favors the expansion of FoxP3 + CD39 + regulatory T cells (Tregs) and type 1 regulatory T cells. Notably, this neurotransmitter also elevated the frequency of Treg17 cells, a novel regulatory T-cell subset. The effect of 5-HT in up-regulating CD39 + Treg and Treg17 cells was inversely correlated with the number of active brain lesions. Finally, in addition to directly reducing cytokine production by purified Th1 and Th17 cells, 5-HT enhanced in vitro Treg function. In summary, our data suggest that serotonin may play a protective role in the pathogenesis of MS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  16. Aspergillus Cell Wall Chitin Induces Anti- and Proinflammatory Cytokines in Human PBMCs via the Fc-γ Receptor/Syk/PI3K Pathway

    Science.gov (United States)

    Becker, K. L.; Aimanianda, V.; Wang, X.; Gresnigt, M. S.; Ammerdorffer, A.; Jacobs, C. W.; Gazendam, R. P.; Joosten, L. A. B.; Netea, M. G.

    2016-01-01

    ABSTRACT Chitin is an important cell wall component of Aspergillus fumigatus conidia, of which hundreds are inhaled on a daily basis. Previous studies have shown that chitin has both anti- and proinflammatory properties; however the exact mechanisms determining the inflammatory signature of chitin are poorly understood, especially in human immune cells. Human peripheral blood mononuclear cells were isolated from healthy volunteers and stimulated with chitin from Aspergillus fumigatus. Transcription and production of the proinflammatory cytokine interleukin-1β (IL-1β) and the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra) were measured from the cell culture supernatant by quantitative PCR (qPCR) or enzyme-linked immunosorbent assay (ELISA), respectively. Chitin induced an anti-inflammatory signature characterized by the production of IL-1Ra in the presence of human serum, which was abrogated in immunoglobulin-depleted serum. Fc-γ-receptor-dependent recognition and phagocytosis of IgG-opsonized chitin was identified as a novel IL-1Ra-inducing mechanism by chitin. IL-1Ra production induced by chitin was dependent on Syk kinase and phosphatidylinositol 3-kinase (PI3K) activation. In contrast, costimulation of chitin with the pattern recognition receptor (PRR) ligands lipopolysaccharide, Pam3Cys, or muramyl dipeptide, but not β-glucan, had synergistic effects on the induction of proinflammatory cytokines by human peripheral blood mononuclear cells (PBMCs). In conclusion, chitin can have both pro- and anti-inflammatory properties, depending on the presence of pathogen-associated molecular patterns and immunoglobulins, thus explaining the various inflammatory signatures reported for chitin. PMID:27247234

  17. Adaptations in the energy metabolism of parasites

    NARCIS (Netherlands)

    van Grinsven, K.W.A.|info:eu-repo/dai/nl/304833436

    2009-01-01

    For this thesis fundamental research was performed on the metabolic adaptations found in parasites. Studying the adaptations in parasite metabolisms leads to a better understanding of parasite bioenergetics and can also result in the identification of new anti-parasitic drug targets. We focussed on

  18. Dietary gluten alters the balance of pro-inflammatory and anti-inflammatory cytokines in T cells of BALB/c mice

    Czech Academy of Sciences Publication Activity Database

    Antvorskov, J. Ch.; Fundová, Petra; Buschard, K.; Funda, David P.

    2013-01-01

    Roč. 138, č. 1 (2013), s. 23-33 ISSN 0019-2805 R&D Projects: GA ČR GA303/06/1329; GA ČR GA310/09/1640; GA MZd(CZ) NS10340 Institutional research plan: CEZ:AV0Z50200510 Keywords : Cytokines * Foxp3 regulatory T cells * Gluten Subject RIV: EC - Immunology Impact factor: 3.735, year: 2013

  19. Chronic Giardia muris infection in anti-IgM-treated mice. I. Analysis of immunoglobulin and parasite-specific antibody in normal and immunoglobulin-deficient animals.

    Science.gov (United States)

    Snider, D P; Gordon, J; McDermott, M R; Underdown, B J

    1985-06-01

    To investigate the role of B cells and antibody in the immune response of mice to the murine intestinal parasite Giardia muris, we used mice treated from birth with rabbit anti-IgM antisera (aIgM). Such mice developed in serum and in gut secretions extreme Ig deficiency (IgM, IgA, and IgG) relative to control animals. The aIgM-treated mice showed no anti-G. muris antibody in serum or in gut wash material. Infections of G. muris in these mice were chronic, with a high load of parasite present in the small bowel, as reflected by prolonged cyst excretion (greater than 11 wk) and high trophozoite counts. In contrast, normal, untreated mice or NRS-treated animals developed anti-parasite IgA and IgG antibody in serum, demonstrated IgA antibody against the parasite in gut washings, and expelled the parasite within 9 wk. These effects of aIgM treatment on the murine response to primary infection with G. muris were demonstrated in two strains of mice: BALB/c and (C57BL/6 X C3H/He) F1. It was also observed that the response to G. muris infection in untreated animals was characterized by higher than normal total secretion of IgA into the gut and a concomitant increase in the serum polymeric IgA level. Mice treated with aIgM had a marked decrease of both monomeric and polymeric IgA in serum, and little detectable IgA in the intestinal lumen. These experiments provide the first demonstration that anti-IgM treatment suppresses a specific intestinal antibody response to antigen, and provide evidence that B cells and antibody play a role in the development of an effective response to a primary infection with G. muris in mice.

  20. IL-4/IL-13 Heteroreceptor Influences Th17 Cell Conversion and Sensitivity to Regulatory T Cell Suppression To Restrain Experimental Allergic Encephalomyelitis.

    Science.gov (United States)

    Barik, Subhasis; Ellis, Jason S; Cascio, Jason A; Miller, Mindy M; Ukah, Tobechukwu K; Cattin-Roy, Alexis N; Zaghouani, Habib

    2017-10-01

    IL-4 and IL-13 have been defined as anti-inflammatory cytokines that can counter myelin-reactive T cells and modulate experimental allergic encephalomyelitis. However, it is not known whether endogenous IL-4 and IL-13 contribute to the maintenance of peripheral tolerance and whether their function is coordinated with T regulatory cells (Tregs). In this study, we used mice in which the common cytokine receptor for IL-4 and IL-13, namely the IL-4Rα/IL-13Rα1 (13R) heteroreceptor (HR), is compromised and determined whether the lack of signaling by endogenous IL-4 and IL-13 through the HR influences the function of effector Th1 and Th17 cells in a Treg-dependent fashion. The findings indicate that mice-deficient for the HR (13R -/- ) are more susceptible to experimental allergic encephalomyelitis than mice sufficient for the HR (13R +/+ ) and develop early onset and more severe disease. Moreover, Th17 cells from 13R -/- mice had reduced ability to convert to Th1 cells and displayed reduced sensitivity to suppression by Tregs relative to Th17 effectors from 13R +/+ mice. These observations suggest that IL-4 and IL-13 likely operate through the HR and influence Th17 cells to convert to Th1 cells and to acquire increased sensitivity to suppression, leading to control of immune-mediated CNS inflammation. These previously unrecognized findings shed light on the intricacies underlying the contribution of cytokines to peripheral tolerance and control of autoimmunity. Copyright © 2017 by The American Association of Immunologists, Inc.

  1. Cytokines and mood in healthy young adults

    NARCIS (Netherlands)

    Jansen, J.; Fernstrand, A.M.; Van De Loo, A.J.A.E.; Garssen, J.; Verster, J.C.

    2015-01-01

    Purpose: A link between chronic inflammation and neuropsychiatric disorders has been demonstrated previously. For example, pro- and anti-inflammatory cytokines have shown to impact neurocircuits relevant to mood regulation. Elevated levels of inflammatory cytokines have been associated with the

  2. Macrophage migration inhibitory factor counter-regulates dexamethasone-induced annexin 1 expression and influences the release of eicosanoids in murine macrophages.

    Science.gov (United States)

    Sun, Yu; Wang, Yu; Li, Jia-Hui; Zhu, Shi-Hui; Tang, Hong-Tai; Xia, Zhao-Fan

    2013-10-01

    Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine and glucocorticoid (GC) counter-regulator, has emerged as an important modulator of inflammatory responses. However, the molecular mechanisms of MIF counter-regulation of GC still remain incomplete. In the present study, we investigated whether MIF mediated the counter-regulation of the anti-inflammatory effect of GC by affecting annexin 1 in RAW 264.7 macrophages. We found that stimulation of RAW 264.7 macrophages with lipopolysaccharide (LPS) resulted in down-regulation of annexin 1, while GC dexamethasone (Dex) or Dex plus LPS led to significant up-regulation of annexin 1 expression. RNA interference-mediated knockdown of intracellular MIF increased annexin 1 expression with or without incubation of Dex, whereas Dex-induced annexin 1 expression was counter-regulated by the exogenous application of recombinant MIF. Moreover, recombinant MIF counter-regulated, in a dose-dependent manner, inhibition of cytosolic phospholipase A2α (cPLA2α) activation and prostaglandin E2 (PGE2 ) and leukotriene B4 (LTB4 ) release by Dex in RAW 264.7 macrophages stimulated with LPS. Endogenous depletion of MIF enhanced the effects of Dex, reflected by further decease of cPLA2α expression and lower PGE2 and LTB4 release in RAW 264.7 macrophages. Based on these data, we suggest that MIF counter-regulates Dex-induced annexin 1 expression, further influencing the activation of cPLA2α and the release of eicosanoids. These findings will add new insights into the mechanisms of MIF counter-regulation of GC. © 2013 John Wiley & Sons Ltd.

  3. Parasitic helminths: a pharmacopeia of anti-inflammatory molecules.

    Science.gov (United States)

    Johnston, M J G; MacDonald, J A; McKay, D M

    2009-02-01

    Infection with parasitic helminths takes a heavy toll on the health and well-being of humans and their domestic livestock, concomitantly resulting in major economic losses. Analyses have consistently revealed bioactive molecules in extracts of helminths or in their excretory/secretory products that modulate the immune response of the host. It is our view that parasitic helminths are an untapped source of immunomodulatory substances that, in pure form, could become new drugs (or models for drug design) to treat disease. Here, we illustrate the range of immunomodulatory molecules in selected parasitic trematodes, cestodes and nematodes, their impact on the immune cells in the host and how the host may recognize these molecules. There are many examples of the partial characterization of helminth-derived immunomodulatory molecules, but these have not yet translated into new drugs, reflecting the difficulty of isolating and fully characterizing proteins, glycoproteins and lipid-based molecules from small amounts of parasite material. However, this should not deter the investigator, since analytical techniques are now being used to accrue considerable structural information on parasite-derived molecules, even when only minute quantities of tissue are available. With the introduction of methodologies to purify and structurally-characterize molecules from small amounts of tissue and the application of high throughput immunological assays, one would predict that an assessment of parasitic helminths will yield a variety of novel drug candidates in the coming years.

  4. Anti-inflammatory effects of the new generation synthetic surfactant CHF5633 on Ureaplasma-induced cytokine responses in human monocytes.

    Science.gov (United States)

    Glaser, Kirsten; Fehrholz, Markus; Henrich, Birgit; Claus, Heike; Papsdorf, Michael; Speer, Christian P

    2017-02-01

    Synthetic surfactants represent a promising alternative to animal-derived preparations in the treatment of neonatal respiratory distress syndrome. The synthetic surfactant CHF5633 has proven biophysical effectiveness and, moreover, demonstrated anti-inflammatory effects in LPS-stimulated monocytes. With ureaplasmas being relevant pathogens in preterm lung inflammation, the present study addressed immunomodulatory features on Ureaplasma-induced monocyte cytokine responses. Ureaplasma parvum-stimulated monocytes were exposed to CHF5633. TNF-α, IL-1β, IL-8, IL-10, TLR2 and TLR4 expression were analyzed using qPCR and flow cytometry. CHF5633 did not induce pro-inflammation, and did not aggravate Ureaplasma-induced pro-inflammatory cytokine responses. It suppressed U. parvum-induced intracellular TNF-α (p Ureaplasma-induced TNF-α mRNA (p Ureaplasma-modulated IL-8, IL-10, TLR2 and TLR4 were unaffected. CHF5633 does neither act pro-apoptotic nor pro-inflammatory in native and Ureaplasma-infected monocytes. Suppression of Ureaplasma-induced TNF-α and IL-1β underlines anti-inflammatory features of CHF5633.

  5. Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity.

    Science.gov (United States)

    Chen, Lili; He, Zhengxiang; Qin, Li; Li, Qinyan; Shi, Xibao; Zhao, Siting; Chen, Ling; Zhong, Nanshan; Chen, Xiaoping

    2011-01-01

    Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+) T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a novel strategy or therapeutic vaccine vector for anti-lung cancer

  6. Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity.

    Directory of Open Access Journals (Sweden)

    Lili Chen

    Full Text Available BACKGROUND: Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL staining and decreased Ki-67 expression in tumors. Through natural killer (NK cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+ T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. CONCLUSIONS/SIGNIFICANCE: Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria

  7. Helminth allergens, parasite-specific IgE and its protective role in human immunity

    Directory of Open Access Journals (Sweden)

    Colin Matthew Fitzsimmons

    2014-02-01

    Full Text Available The Th2 immune response, culminating in eosinophilia and IgE production, is not only characteristic of allergy but also of infection by parasitic worms (helminths. Anti-parasite IgE has been associated with immunity against a range of helminth infections and many believe that IgE and its receptors evolved to help counter metazoan parasites. Allergens (IgE-antigens are present in only a small minority of protein families and known IgE targets in helminths belong to these same families (e.g. EF-hand proteins, tropomyosin, and PR-1 proteins.During some helminth infection, especially with the well adapted hookworm, the Th2 response is moderated by parasite-expressed molecules. This has been associated with reduced allergy in helminth endemic areas and worm infection or products have been proposed as treatments for allergic conditions. However some infections (especially Ascaris are associated with increased allergy and this has been linked to cross-reactivity between worm proteins (e.g., tropomyosins and highly similar molecules in dust mites and insects. The overlap between allergy and helminth infection is best illustrated in Anisakis simplex, a nematode that when consumed in under-cooked fish can be both an infective helminth and a food allergen. Nearly 20 molecular allergens have been isolated from this species, including tropomyosin (Ani s3 and the EF-hand protein, Ani s troponin.In this review, we highlight aspects of the biology and biochemistry of helminths that may have influenced the evolution of the IgE response. We compare dominant IgE antigens in worms with clinically important environmental allergens and suggest that arrays of such molecules will provide important information on anti-worm immunity as well as allergy.

  8. Role of pro- and anti-inflammatory cytokines in activation of inflammation at community-acquired pneumonia of children with different level of physical development

    Directory of Open Access Journals (Sweden)

    Tetyana Frolova

    2018-05-01

    Full Text Available Background: With the aim of better predicting the course of the community-acquired uncomplicated pneumonia (CAUP the study presents the results of research of the cytokine profile based on the obtained rates of pro- (interleukin 1-beta [IL-1β], tumor necrosis factor-alpha [TNF-α] and anti-inflammatory (interleukin 4 [IL-4] cytokines in blood serum as well as results of the combined bacteriological and serological research of children with different level of physical development (PD, sick on CAUP.Methods: In order to reach the purpose of the research the work was carried out by controlled computer-generated randomization schedule in 2 stages. At the 1st stage the examination of 151 children with CAUP aged from 3 to 14 years from the onset of the disease and of 20 apparently healthy children (control group was held. All children passed a study of sputum using staining of swabs according to Gram, culture test and determination of causative agents of pneumonia by the method of enzyme multiplied immunoassay (ELISA; in addition, the cytokine profile (IL-1β, IL-4 and TNF-α was determined by the method of enzyme-linked immunosorbent assay. At the 2nd stage, according to the inclusion/exclusion criteria, 151 children in the dynamics of the disease were examined: on 7.2 ± 0.9 day from the onset of the disease, the cytokine profile rates were evaluated, and on 12.6 ± 0.9 day the level of IgM, IgG to atypical causative agents of pneumonia were recorded.Results: The results obtained during the research of the indices of the pro-inflammatory (IL-1β and TNF-α and anti-inflammatory (IL-4 cytokines in blood serum of the children with CAUP and having different level of PD can be considered as factors for individually predicting the course of the CAUP of children with different PD.Conclusion: Data suggest that the ratio of pro- and anti-inflammatory cytokines during in­flammatory process in children with CAUP with different PD can be one of the additional

  9. Polysaccharides from the fungus Scleroderma nitidum with anti-inflammatory potential modulate cytokine levels and the expression of Nuclear Factor kB

    Directory of Open Access Journals (Sweden)

    Marília S. Nascimento

    2012-02-01

    Full Text Available Several pharmacological properties are attributed to polysaccharides and glucans derived from fungi such as tumor, anti-inflammatory, and immunomodulatory activity. In this work, the anti-inflammatory potential of polysaccharides from the fungus Scleroderma nitidum and their possible action mechanism were studied. The effect of these polymers on the inflammatory process was tested using the carrageenan and histamine-induced paw edema model and the sodium thioglycolate and zymosan-induced model. The polysaccharides from S. nitidum were effective in reducing edema (73% at 50 mg/kg and cell infiltrate (37% at 10 mg/kg in both inflammation models tested. Nitric oxide, a mediator in the inflammatory process, showed a reduction of around 26% at 10 mg/kg of body weight. Analysis of pro-and anti-inflammatory cytokines showed that in the groups treated with polysaccharides from S. nitidum there was an increase in cytokines such as IL-1ra, IL-10, and MIP-1β concomitant with the decrease in INF-γ (75% and IL-2 (22%. We observed the influence of polysaccharides on the modulation of the expression of nuclear factor κB. This compound reduced the expression of NF-κB by up to 64%. The results obtained suggest that NF-κB modulation an mechanisms that explain the anti-inflammatory effect of polysaccharides from the fungus S. nitidum.

  10. Counter-regulatory hormone responses to spontaneous hypoglycaemia during treatment with insulin Aspart or human soluble insulin

    DEFF Research Database (Denmark)

    Brock Jacobsen, I; Vind, B F; Korsholm, Lars

    2011-01-01

    examined in a randomized, double-blinded cross-over study for two periods of 8 weeks. Sixteen patients with type 1 diabetes were subjected to three daily injections of human soluble insulin or Aspart in addition to Neutral Protamine Hagedorn (NPH) insulin twice daily. Each intervention period was followed......-regulatory responses regarding growth hormone, glucagon and ghrelin whereas no differences were found in relation to free fatty acid, cortisol, insulin-like growth factor (IGF)-I, IGF-II and IGF-binding proteins 1 and 2. Treatment with insulin Aspart resulted in well-defined peaks in serum insulin concentrations...... elicited a slightly different physiological response to spontaneous hypoglycaemia compared with human insulin. Keywords hypoglycaemia counter-regulation, insulin Aspart, type 1 diabetes....

  11. Role of Cytokines as a Double-edged Sword in Sepsis

    Science.gov (United States)

    CHAUDHRY, HINA; ZHOU, JUHUA; ZHONG, YIN; ALI, MIR MUSTAFA; MCGUIRE, FRANKLIN; NAGARKATTI, PRAKASH S.; NAGARKATTI, MITZI

    2014-01-01

    Background Sepsis is a deadly immunological disorder and its pathophysiology is still poorly understood. We aimed to determine if specific pro-inflammatory and anti-inflammatory cytokines can be used as diagnostic and therapeutic targets for sepsis. Materials and Methods Recent publications in the MEDLINE database were searched for articles regarding the clinical significance of inflammatory cytokines in sepsis. Results In response to pathogen infection, pro-inflammatory cytokines [interleukin-6 (IL-6), IL-8, IL-18 and tumor necrosis factor-α (TNF-α)] and anti-inflammatory cytokine (IL-10) increased in patients with sepsis. Importantly, a decrease in IL-6 was associated with a better prognosis and overproduction of IL-10 was found to be the main predictor of severity and fatal outcome. Conclusion Both pro-inflammatory and anti-inflammatory cytokines constitute a double-edged sword in sepsis; on one hand they are critical to eliminate the infection while on the other, excessive production can cause tissue and organ damage. Increase in cytokines such as IL-6, Il-8, IL-10, IL-18 and TNF-α may have implications in diagnosis and treatment of sepsis. PMID:24292568

  12. Nuclear techniques in the study of parasitic infections

    International Nuclear Information System (INIS)

    1982-01-01

    Out of 57 papers published, 47 fall within the INIS subject scope. Seven main topics were covered: resistance to infections with protozoan parasites; resistance to infections with African trypanosomes and helminths of ruminant animals; resistance to infections with filarial parasites and schistosomes; pathology of parasitic infections; epidemiology and diagnosis of parasitic infections; physiology and biochemistry of parasitic organisms; pharmacodynamics of anti-parasitic agents

  13. [TNF-α, diabetes type 1 and regulatory T cells].

    Science.gov (United States)

    Ryba, Monika; Myśliwska, Jolanta

    2010-01-01

    Recent studies on animal models of diabetes as well as human regulatory T cells have shown that α impairs the ability of these cells to prevent the disease. NOD mice treated with α had decreased frequency of regulatory T cells, whereas anti-TNF administration induced the increase in the number of these cells and disease prevention. The action of α also influenced the suppressive potential of Tregs. Increased susceptibility of Tregs to the modulatory effects of α involves signaling through TNFR2 that is expressed on the surface of this cell population. It seems that α neutralization may rescue regulatory T cells and restore their function in several autoimmune and inflammatory diseases. This review describes recent data concerning regulatory T cells in the context of inflammation that is present during diabetes type 1. It describes how TNF contributes to the pathogenesis of type 1 diabetes, what is the impact of this cytokine on regulatory T cell population and therapeutic effects that result from its neutralization in several inflammatory and autoimmune diseases.

  14. Genetic variation in anti-parasite behavior in oysters

    Science.gov (United States)

    Behavioral avoidance of disease-causing parasites provides a first line of defense against the threat of infection, particularly when hosts are exposed to free-living parasite stages in the external environment. We report that suspension-feeding oysters (Crassostrea virginica) respond to the presenc...

  15. Role of polymorphic Fc receptor Fc gammaRIIa in cytokine release and adverse effects of murine IgG1 anti-CD3/T cell receptor antibody (WT31).

    Science.gov (United States)

    Tax, W J; Tamboer, W P; Jacobs, C W; Frenken, L A; Koene, R A

    1997-01-15

    Anti-CD3 monoclonal antibody (mAb) OKT3 is immunosuppressive, but causes severe adverse effects during the first administration ("first-dose reaction"). These adverse effects are presumably caused by cytokine release that results from T-cell activation. In vitro, T-cell activation by anti-CD3 mAb requires interaction with monocyte Fc receptors. The Fc receptor for murine IgG1, Fc gammaRIIa, is polymorphic. In some individuals, murine IgG1 anti-CD3 mAb causes T-cell proliferation and cytokine release in vitro (high responders [HR]), whereas in individuals with the low-responder (LR) phenotype it does not. We have now investigated the role of this Fc gammaRIIa polymorphism in the release of cytokines in vivo and the occurrence of adverse effects after the administration of WT31, a murine IgG1 anti-CD3/T cell receptor mAb. WT31 caused an increase of plasma tumor necrosis factor-alpha in all four HR patients and none of the five LR patients. In all HR patients except one, plasma gamma-interferon and interleukin 6 also increased, and a first-dose response was observed, whereas no cytokine release or adverse effects occurred in any of the LR patients. WT31 caused lymphopenia in all HR and none of the LR patients. FACS analysis demonstrated that in HR patients, after the initial disappearance of CD3+ cells from peripheral blood, modulation of CD3 occurred, whereas in LR patients a high degree of coating of the lymphocytes was observed. Surprisingly, WT31 also induced a marked granulocytopenia, as well as a decrease of thrombocytes, in three of the four HR patients (and in none of the LR patients). These data provide direct clinical evidence that Fc receptor interaction determines the release of cytokines and the occurrence of adverse effects after administration of anti-CD3/T cell receptor mAb. Furthermore, these data suggest that tumor necrosis factor-alpha by itself is not sufficient to induce the first-dose reaction.

  16. Increase in complement iC3b is associated with anti-inflammatory cytokine expression during late pregnancy in mice.

    Directory of Open Access Journals (Sweden)

    Keigo Nakamura

    Full Text Available Immunological tolerance between fetal allograft and mother is crucial for pregnancy establishment and maintenance; however, these mechanisms particularly those during the latter part of pregnancy have not been definitively elucidated. The aim of this study was to examine the presence and potential function of innate immunity characteristic to the middle to late pregnancy. We first characterized up-regulated proteins in decidua from day 11 pregnant (P11 mice using 2D-PAGE, followed by MALDI-TOF/MS analysis. These analyses identified increased complement component 3 (C3 and its derivatives in P11 decidua. We then found that in the decidual tissues, C3 mRNA increased on P15 and remained high on P19. C3 is converted to C3b and then iC3b by complement component factor I (Cfi and complement receptor 1-like protein (Crry, both of which were present in P19 placentas. In addition, iC3b proteins and its receptor CR3 (Cd11b/Cd18 in decidual and placental tissues increased toward the latter phase of pregnancy. Moreover, CR3 subunit CD11b protein was predominantly localized to spongiotrophoblast layer in the P19 placenta. Because iC3b is known to induce anti-inflammatory cytokine production, the analysis was extended to examine changes in pro- and anti-inflammatory cytokines, Il12, Il10, and Tgfb1. Il12 expression decreased in P15 and P19 placenta, while high mRNA expression of Il10 and Tgfb1 was found in P19 placental tissues. Furthermore, placental Il10 and Tgfb1 mRNAs were down-regulated when pregnant mice were treated with an anti-C3 antibody, detecting C3, C3b and iC3b. These results indicated that C3 derivatives, in particular, iC3b and its receptor CR3 were up-regulated at the fetal-maternal interface, and suggest that iC3b may regulate the placental expression of anti-inflammatory cytokines, IL10 and TGFB1, during the latter phase of pregnancy.

  17. Benzimidazoles Promote Anti-TNF Mediated Induction of Regulatory Macrophages and Enhance Therapeutic Efficacy in a Murine Model

    NARCIS (Netherlands)

    Wildenberg, Manon E.; Levin, Alon D.; Ceroni, Alessandro; Guo, Zhen; Koelink, Pim J.; Hakvoort, Theodorus B. M.; Westera, Liset; Bloemendaal, Felicia M.; Brandse, Johannan F.; Simmons, Alison; D'Haens, Geert R.; Ebner, Daniel; van den Brink, Gijs R.

    2017-01-01

    Background and Aims: Regulatory macrophages play a critical role in tissue repair, and we have previously shown that anti-tumour necrosis factor [TNF] antibodies induce these macrophages in vitro and in vivo in IBD patients. The induction of regulatory macrophages can be potentiated using the

  18. Cytokines: abnormalities in major depression and implications for pharmacological treatment.

    LENUS (Irish Health Repository)

    O'Brien, Sinead M

    2012-02-03

    The role of cytokines in depression was first considered when the cytokine interferon resulted in "sickness behaviour", the symptoms of which are similar to those of major depression. The latter is associated with an increase in pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). These cytokines are potent modulators of corticotropin-releasing hormone (CRH) which produces heightened hypothalamic-pituitary-adrenal axis (HPA) activity characterized by increases in ACTH and cortisol, both of which are reported elevated in major depression. Antidepressant treatment has immunomodulatory effects with increases in the production of IL-10, which is an anti-inflammatory cytokine. This review based on a Medline search from 1980-2003, focuses on the evidence available of cytokine changes in acute stress, chronic stress and major depression. It examines the effects of antidepressant treatment on immune parameters in both animal models and clinical trials. We suggest that future antidepressants may target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.

  19. Entamoeba lysyl-tRNA synthetase contains a cytokine-like domain with chemokine activity towards human endothelial cells.

    Directory of Open Access Journals (Sweden)

    Manuel Castro de Moura

    2011-11-01

    Full Text Available Immunological pressure encountered by protozoan parasites drives the selection of strategies to modulate or avoid the immune responses of their hosts. Here we show that the parasite Entamoeba histolytica has evolved a chemokine that mimics the sequence, structure, and function of the human cytokine HsEMAPII (Homo sapiens endothelial monocyte activating polypeptide II. This Entamoeba EMAPII-like polypeptide (EELP is translated as a domain attached to two different aminoacyl-tRNA synthetases (aaRS that are overexpressed when parasites are exposed to inflammatory signals. EELP is dispensable for the tRNA aminoacylation activity of the enzymes that harbor it, and it is cleaved from them by Entamoeba proteases to generate a standalone cytokine. Isolated EELP acts as a chemoattractant for human cells, but its cell specificity is different from that of HsEMAPII. We show that cell specificity differences between HsEMAPII and EELP can be swapped by site directed mutagenesis of only two residues in the cytokines' signal sequence. Thus, Entamoeba has evolved a functional mimic of an aaRS-associated human cytokine with modified cell specificity.

  20. Interaction of Dietary Fatty Acids with Tumour Necrosis Factor Family Cytokines during Colon Inflammation and Cancer

    Science.gov (United States)

    Straková, Nicol; Vaculová, Alena Hyršlová; Tylichová, Zuzana; Šafaříková, Barbora; Kozubík, Alois

    2014-01-01

    Intestinal homeostasis is precisely regulated by a number of endogenous regulatory molecules but significantly influenced by dietary compounds. Malfunction of this system may result in chronic inflammation and cancer. Dietary essential n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acid butyrate produced from fibre display anti-inflammatory and anticancer activities. Both compounds were shown to modulate the production and activities of TNF family cytokines. Cytokines from the TNF family (TNF-α, TRAIL, and FasL) have potent inflammatory activities and can also regulate apoptosis, which plays an important role in cancer development. The results of our own research showed enhancement of apoptosis in colon cancer cells by a combination of either docosahexaenoic acid (DHA) or butyrate with TNF family cytokines, especially by promotion of the mitochondrial apoptotic pathway and modulation of NFκB activity. This review is focused mainly on the interaction of dietary PUFAs and butyrate with these cytokines during colon inflammation and cancer development. We summarised recent knowledge about the cellular and molecular mechanisms involved in such effects and outcomes for intestinal cell behaviour and pathologies. Finally, the possible application for the prevention and therapy of colon inflammation and cancer is also outlined. PMID:24876678

  1. Cytokine response during non-cerebral and cerebral malaria: evidence of a failure to control inflammation as a cause of death in African adults

    Directory of Open Access Journals (Sweden)

    Yakhya Dieye

    2016-05-01

    Full Text Available Background. With 214 million cases and 438,000 deaths in 2015, malaria remains one of the deadliest infectious diseases in tropical countries. Several species of the protozoan Plasmodium cause malaria. However, almost all the fatalities are due to Plasmodium falciparum, a species responsible for the severest cases including cerebral malaria. Immune response to Plasmodium falciparum infection is mediated by the production of pro-inflammatory cytokines, chemokines and growth factors whose actions are crucial for the control of the parasites. Following this response, the induction of anti-inflammatory immune mediators downregulates the inflammation thus preventing its adverse effects such as damages to various organs and death. Methods. We performed a retrospective, nonprobability sampling study using clinical data and sera samples from patients, mainly adults, suffering of non-cerebral or cerebral malaria in Dakar, Sénégal. Healthy individuals residing in the same area were included as controls. We measured the serum levels of 29 biomarkers including growth factors, chemokines, inflammatory and anti-inflammatory cytokines. Results. We found an induction of both pro- and anti-inflammatory immune mediators during malaria. The levels of pro-inflammatory biomarkers were higher in the cerebral malaria than in the non-cerebral malaria patients. In contrast, the concentrations of anti-inflammatory cytokines were comparable in these two groups or lower in CM patients. Additionally, four pro-inflammatory biomarkers were significantly increased in the deceased of cerebral malaria compared to the survivors. Regarding organ damage, kidney failure was significantly associated with death in adults suffering of cerebral malaria. Conclusions. Our results suggest that a poorly controlled inflammatory response determines a bad outcome in African adults suffering of cerebral malaria.

  2. Ureaplasma Species Differentially Modulate Pro- and Anti-Inflammatory Cytokine Responses in Newborn and Adult Human Monocytes Pushing the State Toward Pro-Inflammation

    Science.gov (United States)

    Glaser, Kirsten; Silwedel, Christine; Fehrholz, Markus; Waaga-Gasser, Ana M.; Henrich, Birgit; Claus, Heike; Speer, Christian P.

    2017-01-01

    Background: Ureaplasma species have been associated with chorioamnionitis and preterm birth and have been implicated in the pathogenesis of neonatal short and long-term morbidity. However, being mostly commensal bacteria, controversy remains on the pro-inflammatory capacity of Ureaplasma. Discussions are ongoing on the incidence and impact of prenatal, perinatal, and postnatal infection. The present study addressed the impact of Ureaplasma isolates on monocyte-driven inflammation. Methods: Cord blood monocytes of term neonates and adult monocytes, either native or LPS-primed, were cultured with Ureaplasma urealyticum (U. urealyticum) serovar 8 (Uu8) and Ureaplasma parvum serovar 3 (Up3). Using qRT-PCR, cytokine flow cytometry, and multi-analyte immunoassay, we assessed mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-12p40, IL-10, and IL-1 receptor antagonist (IL-1ra) as well as Toll-like receptor (TLR) 2 and TLR4. Results: Uu8 and Up3 induced mRNA expression and protein release of TNF-α, IL-1β and IL-8 in term neonatal and adult monocytes (p Ureaplasma-stimulated cells paralleled those results. Ureaplasma-induced cytokine levels did not significantly differ from LPS-mediated levels except for lower intracellular IL-1β in adult monocytes (Uu8: p ureaplasmas did not induce IL-12p40 response and promoted lower amounts of anti-inflammatory IL-10 and IL-1ra than LPS, provoking a cytokine imbalance more in favor of pro-inflammation (IL-1β/IL-10, IL-8/IL-10 and IL-8/IL-1ra: p Ureaplasma isolates in human monocytes. Stimulating pro-inflammatory cytokine responses while hardly inducing immunomodulatory and anti-inflammatory cytokines, ureaplasmas might push monocyte immune responses toward pro-inflammation. Inhibition of LPS-induced cytokines in adult monocytes in contrast to sustained inflammation in term neonatal monocytes indicates a differential modulation of host immune responses to a second stimulus. Modification of

  3. Phosphoproteomics Reveals Regulatory T Cell-Mediated DEF6 Dephosphorylation That Affects Cytokine Expression in Human Conventional T Cells

    KAUST Repository

    Joshi, Rubin N.

    2017-09-25

    Regulatory T cells (Tregs) control key events of immune tolerance, primarily by suppression of effector T cells. We previously revealed that Tregs rapidly suppress T cell receptor (TCR)-induced calcium store depletion in conventional CD4CD25 T cells (Tcons) independently of IP levels, consequently inhibiting NFAT signaling and effector cytokine expression. Here, we study Treg suppression mechanisms through unbiased phosphoproteomics of primary human Tcons upon TCR stimulation and Treg-mediated suppression, respectively. Tregs induced a state of overall decreased phosphorylation as opposed to TCR stimulation. We discovered novel phosphosites (T595_S597) in the DEF6 (SLAT) protein that were phosphorylated upon TCR stimulation and conversely dephosphorylated upon coculture with Tregs. Mutation of these DEF6 phosphosites abrogated interaction of DEF6 with the IP receptor and affected NFAT activation and cytokine transcription in primary Tcons. This novel mechanism and phosphoproteomics data resource may aid in modifying sensitivity of Tcons to Treg-mediated suppression in autoimmune disease or cancer.

  4. Progesterone and estradiol exert an inhibitory effect on the production of anti-inflammatory cytokine IL-10 by activated MZ B cells.

    Science.gov (United States)

    Bommer, I; Muzzio, D O; Zygmunt, M; Jensen, F

    2016-08-01

    The main message of this work is the fact that female sex hormones, progesterone and estradiol, whose levels significantly rise during pregnancy, inhibit the production of anti-inflammatory cytokine IL-10 with no apparent effect on pro-inflammatory cytokine TNF-α by activated MZ B cells. This is an important piece of information and helps to better understand how the maternal immune system controls the balance between immune tolerance and immune activation during pregnancy leading to the simultaneously acceptance of the semi-allogeneic fetus and the proper defense of the mother against pathogens during this critical period of time. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. On the importance of targeting parasite stem cells in anti-echinococcosis drug development

    Directory of Open Access Journals (Sweden)

    Brehm Klaus

    2014-01-01

    Full Text Available The life-threatening diseases alveolar and cystic echinococcoses are caused by larvae of the tapeworms Echinococcus multilocularis and E. granulosus, respectively. In both cases, intermediate hosts, such as humans, are infected by oral uptake of oncosphere larvae, followed by asexual multiplication and almost unrestricted growth of the metacestode within host organs. Besides surgery, echinococcosis treatment relies on benzimidazole-based chemotherapy, directed against parasite beta-tubulin. However, since beta-tubulins are highly similar between cestodes and humans, benzimidazoles can only be applied at parasitostatic doses and are associated with adverse side effects. Mostly aiming at identifying alternative drug targets, the nuclear genome sequences of E. multilocularis and E. granulosus have recently been characterized, revealing a large number of druggable targets that are expressed by the metacestode. Furthermore, recent cell biological investigations have demonstrated that E. multilocularis employs pluripotent stem cells, called germinative cells, which are the only parasite cells capable of proliferation and which give rise to all differentiated cells. Hence, the germinative cells are the crucial cell type mediating proliferation of E. multilocularis, and most likely also E. granulosus, within host organs and should also be responsible for parasite recurrence upon discontinuation of chemotherapy. Interestingly, recent investigations have also indicated that germinative cells might be less sensitive to chemotherapy because they express a beta-tubulin isoform with limited affinity to benzimidazoles. In this article, we briefly review the recent findings concerning Echinococcus genomics and stem cell research and propose that future research into anti-echinococcosis drugs should also focus on the parasite’s stem cell population.

  6. Effects of vitamin K3 and K5 on proliferation, cytokine production, and regulatory T cell-frequency in human peripheral-blood mononuclear cells.

    Science.gov (United States)

    Hatanaka, Hiroshige; Ishizawa, Hitomi; Nakamura, Yurie; Tadokoro, Hiroko; Tanaka, Sachiko; Onda, Kenji; Sugiyama, Kentaro; Hirano, Toshihiko

    2014-03-18

    The effects of vitamin K (VK) derivatives VK3 and VK5 on human immune cells have not been extensively investigated. We examined the effects of VK3 and VK5 on proliferation, apoptosis, cytokine production, and CD4+CD25+Foxp3+ regulatory T (Treg) cell-frequency in human peripheral blood mononuclear cells (PBMCs) activated by T cell mitogen in vitro. Anti-proliferative effects of VK3 and VK5 on T-cell mitogen activated PBMCs were assessed by WST assay procedures. Apoptotic cells were determined as Annexin V positive/propidium iodide (PI) negative cells. Cytokine concentrations in the supernatant of the culture medium were measured with bead-array procedures followed by analysis with flow cytometry. The CD4+CD25+Foxp3+Treg cells in mitogen-activated PBMCs were stained with fluorescence-labeled specific antibodies followed by flow cytometry. VK3 and VK5 suppressed the mitogen-activated proliferation of PBMCs significantly at 10-100μM (p<0.05). The data also suggest that VK3 and VK5 promote apoptosis in the mitogen-activated T cells. VK3 and VK5 significantly inhibited the production of tumor necrosis factor (TNF) α, interleukin (IL)-4, -6, and -10 from the activated PBMCs at 10-100μM (p<0.05). In contrast, VK3 and VK5 significantly increased Treg cell-frequency in the activated PBMCs at concentrations more than 10μM (p<0.001). Our data suggest that VK3 and VK5 attenuate T cell mediated immunity by inhibiting the proliferative response and inducing apoptosis in activated T cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Transcriptional profiles of cytokine/chemokine factors of immune cell-homing to the parasitic lesions: a comprehensive one-year course study in the liver of E. multilocularis-infected mice.

    Directory of Open Access Journals (Sweden)

    Junhua Wang

    Full Text Available Pathogenesis of chronically developing alveolar echinococcosis (AE is characterized by a continuous, granulomatous, periparasitic infiltration of immune cells surrounding the metacestode of Echinococcus multilocularis (E.multilocularis in the affected liver. A detailed cytokine and chemokine profile analysis of the periparasitic infiltrate in the liver has, however, not yet been carried out in a comprehensive way all along the whole course of infection in E. multilocularis intermediate hosts. We thus assessed the hepatic gene expression profiles of 18 selected cytokine and chemokine genes using qRT-PCR in the periparasitic immune reaction and the subsequent adjacent, not directly affected, liver tissue of mice from day 2 to day 360 post intra-hepatic injection of metacestode. DNA microarray analysis was also used to get a more complete picture of the transcriptional changes occurring in the liver surrounding the parasitic lesions. Profiles of mRNA expression levels in the hepatic parasitic lesions showed that a mixed Th1/Th2 immune response, characterized by the concomitant presence of IL-12α, IFN-γ and IL-4, was established very early in the development of E. multilocularis. Subsequently, the profile extended to a combined tolerogenic profile associating IL-5, IL-10 and TGF-β. IL-17 was permanently expressed in the liver, mostly in the periparasitic infiltrate; this was confirmed by the increased mRNA expression of both IL-17A and IL-17F from a very early stage, with a subsequent decrease of IL-17A after this first initial rise. All measured chemokines were significantly expressed at a given stage of infection; their expression paralleled that of the corresponding Th1, Th2 or Th17 cytokines. In addition to giving a comprehensive insight in the time course of cytokines and chemokines in E. multilocularis lesion, this study contributes to identify new targets for possible immune therapy to minimize E. multilocularis-related pathology and to

  8. Regulatory T cells in induced sputum of asthmatic children: association with inflammatory cytokines

    Directory of Open Access Journals (Sweden)

    Hamzaoui Agnès

    2010-02-01

    Full Text Available Abstract Background and objective CD4+CD25+ regulatory T (Treg cells play an essential role in maintaining immune homeostasis. In this study, we investigated whether the induced sputum (IS pool and the function of CD4+CD25+ Treg cells are altered in asthma pediatric patients. Methods Treg activity was studied in the IS of 40 asthmatic children. CD3+ cells were analyzed for the expression of FoxP3 mRNA by real time reverse transcription-polymerase chain reaction (RT-PCR. IS cells from asthmatics and controls were stained for Treg markers and analyzed by flow cytometry. We also studied the ability of Treg cells to differentiate monocytes toward alternatively activated macrophages (AAM, and to suppress proinflammatory cytokines. Results (i Mild and moderate asthmatics had significantly decreased expression of FoxP3/β-actin mRNA and decreased proportions of CD4+CD25highFoxP3+ cells compared to healthy children; (ii patients with moderate asthma had even lower proportions of FoxP3 expression compared to mild asthmatic patients; (iii monocytes cultured with Treg cells displayed typical features of AAM, including up-regulated expression of CD206 (macrophage mannose receptor and CD163 (hemoglobin scavenger receptor, and an increased production of chemokine ligand 18 (CCL18. In addition, Treg cells from asthmatics have a reduced capacity to suppress LPS-proinflammatory cytokine production from monocytes/macrophages (IL-1, IL-6 and TNF-α. Conclusion Asthma pediatric patients display a decreased bronchial Treg population. The impaired bronchial Treg activity is associated with disease severity.

  9. Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes.

    Science.gov (United States)

    Stinson, Lisa F; Ireland, Demelza J; Kemp, Matthew W; Payne, Matthew S; Stock, Sarah J; Newnham, John P; Keelan, Jeffrey A

    2014-03-01

    Intrauterine infection and inflammation are responsible for the majority of early (PTBs). Anti-inflammatory agents, delivered intra-amniotically together with antibiotics, may be an effective strategy for preventing PTB. In this study, the effects of four cytokine-suppressive anti-inflammatory drugs (CSAIDs: N-acetyl cysteine (NAC), SB239063, TPCA-1 and NEMO binding domain inhibitor (NBDI)) were assessed on human and ovine gestational membrane inflammation. Full-thickness membranes were collected from healthy, term, human placentas delivered by Caesarean section (n=5). Using a Transwell model, they were stimulated ex vivo with γ-irradiation-killed Escherichia coli applied to the amniotic face. Membranes from near-term, ovine placentas were stimulated in utero with lipopolysaccharide, Ureaplasma parvum or saline control and subjected to explant culture. The effects of treatment with CSAIDs or vehicle (1% DMSO) on accumulation of PGE2 and cytokines (human interleukin 6 (IL6), IL10 and TNFα; ovine IL8 (oIL8)) were assessed in conditioned media at various time points (3-20  h). In human membranes, the IKKβ inhibitor TPCA-1 (7  μM) and p38 MAPK inhibitor SB239063 (20  μM) administered to the amniotic compartment were the most effective in inhibiting accumulation of cytokines and PGE2 in the fetal compartment. NAC (10  mM) inhibited accumulation of PGE2 and IL10 only; NBDI (10  μM) had no significant effect. In addition to the fetal compartment, SB239063 also exerted consistent and significant inhibitory effects in the maternal compartment. TPCA-1 and SB239063 suppressed oIL8 production, while all CSAIDs tested suppressed ovine PGE2 production. These results support the further investigation of intra-amniotically delivered CSAIDs for the prevention of inflammation-mediated PTB.

  10. Arthritis is inhibited in Borrelia-primed and infected interleukin-17A-deficient mice after administration of anti-gamma-interferon, anti-tumor necrosis factor alpha and anti-interleukin-6 antibodies.

    Science.gov (United States)

    Kuo, Joseph; Warner, Thomas F; Schell, Ronald F

    2017-08-31

    The role that cytokines play in the induction of Lyme arthritis is gradually being delineated. We showed previously that severe arthritis developed in a T-cell-driven murine model, even in mice lacking interleukin-17A (IL-17A) and administered anti-gamma-interferon (IFN-γ) antibody. Increased levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), two pro-inflammatory cytokines, were detected in cultures of popliteal lymph node cells obtained from these mice. We hypothesized that concomitantly administered anti-IL-6, anti-TNF-α and anti-IFN-γ antibodies would inhibit the development of arthritis in IL-17A-deficient mice. Our results showed that swelling of the hind paws and histopathological changes consistent with arthritis were significantly reduced in IL-17A-deficient mice that administered the three anti-cytokine antibodies. These results suggest that treatment with multiple anti-cytokine antibodies can abrogate the induction of Lyme arthritis in mice. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Serum levels of the pro-inflammatory cytokine interleukin-12 and the anti-inflammatory cytokine interleukin-10 in patients with psoriasis treated by the Goeckerman regimen

    Energy Technology Data Exchange (ETDEWEB)

    Borska, L.; Andrys, C.; Krejsek, J.; Hamakova, K.; Kremlacek, J.; Ettler, K.; Fiala, Z. [Charles University Prague, Hradec Kralove (Czech Republic)

    2008-08-15

    The Goeckerman regimen (GR) involves the dermal application of a crude coal tar (polycyclic aromatic hydrocarbon, PAH) and exposure to ultraviolet (UV) radiation. Both PAH and UV radiation exhibit immunosuppressive activity. This study describes the changes in the serum levels of the pro-inflammatory cytokine interleukin-12 (IL-12) and the anti-inflammatory cytokine IL-10 in patients with psoriasis (n = 55) treated with GR. The serum levels of IL-12 and IL-10 were compared before and after GR. In addition, the IL-12 and IL-10 levels in psoriatic patients were compared with those in a control group of healthy blood donors (n = 47). The Psoriasis Area and Severity Index (PASI) was used to evaluate the efficacy of GR. When compared with the control group, both IL-12 and IL-10 were significantly higher in psoriatic patients in all cases (P < 0.001). When compared before and after GR, the IL-12 and IL-10 levels (P < 0.01) and PASI value (P < 0.001) were significantly lower after GR. The decrease in the serum level of IL-12 and IL-10 after GR was related to the entry value before GR (IL-12, r = 0.60, P < 0.001; IL-10, r = 0.36, P < 0.01). There was a significant correlation between the IL-10 level before GR and the PASI value after GR = -0.39; P < 0.01). The results indicate a strong pro-inflammatory effect of IL-12 in the immunopathogenesis of psoriasis, and confirm the immunosuppressive and anti-inflammatory effect of GR. IL-10 seems to be a promising individual marker for a positive effect of GR therapy.

  12. Anti-Parasitic Activities of Allium sativum and Allium cepa against Trypanosoma b. brucei and Leishmania tarentolae.

    Science.gov (United States)

    Krstin, Sonja; Sobeh, Mansour; Braun, Markus Santhosh; Wink, Michael

    2018-04-21

    Background: Garlics and onions have been used for the treatment of diseases caused by parasites and microbes since ancient times. Trypanosomiasis and leishmaniasis are a concern in many areas of the world, especially in poor countries. Methods: Trypanosoma brucei brucei and Leishmania tarentolae were used to investigate the anti-parasitic effects of dichloromethane extracts of Allium sativum (garlic) and Allium cepa (onion) bulbs. As a confirmation of known antimicrobial activities, they were studied against a selection of G-negative, G-positive bacteria and two fungi. Chemical analyses were performed using high-performance liquid chromatography (HPLC) and electrospray ionization-mass spectrometry (LC-ESI-MS/MS). Results: Chemical analyses confirmed the abundance of several sulfur secondary metabolites in garlic and one (zwiebelane) in the onion extract. Both extracts killed both types of parasites efficiently and inhibited the Trypanosoma brucei trypanothione reductase irreversibly. In addition, garlic extract decreased the mitochondrial membrane potential in trypanosomes. Garlic killed the fungi C. albicans and C. parapsilosis more effectively than the positive control. The combinations of garlic and onion with common trypanocidal and leishmanicidal drugs resulted in a synergistic or additive effect in 50% of cases. Conclusion: The mechanism for biological activity of garlic and onion appears to be related to the amount and the profile of sulfur-containing compounds. It is most likely that vital substances inside the parasitic cell, like trypanothione reductase, are inhibited through disulfide bond formation between SH groups of vital redox compounds and sulfur-containing secondary metabolites.

  13. Selective Expansion of Memory CD4+ T cells By Mitogenic Human CD28 Generates Inflammatory Cytokines and Regulatory T cells

    Science.gov (United States)

    Singh, Manisha; Basu, Sreemanti; Camell, Christina; Couturier, Jacob; Nudelman, Rodolfo J.; Medina, Miguel A.; Rodgers, John R.; Lewis, Dorothy E.

    2009-01-01

    Co-stimulatory signals are important for development of effector and regulatory T cells. In this case, CD28 signaling is usually considered inert in the absence of signaling through the TCR. By contrast, mitogenic rat CD28 mAbs reportedly expand regulatory T cells without TCR stimulation. We found that a commercially available human CD28 mAb (ANC28) stimulated PBMCs without TCR co-ligation or cross-linking; ANC28 selectively expanded CD4+CD25+FoxP3−(T effector) and CD4+CD25+FoxP3+ (Treg) cells. ANC28 stimulated the CD45RO+ CD4+ (memory) population whereas CD45RA+CD4+ (naïve) cells did not respond. ANC28 also induced inflammatory cytokines. Treg induced by ANC28 retain the Treg phenotype longer than did co-stimulated Treg. Treg induced by ANC28 suppressed CD25− T cells through a contact-dependent mechanism. Purity influenced the response of CD4+CD25+ cells because bead-purified CD4+CD25+ cells (85–90% pure) responded strongly to ANC28, whereas 98% pure FACS-sorted CD4+CD25 bright (T-reg) did not respond. Purified CD4+CD25int cells responded similarly to the bead-purified CD4+CD25+ cells. Thus, pre-activated CD4+ T cells (CD25int) respond to ANC28 rather than Treg (CD25bright). The ability of ANC28 to expand both effectors producing inflammatory cytokines as well as suppressive regulatory T cells might be useful for ex vivo expansion of therapeutic T cells. PMID:18446791

  14. PERIPHERAL PARASITAEMIA AND ITS ASSOCIATION WITH PLASMA CYTOKINES LEVELS IN MALARIA-INFECTED PREGNANT WOMEN IN ABA, ABIA STATE, NIGERIA.

    Science.gov (United States)

    Ifeanyichukwu, M O; Okamgba, O C; Amilo, G I; Nwokorie, E A

    2017-01-01

    Cytokines in pregnant female may not be a normal phenomenon as malarial infection is often associated with strong CD4+ cell activation and up-regulation of pro-inflammatory cytokines. We investigated the relationship between peripheral parasitaemia and plasma levels of cytokines among malaria infected pregnant women in Aba, Abia State, Nigeria. A total of 206 non-HIV positive asymptomatic malaria parasitaemic (n=144) and non-parasitaemic (n=62) pregnant women were recruited for this study alongside 80 non-pregnant women who served as positive (n=40) and negative (n=40) controls. Blood samples were aseptically collected from each subject and tested for HIV and malaria parasites using standard methods. Also, plasma levels of cytokines were measured using Th1/Th2 human cytokine ELISA kits (Abcam, UK). Analysis of Variance and Student's t-test were used for Comparison of groups while Pearson's Correlation Coefficient was used for tests of association. The results revealed a mean parasite density of 685.56±484.55 parasites/µl of blood. Malaria infected pregnant subjects showed significantly higher levels of IFN-γ, TNF-α, IL-4, IL-6 and IL-10 when compared with their non-infected counterparts (P< 0.05). The cytokines evaluated were higher in moderate parasitaemia than mild parasitaemia. Positive correlation existed between peripheral parasite density (PPD) and IL-4 (r= 0.24, P=0.004), PPD and IL-6 (r = 0.35, P = 0.001) as well as PPD and IL-10 (r = 0.29, P = 0.001). This study showed that increase in peripheral parasitaemia increased levels of some plasma cytokines (IL-4, IL-6 and IL-10) but not IFN-γ and TNF-α in the malaria infected pregnant women studied.

  15. Insulin-Like Growth Factor-I Induces Arginase Activity in Leishmania amazonensis Amastigote-Infected Macrophages through a Cytokine-Independent Mechanism

    Directory of Open Access Journals (Sweden)

    Celia Maria Vieira Vendrame

    2014-01-01

    Full Text Available Leishmania (Leishmania amazonensis exhibits peculiarities in its interactions with hosts. Because amastigotes are the primary form associated with the progression of infection, we studied the effect of insulin-like growth factor (IGF-I on interactions between L. (L. amazonensis amastigotes and macrophages. Upon stimulation of infected macrophages with IGF-I, we observed decreased nitric oxide production but increased arginase expression and activity, which lead to increased parasitism. However, stimulation of amastigote-infected macrophages with IGF-I did not result in altered cytokine levels compared to unstimulated controls. Because IGF-I is present in tissue fluids and also within macrophages, we examined the possible effect of this factor on phosphatidylserine (PS exposure on amastigotes, seen previously in tissue-derived amastigotes leading to increased parasitism. Stimulation with IGF-I induced PS exposure on amastigotes but not on promastigotes. Using a PS-liposome instead of amastigotes, we observed that the PS-liposome but not the control phosphatidylcholine-liposome led to increased arginase activity in macrophages, and this process was not blocked by anti-TGF-β antibodies. Our results suggest that in L. (L. amazonensis amastigote-infected macrophages, IGF-I induces arginase activity directly in amastigotes and in macrophages through the induction of PS exposure on amastigotes in the latter, which could lead to the alternative activation of macrophages through cytokine-independent mechanisms.

  16. Cytokines in the management of rotavirus infection: A systematic review of in vivo studies.

    Science.gov (United States)

    Gandhi, Gopalsamy Rajiv; Santos, Victor Santana; Denadai, Marina; da Silva Calisto, Valdete Kaliane; de Souza Siqueira Quintans, Jullyana; de Oliveira E Silva, Ana Mara; de Souza Araújo, Adriano Antunes; Narain, Narendra; Cuevas, Luis Eduardo; Júnior, Lucindo José Quintans; Gurgel, Ricardo Queiroz

    2017-08-01

    Rotavirus is a leading cause of childhood diarrhoea. Rotavirus vaccines are effective against severe rotavirus gastroenteritis, but have lower efficacy in low income countries in Africa. Anti-rotavirus treatment is not available. This study reviews the literature of animal studies evaluating whether cytokine mediated pathways of immune activation could improve rotavirus therapy. We performed a systematic review of articles in English published from 2010 to 2016 reporting agents with in vivo antirotavirus activity for the management of rotavirus infection. The search was carried in PubMed, EMBASE, Scopus and Web of Science. Animal experiments where cytokines were investigated to assess the outcome of rotavirus therapy were included. A total of 869 publications were identified. Of these, 19 pertained the objectives of the review, and 11 articles described the effect of probiotics/commensals on rotavirus infection and immune responses in animals. Eight further in vivo studies evaluated the immunomodulating effects of herbs, secondary metabolites and food-derived products on cytokine responses of rotavirus-infected animals. Studies extensively reported the regulatory roles for T-helper (Th)1 (interferon gamma (IFN-γ), interleukin (IL)-2, IL-12) and Th2 (IL-4, IL-6, IL-10) cytokines responses to rotavirus pathogenesis and immunity, inhibiting rotavirus infection through suppression of inflammation by viral inhibition. Th1 and Th2 cytokines stimulate the immune system, inhibiting rotavirus binding and/or replication in animal models. Th1/Th2 cytokine responses have optimal immunomodulating effects to reduce rotavirus diarrhoea and enhance immune responses in experimental rotavirus infection. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Impact of Cytokines and Chemokines on Alzheimer's Disease Neuropathological Hallmarks.

    Science.gov (United States)

    Domingues, Catarina; da Cruz E Silva, Odete A B; Henriques, Ana Gabriela

    2017-01-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder, neuropathologically characterized by aggregates of β-amyloid peptides, which deposit as senile plaques, and of TAU protein, which forms neurofibrillary tangles. It is now widely accepted that neuroinflammation is implicated in AD pathogenesis. Indeed, inflammatory mediators, such as cytokines and chemokines (chemotactic cytokines) can impact on the Alzheimer´s amyloid precursor protein by affecting its expression levels and amyloidogenic processing and/or β -amyloid aggregation. Additionally, cytokines and chemokines can influence kinases' activities, leading to abnormal TAU phosphorylation. To date there is no cure for AD, but several therapeutic strategies have been directed to prevent neuroinflammation. Anti-inflammatory, but also anti-amyloidogenic compounds, such as flavonoids were shown to favourably modulate some pathological events associated with neurodegeneration. This review focuses on the role of cytokines and chemokines in AD-associated pathologies, and summarizes the potential anti-inflammatory therapeutic approaches aimed at preventing or slowing down disease progression. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Trypanosoma cruzi Evades the Complement System as an Efficient Strategy to Survive in the Mammalian Host: The Specific Roles of Host/Parasite Molecules and Trypanosoma cruzi Calreticulin

    Directory of Open Access Journals (Sweden)

    Galia Ramírez-Toloza

    2017-09-01

    Full Text Available American Trypanosomiasis is an important neglected reemerging tropical parasitism, infecting about 8 million people worldwide. Its agent, Trypanosoma cruzi, exhibits multiple mechanisms to evade the host immune response and infect host cells. An important immune evasion strategy of T. cruzi infective stages is its capacity to inhibit the complement system activation on the parasite surface, avoiding opsonizing, immune stimulating and lytic effects. Epimastigotes, the non-infective form of the parasite, present in triatomine arthropod vectors, are highly susceptible to complement-mediated lysis while trypomastigotes, the infective form, present in host bloodstream, are resistant. Thus T. cruzi susceptibility to complement varies depending on the parasite stage (amastigote, trypomastigotes or epimastigote and on the T. cruzi strain. To avoid complement-mediated lysis, T. cruzi trypomastigotes express on the parasite surface a variety of complement regulatory proteins, such as glycoprotein 58/68 (gp58/68, T. cruzi complement regulatory protein (TcCRP, trypomastigote decay-accelerating factor (T-DAF, C2 receptor inhibitor trispanning (CRIT and T. cruzi calreticulin (TcCRT. Alternatively, or concomitantly, the parasite captures components with complement regulatory activity from the host bloodstream, such as factor H (FH and plasma membrane-derived vesicles (PMVs. All these proteins inhibit different steps of the classical (CP, alternative (AP or lectin pathways (LP. Thus, TcCRP inhibits the CP C3 convertase assembling, gp58/68 inhibits the AP C3 convertase, T-DAF interferes with the CP and AP convertases assembling, TcCRT inhibits the CP and LP, CRIT confers ability to resist the CP and LP, FH is used by trypomastigotes to inhibit the AP convertases and PMVs inhibit the CP and LP C3 convertases. Many of these proteins have similar molecular inhibitory mechanisms. Our laboratory has contributed to elucidate the role of TcCRT in the host-parasite

  19. Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from LPS-stimulated myeloid cells.

    LENUS (Irish Health Repository)

    Gleeson, Eimear M

    2013-07-19

    Vitamin K-dependent proteases generated in response to vascular injury and infection enable fibrin clot formation, but also trigger distinct immuno-regulatory signaling pathways on myeloid cells. Factor Xa, a protease crucial for blood coagulation, also induces protease-activated receptor-dependent cell signaling. Factor Xa can bind both monocytes and macrophages, but whether factor Xa-dependent signaling stimulates or suppresses myeloid cell cytokine production in response to Toll-like receptor activation is not known. In this study, exposure to factor Xa significantly impaired pro-inflammatory cytokine production from lipopolysaccharide-treated peripheral blood mononuclear cells, THP-1 monocytic cells and murine macrophages. Furthermore, factor Xa inhibited nuclear factor-kappa B activation in THP-1 reporter cells, requiring phosphatidylinositide 3-kinase activity for its anti-inflammatory effect. Active-site blockade, γ-carboxyglutamic acid domain truncation and a peptide mimic of the factor Xa inter-epidermal growth factor-like region prevented factor Xa inhibition of lipopolysaccharide-induced tumour necrosis factor-α release. In addition, factor Xa anti-inflammatory activity was markedly attenuated by the presence of an antagonist of protease-activated receptor 2, but not protease-activated receptor 1. The key role of protease-activated receptor 2 in eliciting factor Xa-dependent anti-inflammatory signaling on macrophages was further underscored by the inability of factor Xa to mediate inhibition of tumour necrosis factor-α and interleukin-6 release from murine bone marrow-derived protease-activated receptor 2-deficient macrophages. We also show for the first time that, in addition to protease-activated receptor 2, factor Xa requires a receptor-associated protein-sensitive low-density lipoprotein receptor to inhibit lipopolysaccharide-induced cytokine production. Collectively, this study supports a novel function for factor Xa as an endogenous, receptor

  20. Caspase-8 regulates the expression of pro- and anti-inflammatory cytokines in human bone marrow-derived mesenchymal stromal cells.

    Science.gov (United States)

    Moen, Siv H; Westhrin, Marita; Zahoor, Muhammad; Nørgaard, Nikolai N; Hella, Hanne; Størdal, Berit; Sundan, Anders; Nilsen, Nadra J; Sponaas, Anne-Marit; Standal, Therese

    2016-09-01

    Mesenchymal stem cells, also called mesenchymal stromal cells, MSCs, have great potential in stem cell therapy partly due to their immunosuppressive properties. How these cells respond to chronic inflammatory stimuli is therefore of importance. Toll-like receptors (TLR)s are innate immune receptors that mediate inflammatory signals in response to infection, stress, and damage. Caspase-8 is involved in activation of NF-kB downstream of TLRs in immune cells. Here we investigated the role of caspase-8 in regulating TLR-induced cytokine production from human bone marrow-derived mesenchymal stromal cells (hBMSCs). Cytokine expression in hBMCs in response to poly(I:C) and LPS was evaluated by PCR, multiplex cytokine assay, and ELISA. TLR3, TRIF, and caspase-8 were silenced using siRNA. Caspase-8 was also inhibited using a caspase-8 inhibitor, z-IEDT. We found that TLR3 agonist poly(I:C) and TLR4 agonist LPS induced secretion of several pro-inflammatory cytokines in a TLR-dependent manner which required the TLR signaling adaptor molecule TRIF. Further, poly(I:C) reduced the expression of anti-inflammatory cytokines HGF and TGFβ whereas LPS reduced HGF expression only. Notably, caspase-8 was involved in the induction of IL- IL-1β, IL-6, CXCL10, and in the inhibition of HGF and TGFβ. Caspase-8 appears to modulate hBMSCs into gaining a pro-inflammatory phenotype. Therefore, inhibiting caspase-8 in hBMSCs might promote an immunosuppressive phenotype which could be useful in clinical applications to treat inflammatory disorders.

  1. Dose response relationship in anti-stress gene regulatory networks.

    Science.gov (United States)

    Zhang, Qiang; Andersen, Melvin E

    2007-03-02

    To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on

  2. Dose response relationship in anti-stress gene regulatory networks.

    Directory of Open Access Journals (Sweden)

    Qiang Zhang

    2007-03-01

    Full Text Available To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear depends on changes in the specific values of local response coefficients (gains distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear

  3. Helminth parasites alter protection against Plasmodium infection.

    Science.gov (United States)

    Salazar-Castañon, Víctor H; Legorreta-Herrera, Martha; Rodriguez-Sosa, Miriam

    2014-01-01

    More than one-third of the world's population is infected with one or more helminthic parasites. Helminth infections are prevalent throughout tropical and subtropical regions where malaria pathogens are transmitted. Malaria is the most widespread and deadliest parasitic disease. The severity of the disease is strongly related to parasite density and the host's immune responses. Furthermore, coinfections between both parasites occur frequently. However, little is known regarding how concomitant infection with helminths and Plasmodium affects the host's immune response. Helminthic infections are frequently massive, chronic, and strong inductors of a Th2-type response. This implies that infection by such parasites could alter the host's susceptibility to subsequent infections by Plasmodium. There are a number of reports on the interactions between helminths and Plasmodium; in some, the burden of Plasmodium parasites increased, but others reported a reduction in the parasite. This review focuses on explaining many of these discrepancies regarding helminth-Plasmodium coinfections in terms of the effects that helminths have on the immune system. In particular, it focuses on helminth-induced immunosuppression and the effects of cytokines controlling polarization toward the Th1 or Th2 arms of the immune response.

  4. The effect of feed supplementation with effective microorganisms (EM) on pro- and anti-inflammatory cytokine concentrations in pigs.

    Science.gov (United States)

    Laskowska, Ewa; Jarosz, Łukasz; Grądzki, Zbigniew

    2017-12-01

    Effective microorganisms (EM) are used in numerous fields associated with agriculture. The beneficial effects of EM on the general health of pigs and on production parameters are also determined by the influence of these microbes on immunity. The aim of the study was to assess the effect of feed supplementation with EM on the concentration of pro- and anti-inflammatory cytokines in the serum and in a culture of PBMCs with and without ConA stimulation in pigs. ELISA kits were used to determine the cytokine levels in the porcine serum and the PBMC culture supernatants. Evaluation of the serum concentration of cytokines revealed statistically significantly higher concentrations of IL-2, IL-4, IL-10, IFN-γ and TNF-α in the pigs receiving EM Bokashi. The highest concentration of TGF-β in the experimental group was noted on the final test day. Evaluation of cytokine concentrations in the PBMC cultures revealed statistically significantly higher concentrations of IL-2, IL-4 and IL-10 from the third day of the experiment. Statistically significantly higher concentrations of TNF-α were obtained in the unstimulated PBMC culture on the second test day and in the culture treated with ConA on the second and the third test days. The results of our study indicate that supplementation of pig feed with EM Bokashi activates the cell-mediated and humoral immune response, ensuring that Th1/Th2 balance is maintained and enhancing immune processes protecting the body against infection. Copyright © 2017. Published by Elsevier Ltd.

  5. Anti-inflammatory properties of clovamide and Theobroma cacao phenolic extracts in human monocytes: evaluation of respiratory burst, cytokine release, NF-κB activation, and PPARγ modulation.

    Science.gov (United States)

    Zeng, Huawu; Locatelli, Monica; Bardelli, Claudio; Amoruso, Angela; Coisson, Jean Daniel; Travaglia, Fabiano; Arlorio, Marco; Brunelleschi, Sandra

    2011-05-25

    There is a great interest in the potential health benefits of biologically active phenolic compounds in cocoa (Theobroma cacao) and dark chocolate. We investigated the anti-inflammatory potential of clovamide (a N-phenylpropenoyl-L-amino acid amide present in cocoa beans) and two phenolic extracts from unroasted and roasted cocoa beans, by evaluating superoxide anion (O(2)(-)) production, cytokine release, and NF-κB activation in human monocytes stimulated by phorbol 12-myristate 13-acetate (PMA). The effects of rosmarinic acid are shown for comparison. Clovamide and rosmarinic acid inhibited PMA-induced O(2)(-) production and cytokine release (with a bell-shaped curve and maximal inhibition at 10-100 nM), as well as PMA-induced NF-κB activation; the two cocoa extracts were less effective. In all tests, clovamide was the most potent compound and also enhanced peroxisome proliferator-activated receptor-γ (PPARγ) activity, which may exert anti-inflammatory effects. These findings indicate clovamide as a possible bioactive compound with anti-inflammatory activity in human cells.

  6. Regulatory role of NKG2D+ NK cells in intestinal lamina propria by secreting double-edged Th1 cytokines in ulcerative colitis.

    Science.gov (United States)

    Wang, Fan; Peng, Pai-Lan; Lin, Xue; Chang, Ying; Liu, Jing; Zhou, Rui; Nie, Jia-Yan; Dong, Wei-Guo; Zhao, Qiu; Li, Jin

    2017-11-17

    The role of intestinal lamina propria (LP) NKG2D+ NK cells is unclear in regulating Th1/Th2 balance in ulcerative colitis (UC). In this study, we investigated the frequency of LP NKG2D+ NK cells in DSS-induced colitis model and intestinal mucosal samples of UC patients, as well as the secretion of Th1/Th2/Th17 cytokines in NK cell lines after MICA stimulation. The role of Th1 cytokines in UC was validated by bioinformatics analysis. We found that DSS-induced colitis in mice was characterized by a Th2-mediated process. In acute phrase, the frequency of LP NKG2D+ lymphocytes increased significantly and decreased in remission, while the frequency of LP NKG2D+ NK cells decreased significantly in acute phase and increased in remission. No obvious change was found in the frequency of total LP NK cells. Similarly, severe UC patients had a higher expression of mucosal NKG2D and a lower number of NKG2D+ NK cells than mild to moderate UC. In NK cell lines, the MICA stimulation could induce a predominant secretion of Th1 cytokines (TNF, IFN-γ). Furthermore, in bioinformatics analysis, mucosal Th1 cytokine of TNF, showed a double-edged role in UC when compared to the Th1-mediated disease of Crohn's colitis. In conclusion, LP NKG2D+ NK cells partially played a regulatory role in UC through secreting Th1 cytokines to regulate the Th2-predominant Th1/Th2 imbalance, despite of the concomitant pro-inflammatory effects of Th1 cytokines.

  7. The Eros of Counter Education

    Science.gov (United States)

    Luzon, Pinhas

    2016-01-01

    Erotic Counter Education (ECE) is the educational position of the late Ilan Gur-Ze'ev. In ECE Gur-Ze'ev combines two opposing positions in the philosophy of education, one teleological and anti-utopian, the other teleological and utopian. In light of this unique combination, I ask what mediates between these two poles and suggest that the answer…

  8. Regulatory T-cell cytokines in patients with nonsegmental vitiligo.

    Science.gov (United States)

    Kidir, Mehtap; Karabulut, Ayse A; Ercin, Mustafa E; Atasoy, Pınar

    2017-05-01

    In the etiopathogenesis of vitiligo, the role of suppressor cytokines, such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), associated with regulatory T-cells (Treg) is not completely known. In this study, the role of Treg-cell functions in the skin of patients with nonsegmental vitiligo was investigated. Lesional and nonlesional skin samples from 30 adult volunteers ranging in age from 18 to 36 years with nonsegmental vitiligo were compared with normal skin area excision specimens of 30 benign melanocytic nevus cases as controls. All samples were evaluated staining for forkhead box P3 (Foxp3), TGF-β, and IL-10 using the standardized streptavidin-biotin immunoperoxidase immunohistochemistry method. Foxp3 expression was lower in lesional vitiligo skin specimens compared to controls; it was also lower in lesional vitiligo specimens than nonlesional vitiligo specimens. IL-10 levels were lower in lesional vitiligo specimens compared to the controls, whereas IL-10 expression was significantly lower in lesional specimens compared with nonlesional specimens. TGF-β expression was higher in both lesional and nonlesional skin specimens of patients with vitiligo compared to controls. TGF-β expression was lower in lesional skin specimens than nonlesional skin specimens. In addition, there was no significant correlation between Foxp3 expression with TGF-β and IL-10 expressions in lesional skin specimens in the vitiligo group. In this study, results supporting the contribution of Treg cells and IL-10 deficiency to the autoimmune process were obtained. Therefore, future studies are necessary to demonstrate the definitive role of Treg-cell functions in the etiopathogenesis of vitiligo. © 2017 The International Society of Dermatology.

  9. Effect of Multi-Microbial Probiotic Formulation Bokashi on Pro- and Anti-Inflammatory Cytokines Profile in the Serum, Colostrum and Milk of Sows, and in a Culture of Polymorphonuclear Cells Isolated from Colostrum.

    Science.gov (United States)

    Laskowska, Ewa; Jarosz, Łukasz; Grądzki, Zbigniew

    2018-01-05

    The use of probiotics in sows during pregnancy and lactation and their impact on the quality of colostrum and milk, as well as the health conditions of their offspring during the rearing period, are currently gaining the attention of researchers. The aim of the study was to determine the effect of Bokashi formulation on the concentrations of pro- and anti-inflammatory cytokines in the serum of sows during pregnancy, in their colostrum and milk, and in a culture of Con-A-stimulated polymorphonuclear cells (PMNs) isolated from the colostrum. The study was conducted on 60 sows aged 2-4 years. EM Bokashi were added to the sows' feed. The material for the study consisted of peripheral blood, colostrum, and milk. Blood samples were collected from the sows on days 60 and 114 of gestation. Colostrum and milk samples were collected from all sows at 0, 24, 48, 72, 96, 120, 144, and 168 h after parturition. The results indicate that the use of Bokashi as feed additives resulted in increased concentrations of pro-inflammatory cytokines TNF-α and IL-6, which increase the protective capacity of the colostrum by stimulating cellular immune mechanisms protecting the sow and neonates against infection. At the same time, the increased concentrations of cytokines IL-4, IL-10, TGF-β, and of immunoglobulins in the colostrum and milk from sows in the experimental group demonstrate the immunoregulatory effect of Bokashi on Th2 cells and may lead to increased expression of regulatory T cells and polarization of the immune response from Th1 to Th2.

  10. Cuckoos versus hosts in insects and birds: adaptations, counter-adaptations and outcomes.

    Science.gov (United States)

    Kilner, Rebecca M; Langmore, Naomi E

    2011-11-01

    Avian parents and social insect colonies are victimized by interspecific brood parasites-cheats that procure costly care for their dependent offspring by leaving them in another species' nursery. Birds and insects defend themselves from attack by brood parasites; their defences in turn select counter-strategies in the parasite, thus setting in motion antagonistic co-evolution between the two parties. Despite their considerable taxonomic disparity, here we show striking parallels in the way that co-evolution between brood parasites and their hosts proceeds in insects and birds. First, we identify five types of co-evolutionary arms race from the empirical literature, which are common to both systems. These are: (a) directional co-evolution of weaponry and armoury; (b) furtiveness in the parasite countered by strategies in the host to expose the parasite; (c) specialist parasites mimicking hosts who escape by diversifying their genetic signatures; (d) generalist parasites mimicking hosts who escape by favouring signatures that force specialization in the parasite; and (e) parasites using crypsis to evade recognition by hosts who then simplify their signatures to make the parasite more detectable. Arms races a and c are well characterized in the theoretical literature on co-evolution, but the other types have received little or no formal theoretical attention. Empirical work suggests that hosts are doomed to lose arms races b and e to the parasite, in the sense that parasites typically evade host defences and successfully parasitize the nest. Nevertheless hosts may win when the co-evolutionary trajectory follows arms race a, c or d. Next, we show that there are four common outcomes of the co-evolutionary arms race for hosts. These are: (1) successful resistance; (2) the evolution of defence portfolios (or multiple lines of resistance); (3) acceptance of the parasite; and (4) tolerance of the parasite. The particular outcome is not determined by the type of preceding

  11. A preliminary investigation of the mechanism of anti-pain and counter-injury effects of the acupuncture anaesthesia.

    Science.gov (United States)

    1976-01-01

    In accordance with dialectical materialism and by dint of experimental acupuncture anaesthesia, the present investigation has: (1) Made an objective evaluation of the efficiency of acupuncture anaesthesia. (2) Brought forth some experimental evidence about the material basis of the anti-pain and counter-injury effect of acupuncture anaesthesia as well as the significance of its induction period. (3) Proposed the concept of humoral anaesthesia and its technique in order to improve the efficiency of animal laparotomies with acupuncture anaesthesia. Furthermore, it attempts to offer a theoretical explanation of the process of acupuncture anaesthesia under the combination of Chinese and Western medical theories and thereby gives some support to the "meridian-cerebral cortex-viscera inter-correlation hypothesis."

  12. Seroprevalence rates of antibodies againstLeishmania infantum and other protozoan and rickettsial parasites in dogs

    Directory of Open Access Journals (Sweden)

    Silvana de Cássia Paulan

    Full Text Available Canine visceral leishmaniasis (CVL is caused by the protozoan Leishmania infantum, which infects dogs and humans in many regions of Brazil. The present study involved an indirect fluorescent antibody test (IFAT to analyze L. infantum,Ehrlichia spp., Babesia canis,Toxoplasma gondii and Neospora caninuminfection rates in serum samples from 93 dogs in a rural settlement in Ilha Solteira, SP, Brazil. The seroprevalence rates of anti-L. infantum, anti-Ehrlichia, anti-B. canis, anti-T. gondii and anti-N. caninum antibodies were 37.6%, 75.3%, 72%, 47.3% and 6.4%, respectively. In addition to IFAT, direct microscopic examination of popliteal lymph node aspirates revealed 26.9% of CVL positive dogs. Serological tests revealed that 17.2% of the dogs were seropositive for a single parasite, 29% for two parasites, 33% for three, 16.1% for four, and 1.1% for five parasites, while 3.2% were seronegative for five parasites. The presence of antibodies against these parasites in serum samples from dogs confirmed their exposure to these parasites in this rural area. Because of the potential zoonotic risk of these diseases, mainly leishmaniasis, ehrlichiosis and toxoplasmosis, special attention should focus on programs for the improvement of diagnostic assays and control measures against these parasites.

  13. Delivery of TLR7 agonist to monocytes and dendritic cells by DCIR targeted liposomes induces robust production of anti-cancer cytokines

    DEFF Research Database (Denmark)

    Klauber, Thomas Christopher Bogh; Laursen, Janne Marie; Zucker, Daniel

    2017-01-01

    Tumor immune escape is today recognized as an important cancer hallmark and is therefore a major focus area in cancer therapy. Monocytes and dendritic cells (DCs), which are central to creating a robust anti-tumor immune response and establishing an anti-tumorigenic microenvironment, are directly...... targeted by the tumor escape mechanisms to develop immunosuppressive phenotypes. Providing activated monocytes and DCs to the tumor tissue is therefore an attractive way to break the tumor-derived immune suppression and reinstate cancer immune surveillance. To activate monocytes and DCs with high...... as their immune activating potential in blood-derived monocytes, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs). Monocytes and mDCs were targeted with high specificity over lymphocytes, and exhibited potent TLR7-specific secretion of the anti-cancer cytokines IL-12p70, IFN-α 2a, and IFN-γ. This delivery system...

  14. [Research progress on cathepsin F of parasitic helminths].

    Science.gov (United States)

    Qu, Zi-Gang; Fu, Bao-Quan

    2013-10-01

    Cathepsin F is an important member of papain-like subfamily in cysteine protease family. Cathepsin F of helminth parasites can hydrolyze the specific substrate, degrade host protein such as hemoglobin for nutrition, and be involved in invasion into host tissue. Therefore, cathepsin F serves as a potential target for parasitic disease immunodiagnosis, vaccine design and anti-parasite drug screening. This article reviews the structural characteristics and mechanisms of cathepsin F, and research advances on cathepsin F of parasitic helminths.

  15. Regulatory responses to over-the-counter codeine analgesic misuse in Australia, New Zealand and the United Kingdom.

    Science.gov (United States)

    Tobin, Claire L; Dobbin, Malcolm; McAvoy, Brian

    2013-10-01

    Analysis of the policy response by Australia's National Drugs and Poisons Schedule Committee (NDPSC) and comparison with recommendations by expert advisory committees in New Zealand and the United Kingdom. Analysis of public policy documents of relevant regulatory authorities was conducted. Data were extracted regarding changes to over-the-counter (OTC) codeine analgesic scheduling, indications, maximum unit dose, maximum daily dose, maximum pack size, warning labels, consumer medicine information and advertising. Where available, public submissions and other issues considered by the committees and rationale for their recommendations were recorded and thematically analysed. Expert advisory committees in Australia, NZ and the UK defined the policy problem of OTC codeine misuse and harm as small relative to total use and responded by restricting availability. Pharmacist supervision was required at the point-of-sale and pack sizes were reduced to short-term use. Comparison with recommendations by expert advisory committees in NZ and the UK suggests the NDPSC's actions in response to OTC codeine misuse were appropriate given the available evidence of misuse and harm, but highlights opportunities to utilise additional regulatory levers. Framing policy problems as matters of public health in the context of limited evidence may support decision makers to implement cautionary incremental policy change. © 2013 The Authors. ANZJPH © 2013 Public Health Association of Australia.

  16. The self-antigen, thyroglobulin, induces antigen-experienced CD4+ T cells from healthy donors to proliferate and promote production of the regulatory cytokine, interleukin-10, by monocytes

    DEFF Research Database (Denmark)

    Nielsen, Claus H; Galdiers, Marcel P; Hedegaard, Chris J

    2010-01-01

    . Whereas TT induced pro-inflammatory cytokines [interleukin-2 (IL-2)/interferon-gamma (IFN-gamma)/IL-4/IL-5], TG evoked persistent release of the regulatory IL-10. Some donors, however, also responded with late IFN-gamma production, suggesting that the regulation by IL-10 could be overridden. Although...

  17. Plasmodium falciparum in vitro continuous culture conditions: A comparison of parasite susceptibility and tolerance to anti-malarial drugs throughout the asexual intra-erythrocytic life cycle.

    Science.gov (United States)

    Duffy, Sandra; Avery, Vicky M

    2017-12-01

    The continuous culture of Plasmodium falciparum is often seen as a means to an end, that end being to probe the biology of the parasite in question, and ultimately for many in the malaria drug discovery arena, to identify means of killing the parasite in order to treat malaria. In vitro continuous culture of Plasmodium falciparum is a fundamental requirement when undertaking malaria research where the primary objectives utilise viable parasites of a desired lifecycle stage. This investigation, and resulting data, compared the impact culturing Plasmodium falciparum long term (4 months) in different environmental conditions had on experimental outcomes and thus conclusions. The example presented here focused specifically on the effect culture conditions had on the in vitro tolerance of Plasmodium falciparum to standard anti-malarial drugs, including artemisinin and lumefantrine. Historical data from an independent experiment for 3D7-ALB (5% O 2 ) was also compared with that obtained from this study. We concluded that parasites cultured for several months in media supplemented with a serum substitute such as Albumax II ® or within hyperoxic conditions (21% O 2 ), demonstrate highly variable responses to artemisinin and lumefantrine but not all anti-malarial drugs, when compared to those cultured in human serum in combination with Albumax II ® under normoxic conditions (5% O 2 ) for the parasite. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Paradigms for parasite conservation.

    Science.gov (United States)

    Dougherty, Eric R; Carlson, Colin J; Bueno, Veronica M; Burgio, Kevin R; Cizauskas, Carrie A; Clements, Christopher F; Seidel, Dana P; Harris, Nyeema C

    2016-08-01

    Parasitic species, which depend directly on host species for their survival, represent a major regulatory force in ecosystems and a significant component of Earth's biodiversity. Yet the negative impacts of parasites observed at the host level have motivated a conservation paradigm of eradication, moving us farther from attainment of taxonomically unbiased conservation goals. Despite a growing body of literature highlighting the importance of parasite-inclusive conservation, most parasite species remain understudied, underfunded, and underappreciated. We argue the protection of parasitic biodiversity requires a paradigm shift in the perception and valuation of their role as consumer species, similar to that of apex predators in the mid-20th century. Beyond recognizing parasites as vital trophic regulators, existing tools available to conservation practitioners should explicitly account for the unique threats facing dependent species. We built upon concepts from epidemiology and economics (e.g., host-density threshold and cost-benefit analysis) to devise novel metrics of margin of error and minimum investment for parasite conservation. We define margin of error as the risk of accidental host extinction from misestimating equilibrium population sizes and predicted oscillations, while minimum investment represents the cost associated with conserving the additional hosts required to maintain viable parasite populations. This framework will aid in the identification of readily conserved parasites that present minimal health risks. To establish parasite conservation, we propose an extension of population viability analysis for host-parasite assemblages to assess extinction risk. In the direst cases, ex situ breeding programs for parasites should be evaluated to maximize success without undermining host protection. Though parasitic species pose a considerable conservation challenge, adaptations to conservation tools will help protect parasite biodiversity in the face of

  19. Countering Craving with Disgust Images: Examining Nicotine Withdrawn Smokers' Motivated Message Processing of Anti-Tobacco Public Service Announcements.

    Science.gov (United States)

    Clayton, Russell B; Leshner, Glenn; Tomko, Rachel L; Trull, Timothy J; Piasecki, Thomas M

    2017-03-01

    There is a lack of research examining whether smoking cues in anti-tobacco advertisements elicit cravings, or whether this effect is moderated by countervailing message attributes, such as disgusting images. Furthermore, no research has examined how these types of messages influence nicotine withdrawn smokers' cognitive processing and associated behavioral intentions. At a laboratory session, participants (N = 50 nicotine-deprived adults) were tested for cognitive processing and recognition memory of 12 anti-tobacco advertisements varying in depictions of smoking cues and disgust content. Self-report smoking urges and intentions to quit smoking were measured after each message. The results from this experiment indicated that smoking cue messages activated appetitive/approach motivation resulting in enhanced attention and memory, but increased craving and reduced quit intentions. Disgust messages also enhanced attention and memory, but activated aversive/avoid motivation resulting in reduced craving and increased quit intentions. The combination of smoking cues and disgust content resulted in moderate amounts of craving and quit intentions, but also led to heart rate acceleration (indicating defensive processing) and poorer recognition of message content. These data suggest that in order to counter nicotine-deprived smokers' craving and prolong abstinence, anti-tobacco messages should omit smoking cues but include disgust. Theoretical implications are also discussed.

  20. Malaria: toxins, cytokines and disease

    DEFF Research Database (Denmark)

    Jakobsen, P H; Bate, C A; Taverne, J

    1995-01-01

    In this review the old concept of severe malaria as a toxic disease is re-examined in the light of recent discoveries in the field of cytokines. Animal studies suggest that the induction of TNF by parasite-derived molecules may be partly responsible for cerebral malaria and anemia, while...... hypoglycaemia may be due to direct effects of similar molecules on glucose metabolism. These molecules appear to be phospholipids and we suggest that when fully characterized they might form the basis of antitoxic therapy for malaria....

  1. Assessing the usefulness of mineral licks containing herbal extracts with anti-parasitic properties for the control of gastrointestinal helminths in grazing sheep – a field trial

    Directory of Open Access Journals (Sweden)

    Nosal P.

    2016-06-01

    Full Text Available One of the alternative methods of parasite control, of particular importance in sustainable farming, is the use of medicinal plants. The specific aim of the present field trial was to assess the anti-parasitic effects of herbal extracts contained in a commercially available lick formulation for sheep. At the outset of this study conducted during the grazing season, all animals were de-wormed and then randomly assigned to one of the two separately kept groups (treatment and control, each consisting of 25 animals (11 ewes and 14 lambs. The treatment group received mineral licks containing the extracts of the plants with anti-parasitic properties, while control animals received standard mineral licks ad libitum. Rectal fecal samples were collected monthly from all animals for the McMaster analyses. There were no significant differences in the prevalence and intensity of helminth infections between the treatment and control groups. Thus, we were not able to ascertain the efficacy of the commercial herbal de-wormer tested for the control of gastrointestinal helminths in grazing ewes and their lambs.

  2. Parasitic crossing at an asymmetric B factory, APIARY

    International Nuclear Information System (INIS)

    Chin, Y.H.

    1991-05-01

    Effects of parasitic crossings (''near miss'' collisions of two counter-rotating beams at unwanted positions near the IP) are studied in terms of computer simulations for an asymmetric B Factory, APIARY- 6.3d. Beams are separated horizontally at the first parasitic crossing points by about 7.6 times the horizontal rms size of the low energy beam (the larger in size of the two beams), σ 0x,+ . Simulations, including both the beam collision at the IP and parasitic crossings, have been performed for different separation distances, d. It is found that the ratio d/σ 0x,+ is a good scaling parameter of beam blowup behavior. The results show that beam blowup due to the parasitic crossings is diminished for d ≥ 7σ 0x,+ , in agreement with the bunch separation experiment at CESR. Thus, the nominal separation 7.6 σ 0x,+ turns out to be acceptable, but with only a small margin. Some methods to mitigate the effects of the parasitic crossings are discussed. 3 refs. , 5 figs., 2 tabs

  3. Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors

    Directory of Open Access Journals (Sweden)

    Nir Qvit

    2016-04-01

    Full Text Available Parasitic diseases cause ∼500,000 deaths annually and remain a major challenge for therapeutic development. Using a rational design based approach, we developed peptide inhibitors with anti-parasitic activity that were derived from the sequences of parasite scaffold proteins LACK (Leishmania's receptor for activated C-kinase and TRACK (Trypanosoma receptor for activated C-kinase. We hypothesized that sequences in LACK and TRACK that are conserved in the parasites, but not in the mammalian ortholog, RACK (Receptor for activated C-kinase, may be interaction sites for signaling proteins that are critical for the parasites' viability. One of these peptides exhibited leishmanicidal and trypanocidal activity in culture. Moreover, in infected mice, this peptide was also effective in reducing parasitemia and increasing survival without toxic effects. The identified peptide is a promising new anti-parasitic drug lead, as its unique features may limit toxicity and drug-resistance, thus overcoming central limitations of most anti-parasitic drugs. Keywords: Chagas disease, Leishmaniasis, Peptide, LACK, TRACK, Scaffold protein

  4. Neuro-immune interactions via the cholinergic anti-inflammatory pathway

    Science.gov (United States)

    Gallowitsch-Puerta, Margot; Pavlov, Valentin A.

    2010-01-01

    The overproduction of TNF and other cytokines can cause the pathophysiology of numerous diseases. Controlling cytokine synthesis and release is critical for preventing unrestrained inflammation and maintaining health. Recent studies identified an efferent vagus nerve-based mechanism termed “the cholinergic anti-inflammatory pathway” that controls cytokine production and inflammation. Here we review current advances related to the role of this pathway in neuro-immune interactions that prevent excessive inflammation. Experimental evidence indicates that vagus nerve cholinergic anti-inflammatory signaling requires alpha7 nicotinic acetylcholine receptors expressed on non-neuronal cytokine producing cells. Alpha7 nicotinic acetylcholine receptor agonists inhibit cytokine release and protect animals in a variety of experimental lethal inflammatory models. Knowledge related to the cholinergic anti-inflammatory pathway can be exploited in therapeutic approaches directed towards counteracting abnormal chronic and hyper-activated inflammatory responses. PMID:17289087

  5. The changing face of cytokines in the brain: perspectives from EAE

    DEFF Research Database (Denmark)

    Wheeler, R D; Owens, T

    2005-01-01

    There has been a significant increase in the number of cytokines known to exist, over the past few years. This has led to a re-examination of the established roles of cytokines, as the functions of newly identified members are characterized. In this review, we describe how the recent discovery...... effector cell, and may even have a regulatory function. The impact of this on current understanding of cytokine networks underlying CNS inflammation in EAE is discussed....

  6. Host exploitation strategies of the social parasite Maculinea alcon

    DEFF Research Database (Denmark)

    Fürst, Matthias Alois

    as model systems. These enable the study of adaptations and counter-adaptations that might evolve in the arms-race between a parasite pursuing maximum gain and a host trying to avoid exploitation. One such system is the socially parasitic butterfly Maculinea alcon and its host the ant Myrmica rubra....... Throughout the first instars M. alcon lives on a specific food plant, however, in the last instar before pupation it develops into an obligate social parasite, posing a considerably cost to its host ant colony. I here focus on the different exploitation strategies of M. alcon throughout its lifecycle...... a fitness cost to infected host ant colonies, the host ants are expected to have developed defense mechanisms in response to the presence of the social parasite. I was able to demonstrate that the efficiency of ant colonies to defend themselves against intruders depends on a multitude of often correlated...

  7. In vitro studies on the relationship between the anti-inflammatory activity of Physalis peruviana extracts and the phagocytic process.

    Science.gov (United States)

    Martínez, Willington; Ospina, Luis Fernando; Granados, Diana; Delgado, Gabriela

    2010-03-01

    The study of plants used in traditional medicine has drawn the attention of researchers as an alternative in the development of new therapeutics agents, such as the American Solanaceae Physalis peruviana, which has significant anti-inflammatory activity. The Physalis peruviana anti-inflammatory effect of ethanol or ether calyces extracts on the phagocytic process was assessed by using an in vitro phagocytosis model (Leishmania panamensis infection to murine macrophages). The Physalis peruviana extracts do not inhibit microorganism internalization and have no parasiticide effect. Most ET and EP extracts negatively affected the parasite's invasion of macrophages (Infected cells increased.). This observation might result from a down-regulation of the macrophage's microbicide ability associated with a selective reduction of proinflammatory cytokines levels. Physalis peruviana's anti-inflammatory activity described in this model is related to an immunomodulatory effect exerted on macrophages infected, which directly or indirectly "blocks" their ability to secrete soluble proinflammatory mediators.

  8. Cytokine gene expression and pathology in mice experimentally infected with different isolates of Trypanosoma evansi.

    Science.gov (United States)

    Krishnamoorthy, P; Sengupta, P P; Das, Sangita; Ligi, M; Shome, B R; Rahman, H

    2016-11-01

    Aim of the present study was to assess the cytokine gene expression in liver, kidney and spleen and histopathological changes in mice infected with buffalo and dog isolates of Trypanosoma evansi. Forty-four Swiss albino mice was divided into eleven groups of four mice each and injected subcutaneously with 1 × 10 5 trypanosomes of buffalo and dog isolate to twenty mice each, four mice served as control. Mice were examined for clinical signs, blood smear for trypanosome counts. Blood for PCR, liver, kidney, spleen, heart, lung, testis and abdominal muscle for histopathology and liver, kidney, spleen for cytokine gene expression studies, were collected. Mice showed dullness, lethargy, hunched back, sluggish movements on D4 and D5 in buffalo and dog isolate, respectively. Parasite count in blood varied between the two isolates of T. evansi. By PCR, trypanosome DNA was detected on D1 and D2 for buffalo and dog isolate, respectively. Splenomegaly was observed in mice infected with buffalo isolate but not with dog isolate. Histopathological changes were observed in liver, kidney, spleen and heart of mice but no changes in testis and abdominal muscles. Blood vessels of liver, heart, lung showed presence of trypanosomes in mice infected with buffalo isolate but not for dog isolate. Cytokine gene expression of IL-2, IL-4, IL-6, IL-12, TNF-α and IFN-γ increased in liver, kidney and spleen in both these isolates. However, the buffalo isolate exhibited pronounced increase in cytokine gene expression when compare to dog isolate of T. evansi. Anti-inflammatory cytokine gene IL-10 showed 50-60 and 10-20 folds increment in buffalo and dog isolates, respectively. This is the first report of IL-4, IL-6, IL-10 and IL-12 cytokine changes in mice infected with T. evansi. A variation in pathogenicity between buffalo and dog isolates was recorded indicating buffalo isolate of T. evansi remained more pathogenic in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Identification of a secreted casein kinase 1 in Leishmania donovani: effect of protein over expression on parasite growth and virulence.

    Directory of Open Access Journals (Sweden)

    Mary Dan-Goor

    Full Text Available Casein kinase 1 (CK1 plays an important role in eukaryotic signaling pathways, and their substrates include key regulatory proteins involved in cell differentiation, proliferation and chromosome segregation. The Leishmania genome encodes six potential CK1 isoforms, of which five have orthologs in other trypanosomatidae. Leishmania donovani CK1 isoform 4 (Ldck1.4, orthologous to LmjF27.1780 is unique to Leishmania and contains a putative secretion signal peptide. The full-length gene and three shorter constructs were cloned and expressed in E. coli as His-tag proteins. Only the full-length 62.3 kDa protein showed protein kinase activity indicating that the N-terminal and C-terminal domains are essential for protein activity. LdCK1.4-FLAG was stably over expressed in L. donovani, and shown by immunofluorescence to be localized primarily in the cytosol. Western blotting using anti-FLAG and anti-CK1.4 antibodies showed that this CK1 isoform is expressed and secreted by promastigotes. Over expression of LdCK1.4 had a significant effect on promastigote growth in culture with these parasites growing to higher cell densities than the control parasites (wild-type or Ld:luciferase, P<0.001. Analysis by flow cytometry showed a higher percentage, ∼4-5-fold, of virulent metacyclic promastigotes on day 3 among the LdCK1.4 parasites. Finally, parasites over expressing LdCK1.4 gave significantly higher infections of mouse peritoneal macrophages compared to wild-type parasites, 28.6% versus 6.3%, respectively (p = 0.0005. These results suggest that LdCK1.4 plays an important role in parasite survival and virulence. Further studies are needed to validate CK1.4 as a therapeutic target in Leishmania.

  10. Anti-CD20 B-cell depletion enhances monocyte reactivity in neuroimmunological disorders

    Directory of Open Access Journals (Sweden)

    Hohlfeld Reinhard

    2011-10-01

    Full Text Available Abstract Background Clinical trials evaluating anti-CD20-mediated B-cell depletion in multiple sclerosis (MS and neuromyelitis optica (NMO generated encouraging results. Our recent studies in the MS model experimental autoimmune encephalomyelitis (EAE attributed clinical benefit to extinction of activated B-cells, but cautioned that depletion of naïve B-cells may be undesirable. We elucidated the regulatory role of un-activated B-cells in EAE and investigated whether anti-CD20 may collaterally diminish regulatory B-cell properties in treatment of neuroimmunological disorders. Methods Myelin oligodendrocyte glycoprotein (MOG peptide-immunized C57Bl/6 mice were depleted of B-cells. Functional consequences for regulatory T-cells (Treg and cytokine production of CD11b+ antigen presenting cells (APC were assessed. Peripheral blood mononuclear cells from 22 patients receiving anti-CD20 and 23 untreated neuroimmunological patients were evaluated for frequencies of B-cells, T-cells and monocytes; monocytic reactivity was determined by TNF-production and expression of signalling lymphocytic activation molecule (SLAM. Results We observed that EAE-exacerbation upon depletion of un-activated B-cells closely correlated with an enhanced production of pro-inflammatory TNF by CD11b+ APC. Paralleling this pre-clinical finding, anti-CD20 treatment of human neuroimmunological disorders increased the relative frequency of monocytes and accentuated pro-inflammatory monocyte function; when reactivated ex vivo, a higher frequency of monocytes from B-cell depleted patients produced TNF and expressed the activation marker SLAM. Conclusions These data suggest that in neuroimmunological disorders, pro-inflammatory APC activity is controlled by a subset of B-cells which is eliminated concomitantly upon anti-CD20 treatment. While this observation does not conflict with the general concept of B-cell depletion in human autoimmunity, it implies that its safety and

  11. Regulation of cytokines by small RNAs during skin inflammation

    Directory of Open Access Journals (Sweden)

    Mikkelsen Jacob G

    2010-07-01

    Full Text Available Abstract Intercellular signaling by cytokines is a vital feature of the innate immune system. In skin, an inflammatory response is mediated by cytokines and an entwined network of cellular communication between T-cells and epidermal keratinocytes. Dysregulated cytokine production, orchestrated by activated T-cells homing to the skin, is believed to be the main cause of psoriasis, a common inflammatory skin disorder. Cytokines are heavily regulated at the transcriptional level, but emerging evidence suggests that regulatory mechanisms that operate after transcription play a key role in balancing the production of cytokines. Herein, we review the nature of cytokine signaling in psoriasis with particular emphasis on regulation by mRNA destabilizing elements and the potential targeting of cytokine-encoding mRNAs by miRNAs. The proposed linkage between mRNA decay mediated by AU-rich elements and miRNA association is described and discussed as a possible general feature of cytokine regulation in skin. Moreover, we describe the latest attempts to therapeutically target cytokines at the RNA level in psoriasis by exploiting the cellular RNA interference machinery. The applicability of cytokine-encoding mRNAs as future clinical drug targets is evaluated, and advances and obstacles related to topical administration of RNA-based drugs targeting the cytokine circuit in psoriasis are described.

  12. Regulation of human cytokines by Cordyceps militaris

    Directory of Open Access Journals (Sweden)

    Yong Sun

    2014-12-01

    Full Text Available Cordyceps (Cordyceps militaris exhibits many biological activities including antioxidant, inhibition of inflammation, cancer prevention, hypoglycemic, and antiaging properties, etc. However, a majority of studies involving C. militaris have focused only on in vitro and animal models, and there is a lack of direct translation and application of study results to clinical practice (e.g., health benefits. In this study, we investigated the regulatory effects of C. militaris micron powder (3 doses on the human immune system. The study results showed that administration of C. militaris at various dosages reduced the activity of cytokines such as eotaxin, fibroblast growth factor-2, GRO, and monocyte chemoattractant protein-1. In addition, there was a significant decrease in the activity of various cytokines, including GRO, sCD40L, and tumor necrosis factor-α, and a significant downregulation of interleukin-12(p70, interferon-γ inducible protein 10, and macrophage inflammatory protein-1β activities, indicating that C. militaris at all three dosages downregulated the activity of cytokines, especially inflammatory cytokines and chemokines. Different dosages of C. militaris produced different changes in cytokines.

  13. Cytokine-mediated inflammation mediates painful neuropathy from metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Can Zhang

    Full Text Available Painful neuropathy (PN is a prevalent condition in patients with metabolic syndrome (MetS. However, the pathogenic mechanisms of metabolic syndrome-associated painful neuropathy (MetSPN remain unclear. In the current study, high-fat-fed mice (HF mice were used to study MetSPN. HF mice developed MetS phenotypes, including increased body weight, elevated plasma cholesterol levels, and insulin resistance in comparison with control-fat-fed (CF mice. Subsequently, HF mice developed mechanical allodynia and thermal hyperalgesia in hind paws after 8 wk of diet treatment. These pain behaviors coincided with increased densities of nociceptive epidermal nerve fibers and inflammatory cells such as Langerhans cells and macrophages in hind paw skin. To study the effect of MetS on profiles of cytokine expression in HF mice, we used a multiplex cytokine assay to study the protein expression of 12 pro-inflammatory and anti-inflammatory cytokines in dorsal root ganglion and serum samples. This method detected the elevated levels of proinflammatory cytokines, including tumor necrosis factor (TNF-α, and interleukin (IL-6, IL-1β as well as reduced anti-inflammatory IL-10 in lumbar dorsal root ganglia (LDRG of HF mice. Intraperitoneal administration of IL-10 reduced the upregulation of pro-inflammatory cytokines and alleviated pain behaviors in HF mice without affecting MetS phenotypes. Our findings suggested targeting HF-induced cytokine dysregulation could be an effective strategy for treating MetSPN.

  14. Modulation of cytokine expression in human macrophages by endocrine-disrupting chemical Bisphenol-A

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yanzhen; Mei, Chenfang [State Key Laboratory of Applied Microbiology Southern China, Guangzhou 510070 (China); Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou 510070 (China); Liu, Hao [Affiliated Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou 510095 (China); Wang, Hongsheng [Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006 (China); Zeng, Guoqu; Lin, Jianhui [State Key Laboratory of Applied Microbiology Southern China, Guangzhou 510070 (China); Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou 510070 (China); Xu, Meiying, E-mail: xumy@gdim.cn [State Key Laboratory of Applied Microbiology Southern China, Guangzhou 510070 (China); Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou 510070 (China)

    2014-09-05

    Highlights: • Effects of BPA on the cytokines expression of human macrophages were investigated. • BPA increased pro-inflammation cytokines TNF-α and IL-6 production. • BPA decreased anti-inflammation IL-10 and TGF-β production. • ERα/β/ERK/NF-κB signaling involved in BPA-mediated cytokines expression. - Abstract: Exposure to environmental endocrine-disrupting chemical Bisphenol-A (BPA) is often associated with dysregulated immune homeostasis, but the mechanisms remain unclear. In the present study, the effects of BPA on the cytokines responses of human macrophages were investigated. Treatment with BPA increased pro-inflammation cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production, but decreased anti-inflammation cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) production in THP1 macrophages, as well as in primary human macrophages. BPA effected cytokines expression through estrogen receptor α/β (ERα/β)-dependent mechanism with the evidence of ERα/β antagonist reversed the expression of cytokines. We also identified that activation of extracellular regulated protein kinases (ERK)/nuclear factor κB (NF-κB) signal cascade marked the effects of BPA on cytokines expression. Our results indicated that BPA effected inflammatory responses of macrophages via modulating of cytokines expression, and provided a new insight into the link between exposure to BPA and human health.

  15. Modulation of cytokine expression in human macrophages by endocrine-disrupting chemical Bisphenol-A

    International Nuclear Information System (INIS)

    Liu, Yanzhen; Mei, Chenfang; Liu, Hao; Wang, Hongsheng; Zeng, Guoqu; Lin, Jianhui; Xu, Meiying

    2014-01-01

    Highlights: • Effects of BPA on the cytokines expression of human macrophages were investigated. • BPA increased pro-inflammation cytokines TNF-α and IL-6 production. • BPA decreased anti-inflammation IL-10 and TGF-β production. • ERα/β/ERK/NF-κB signaling involved in BPA-mediated cytokines expression. - Abstract: Exposure to environmental endocrine-disrupting chemical Bisphenol-A (BPA) is often associated with dysregulated immune homeostasis, but the mechanisms remain unclear. In the present study, the effects of BPA on the cytokines responses of human macrophages were investigated. Treatment with BPA increased pro-inflammation cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production, but decreased anti-inflammation cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) production in THP1 macrophages, as well as in primary human macrophages. BPA effected cytokines expression through estrogen receptor α/β (ERα/β)-dependent mechanism with the evidence of ERα/β antagonist reversed the expression of cytokines. We also identified that activation of extracellular regulated protein kinases (ERK)/nuclear factor κB (NF-κB) signal cascade marked the effects of BPA on cytokines expression. Our results indicated that BPA effected inflammatory responses of macrophages via modulating of cytokines expression, and provided a new insight into the link between exposure to BPA and human health

  16. Regulatory effect of gamma-chain cytokines on expression of TIM-3 on CD8+ T cells in patients with chronic hepatitis B

    Directory of Open Access Journals (Sweden)

    DONG Jie

    2015-02-01

    Full Text Available ObjectiveTo measure the expression of T-cell immunoglobulin- and mucin domain-3-containing molecule 3 (TIM-3 on CD8+ T cells in peripheral blood mononuclear cells (PBMCs among patients with chronic hepatitis B (CHB and to investigate the effect of common gamma-chain cytokines on the expression of TIM-3 on CD8+ T cells in these patients. MethodsFifteen previously untreated patients with CHB who visited the Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, from January to May, 2014, as well as 8 healthy controls, were included in the study. Blood was collected from these subjects, and PBMCs were isolated from blood by Ficoll density gradient centrifugation. PBMCs were separately stimulated with gamma-chain cytokines, interleukin (IL2, IL-7, IL-15, and IL-21, and anti-CD3/CD28, and the untreated cells were used as a negative control. After four days of culture, PBMCs were stained with monoclonal antibody. Flow cytometry was used to measure the expression of TIM-3 on CD8+ T cells. Comparison of continuous data was made by independent-samples t test. ResultsCompared with the untreated group, the anti-CD3/CD28, IL-2, IL-15, and IL-7 groups had significantly increased expression of TIM-3 on CD8+ T cells (9.629%±9.916%, P=0000 1; 3.817%±2.694%, P = 0.000 6; 5.772%±4.732%, P = 0.005 4; 3.560%±2.045%, P = 0.030 2, while the IL-21 group had nonsignificantly increased expression of TIM-3 on CD8+ T cells (2.503%±2.117%, P = 0.934 1. ConclusionAnti-CD3/CD28 and gamma-chain cytokines IL-2, IL-7, and IL-15 can effectively upregulate the expression of TIM-3 on CD8+ T cells in patients with CHB. It indicates that the inhibition of them can not only reduce the expression of TIM-3, but also may enhance the killing function of CD8+ T cells in patients with CHB.

  17. Short-term heating reduces the anti-inflammatory effects of fresh raw garlic extracts on the LPS-induced production of NO and pro-inflammatory cytokines by downregulating allicin activity in RAW 264.7 macrophages.

    Science.gov (United States)

    Shin, Jung-Hye; Ryu, Ji Hyeon; Kang, Min Jung; Hwang, Cho Rong; Han, Jaehee; Kang, Dawon

    2013-08-01

    Garlic has a variety of biologic activities, including anti-inflammatory properties. Although garlic has several biologic activities, some people dislike eating fresh raw garlic because of its strong taste and smell. Therefore, garlic formulations involving heating procedures have been developed. In this study, we investigated whether short-term heating affects the anti-inflammatory properties of garlic. Fresh and heated raw garlic extracts (FRGE and HRGE) were prepared with incubation at 25 °C and 95 °C, respectively, for 2 h. Treatment with FRGE and HRGE significantly reduced the LPS-induced increase in the pro-inflammatory cytokine concentration (TNF-α, IL-1β, and IL-6) and NO through HO-1 upregulation in RAW 264.7 macrophages. The anti-inflammatory effect was greater in FRGE than in HRGE. The allicin concentration was higher in FRGE than in HRGE. Allicin treatment showed reduced production of pro-inflammatory cytokines and NO and increased HO-1 activity. The results show that the decrease in LPS-induced NO and pro-inflammatory cytokines in RAW 264.7 macrophages through HO-1 induction was greater for FRGE compared with HRGE. Additionally, the results indicate that allicin is responsible for the anti-inflammatory effect of FRGE. Our results suggest a potential therapeutic use of allicin in the treatment of chronic inflammatory disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Peripheral blood mononuclear cells of patients with latent autoimmune diabetes secrete higher levels of pro- & anti-inflammatory cytokines compared to those with type-1 diabetes mellitus following in vitro stimulation with β-cell autoantigens

    Directory of Open Access Journals (Sweden)

    Darshan Badal

    2017-01-01

    Interpretation & conclusions: There are differences in the portfolio of cytokine secretion in diabetic subjects with varying rates of β-cell destruction as LADA subjects secrete higher levels of both pro- and anti-inflammatory cytokines on exposure to β-cell autoantigens, thus highlighting another distinguishing feature in the pathophysiology of the two forms of autoimmune diabetes.

  19. Regulatory T cells as suppressors of anti-tumor immunity: Role of metabolism.

    Science.gov (United States)

    De Rosa, Veronica; Di Rella, Francesca; Di Giacomo, Antonio; Matarese, Giuseppe

    2017-06-01

    Novel concepts in immunometabolism support the hypothesis that glucose consumption is also used to modulate anti-tumor immune responses, favoring growth and expansion of specific cellular subsets defined in the past as suppressor T cells and currently reborn as regulatory T (Treg) cells. During the 1920s, Otto Warburg and colleagues observed that tumors consumed high amounts of glucose compared to normal tissues, even in the presence of oxygen and completely functioning mitochondria. However, the role of the Warburg Effect is still not completely understood, particularly in the context of an ongoing anti-tumor immune response. Current experimental evidence suggests that tumor-derived metabolic restrictions can drive T cell hyporesponsiveness and immune tolerance. For example, several glycolytic enzymes, deregulated in cancer, contribute to tumor progression independently from their canonical metabolic activity. Indeed, they can control apoptosis, gene expression and activation of specific intracellular pathways, thus suggesting a direct link between metabolic switches and pro-tumorigenic transcriptional programs. Focus of this review is to define the specific metabolic pathways controlling Treg cell immunobiology in the context of anti-tumor immunity and tumor progression. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Integrative biology approach identifies cytokine targeting strategies for psoriasis.

    Science.gov (United States)

    Perera, Gayathri K; Ainali, Chrysanthi; Semenova, Ekaterina; Hundhausen, Christian; Barinaga, Guillermo; Kassen, Deepika; Williams, Andrew E; Mirza, Muddassar M; Balazs, Mercedesz; Wang, Xiaoting; Rodriguez, Robert Sanchez; Alendar, Andrej; Barker, Jonathan; Tsoka, Sophia; Ouyang, Wenjun; Nestle, Frank O

    2014-02-12

    Cytokines are critical checkpoints of inflammation. The treatment of human autoimmune disease has been revolutionized by targeting inflammatory cytokines as key drivers of disease pathogenesis. Despite this, there exist numerous pitfalls when translating preclinical data into the clinic. We developed an integrative biology approach combining human disease transcriptome data sets with clinically relevant in vivo models in an attempt to bridge this translational gap. We chose interleukin-22 (IL-22) as a model cytokine because of its potentially important proinflammatory role in epithelial tissues. Injection of IL-22 into normal human skin grafts produced marked inflammatory skin changes resembling human psoriasis. Injection of anti-IL-22 monoclonal antibody in a human xenotransplant model of psoriasis, developed specifically to test potential therapeutic candidates, efficiently blocked skin inflammation. Bioinformatic analysis integrating both the IL-22 and anti-IL-22 cytokine transcriptomes and mapping them onto a psoriasis disease gene coexpression network identified key cytokine-dependent hub genes. Using knockout mice and small-molecule blockade, we show that one of these hub genes, the so far unexplored serine/threonine kinase PIM1, is a critical checkpoint for human skin inflammation and potential future therapeutic target in psoriasis. Using in silico integration of human data sets and biological models, we were able to identify a new target in the treatment of psoriasis.

  1. Filarial lymphedema is characterized by antigen-specific Th1 and th17 proinflammatory responses and a lack of regulatory T cells.

    Directory of Open Access Journals (Sweden)

    Subash Babu

    Full Text Available Lymphatic filariasis can be associated with development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients.To elucidate the role of CD4(+ T cell subsets in the development of lymphatic pathology, we examined specific sets of cytokines in individuals with filarial lymphedema in response to parasite antigen (BmA and compared them with responses from asymptomatic infected individuals. We also examined expression patterns of Toll-like receptors (TLR1-10 and Nod-like receptors (Nod1, Nod2, and NALP3 in response to BmA. BmA induced significantly higher production of Th1-type cytokines-IFN-gamma and TNF-alpha-in patients with lymphedema compared with asymptomatic individuals. Notably, expression of the Th17 family of cytokines-IL-17A, IL-17F, IL-21, and IL-23-was also significantly upregulated by BmA stimulation in lymphedema patients. In contrast, expression of Foxp3, GITR, TGFbeta, and CTLA-4, known to be expressed by regulatory T cells, was significantly impaired in patients with lymphedema. BmA also induced significantly higher expression of TLR2, 4, 7, and 9 as well Nod1 and 2 mRNA in patients with lymphedema compared with asymptomatic controls.Our findings implicate increased Th1/Th17 responses and decreased regulatory T cells as well as regulation of Toll- and Nod-like receptors in pathogenesis of filarial lymphedema.

  2. INDICATORS OF CYTOKINE ACTIVITY AND BETA-ENDORPHIN PRODUCTION LEVEL IN ARTERIAL HYPERTENSION ASSOCIATED WITH ASTHENIC/NEUROTIC DISORDERS IN YOUNG MEN EMPLOYED IN STRESSFUL PROFESSIONS

    Directory of Open Access Journals (Sweden)

    A. V. Gertsev

    2017-01-01

    Full Text Available At the present time, arterial hypertension is the most common somatic pathology among young and able-bodied persons. Development and progression of hypertension in young people occupied with stressful jobs presents a particular problem. Anxiety and depression arise quite commonly in such persons subjected to chronic stress. Direct pathophysiological effects of anxiety and depressive disorders upon cardiovascular system leads to development of disturbances of basic regulatory processes and life-threatening clinical forms of ischemic heart disease and hypertension. However, despite sufficient data about the impact of anxiety and depressive disorders on the course of cardiac pathology, some open questions remain concerning the degree of changes in neuropeptide-cytokine pool of immune system in young, intensively working hypertensive patients.Moreover, there is lack of knowledge concerning interdependence in functioning of the major regulatory systems (autonomic nervous and immune in such patients.In this connection, the aim of this work was to study cytokines of the immune system, and the levels of betaendorphin production in hypertension, proceeding with astheno-neurotic disorders in young men of intensive specialties, as well as study of interactions between the indices of autonomic nervous system functioning, and immunity parameters in these patients. The following groups were under study: 1st (n = 34 included patients with hypertension and astheno-neurotic problems; 2nd (n = 20, patients with hypertension without psychological disorders, with acute or chronic stress in previous history (controls. Neuropeptide-cytokine profile of the immune system was evaluated by levels of proinflammatory cytokines (TNFα, IL-1β, IL-6, antiinflammatory cytokines (IL-4, IL-10, and β-endorphin.In the course of clinical and laboratory examination, we have found that, in the patients with hypertension and astheno-neurotic disorders, activation of proinflammatory

  3. Cytokine profile and lymphocyte subsets in type 2 diabetes

    Directory of Open Access Journals (Sweden)

    C.O. Francisco

    2016-01-01

    Full Text Available Type 2 diabetes mellitus (T2D is a metabolic disease with inflammation as an important pathogenic background. However, the pattern of immune cell subsets and the cytokine profile associated with development of T2D are unclear. The objective of this study was to evaluate different components of the immune system in T2D patients' peripheral blood by quantifying the frequency of lymphocyte subsets and intracellular pro- and anti-inflammatory cytokine production by T cells. Clinical data and blood samples were collected from 22 men (51.6±6.3 years old with T2D and 20 nonsmoking men (49.4±7.6 years old who were matched for age and sex as control subjects. Glycated hemoglobin, high-sensitivity C-reactive protein concentrations, and the lipid profile were measured by a commercially available automated system. Frequencies of lymphocyte subsets in peripheral blood and intracellular production of interleukin (IL-4, IL-10, IL-17, tumor necrosis factor-α, and interferon-γ cytokines by CD3+ T cells were assessed by flow cytometry. No differences were observed in the frequency of CD19+ B cells, CD3+CD8+ and CD3+CD4+ T cells, CD16+56+ NK cells, and CD4+CD25+Foxp3+ T regulatory cells in patients with T2D compared with controls. The numbers of IL-10- and IL-17-producing CD3+ T cells were significantly higher in patients with T2D than in controls (P<0.05. The frequency of interferon-γ-producing CD3+ T cells was positively correlated with body mass index (r=0.59; P=0.01. In conclusion, this study shows increased numbers of circulating IL-10- and IL-17-producing CD3+ T cells in patients with T2D, suggesting that these cytokines are involved in the immune pathology of this disease.

  4. 17DD and 17D-213/77 yellow fever substrains trigger a balanced cytokine profile in primary vaccinated children.

    Directory of Open Access Journals (Sweden)

    Ana Carolina Campi-Azevedo

    Full Text Available BACKGROUND: This study aimed to compare the cytokine-mediated immune response in children submitted to primary vaccination with the YF-17D-213/77 or YF-17DD yellow fever (YF substrains. METHODS: A non-probabilistic sample of eighty healthy primary vaccinated (PV children was selected on the basis of their previously known humoral immune response to the YF vaccines. The selected children were categorized according to their YF-neutralizing antibody titers (PRNT and referred to as seroconverters (PV-PRNT(+ or nonseroconverters (PV-PRNT(-. Following revaccination with the YF-17DD, the PV-PRNT(- children (YF-17D-213/77 and YF-17DD groups seroconverted and were referred as RV-PRNT(+. The cytokine-mediated immune response was investigated after short-term in vitro cultures of whole blood samples. The results are expressed as frequency of high cytokine producers, taking the global median of the cytokine index (YF-Ag/control as the cut-off. RESULTS: The YF-17D-213/77 and the YF-17DD substrains triggered a balanced overall inflammatory/regulatory cytokine pattern in PV-PRNT(+, with a slight predominance of IL-12 in YF-17DD vaccinees and a modest prevalence of IL-10 in YF-17D-213/77. Prominent frequency of neutrophil-derived TNF-α and neutrophils and monocyte-producing IL-12 were the major features of PV-PRNT(+ in the YF-17DD, whereas relevant inflammatory response, mediated by IL-12(+CD8(+ T cells, was the hallmark of the YF-17D-213/77 vaccinees. Both substrains were able to elicit particular but relevant inflammatory events, regardless of the anti-YF PRNT antibody levels. PV-PRNT(- children belonging to the YF-17DD arm presented gaps in the inflammatory cytokine signature, especially in terms of the innate immunity, whereas in the YF-17D-213/77 arm the most relevant gap was the deficiency of IL-12-producing CD8(+T cells. Revaccination with YF-17DD prompted a balanced cytokine profile in YF-17DD nonresponders and a robust inflammatory profile in YF-17D

  5. Cytokine-like factor-1, a novel soluble protein, shares homology with members of the cytokine type I receptor family.

    Science.gov (United States)

    Elson, G C; Graber, P; Losberger, C; Herren, S; Gretener, D; Menoud, L N; Wells, T N; Kosco-Vilbois, M H; Gauchat, J F

    1998-08-01

    In this report we describe the identification, cloning, and expression pattern of human cytokine-like factor 1 (hCLF-1) and the identification and cloning of its murine homologue. They were identified from expressed sequence tags using amino acid sequences from conserved regions of the cytokine type I receptor family. Human CLF-1 and murine CLF-1 shared 96% amino acid identity and significant homology with many cytokine type I receptors. CLF-1 is a secreted protein, suggesting that it is either a soluble subunit within a cytokine receptor complex, like the soluble form of the IL-6R alpha-chain, or a subunit of a multimeric cytokine, e.g., IL-12 p40. The highest levels of hCLF-1 mRNA were observed in lymph node, spleen, thymus, appendix, placenta, stomach, bone marrow, and fetal lung, with constitutive expression of CLF-1 mRNA detected in a human kidney fibroblastic cell line. In fibroblast primary cell cultures, CLF-1 mRNA was up-regulated by TNF-alpha, IL-6, and IFN-gamma. Western blot analysis of recombinant forms of hCLF-1 showed that the protein has the tendency to form covalently linked di- and tetramers. These results suggest that CLF-1 is a novel soluble cytokine receptor subunit or part of a novel cytokine complex, possibly playing a regulatory role in the immune system and during fetal development.

  6. Advertising health: the case for counter-ads.

    Science.gov (United States)

    Dorfman, L; Wallack, L

    1993-01-01

    Public service advertisements have been used by many in hopes of "selling" good health behaviors. But selling good behavior--even if it could be done more effectively--is not the best goal for using mass media to prevent health problems. Personal behavior is only part of what determines health status. Social conditions and the physical environment are important determinants of health that are usually ignored by health promotion advertising. Public service advertising may be doing more harm than good if it is diverting attention from more effective socially based health promotion strategies. Counter-ads are one communications strategy that could be used to promote a broader responsibility for rectifying health problems. In the tradition of advocacy advertising directly promoting policy rather than products, counter-ads promote views consistent with a public health perspective. Counter-ads set the agenda for health issues, conferring status on policy-oriented strategies for addressing health problems. The primary purpose of counter-ads is to challenge the dominant view that public health problems reflect personal health habits. They are controversial because they place health issues in a social and political context. Advertising strategies for health promotion range over a spectrum from individually oriented public service advertising to socially oriented counter-advertising. The recent anti-tobacco campaign from the California Department of Health Services represents advertisements across the spectrum. Counter-ads that focus on a politically controversial definition for health problems are an appropriate and necessary alternative to public service advertising. PMID:8265756

  7. BALB/c Mice Vaccinated with Leishmania major Ribosomal Proteins Extracts Combined with CpG Oligodeoxynucleotides Become Resistant to Disease Caused by a Secondary Parasite Challenge

    Directory of Open Access Journals (Sweden)

    Laura Ramírez

    2010-01-01

    Full Text Available Leishmaniasis is an increasing public health problem and effective vaccines are not currently available. We have previously demonstrated that vaccination with ribosomal proteins extracts administered in combination of CpG oligodeoxynucleotides protects susceptible BALB/c mice against primary Leishmania major infection. Here, we evaluate the long-term immunity to secondary infection conferred by this vaccine. We show that vaccinated and infected BALB/c mice were able to control a secondary Leishmania major challenge, since no inflammation and very low number of parasites were observed in the site of reinfection. In addition, although an increment in the parasite burden was observed in the draining lymph nodes of the primary site of infection we did not detected inflammatory lesions at that site. Resistance against reinfection correlated to a predominant Th1 response against parasite antigens. Thus, cell cultures established from spleens and the draining lymph node of the secondary site of infection produced high levels of parasite specific IFN-γ in the absence of IL-4 and IL-10 cytokine production. In addition, reinfected mice showed a high IgG2a/IgG1 ratio for anti-Leishmania antibodies. Our results suggest that ribosomal vaccine, which prevents pathology in a primary challenge, in combination with parasite persistence might be effective for long-term maintenance of immunity.

  8. Therapeutic Applicability of Anti-Inflammatory and Proresolving Polyunsaturated Fatty Acid-Derived Lipid Mediators

    Directory of Open Access Journals (Sweden)

    Gerard L. Bannenberg

    2010-01-01

    Full Text Available The enzymatic oxygenation of polyunsaturated fatty acids by lipoxygenases and cyclo-oxygenases is a resourceful mode of formation of specific autacoids that regulate the extent and pace of the inflammatory response. Arachidonate-derived eicosanoids, such as lipoxin A4, prostaglandin (PGD2, PGF2α, PGE2, and PGD2-derived cyclopentenones exert specific roles in counter-regulating inflammation and turning on resolution. Recently recognized classes of autacoids derived from long-chain ω-3 polyunsaturated fatty acids, the E- and D-series resolvins, protectin D1, and maresin 1, act as specialized mediators to dampen inflammation actively, afford tissue protection, stimulate host defense, and activate resolution. It is held that counter-regulatory lipid mediators and the specific molecular pathways activated by such endogenous agonists may be suitable for pharmacological use in the treatment of inflammatory disease. The anti-inflammatory drug aspirin is a striking example of a drug that is able to act in such a manner, namely through triggering the formation of 15-epi-lipoxin A4 and aspirin-triggered resolvins. Different aspects of the therapeutic applicability of lipid mediators have been addressed here, and indicate that the development of innovative pharmacotherapy based on anti-inflammatory and proresolution lipid mediators presents novel prospects for the treatment of inflammatory disease.

  9. Variability in tuberculosis granuloma T cell responses exists, but a balance of pro- and anti-inflammatory cytokines is associated with sterilization.

    Directory of Open Access Journals (Sweden)

    Hannah Priyadarshini Gideon

    2015-01-01

    Full Text Available Lung granulomas are the pathologic hallmark of tuberculosis (TB. T cells are a major cellular component of TB lung granulomas and are known to play an important role in containment of Mycobacterium tuberculosis (Mtb infection. We used cynomolgus macaques, a non-human primate model that recapitulates human TB with clinically active disease, latent infection or early infection, to understand functional characteristics and dynamics of T cells in individual granulomas. We sought to correlate T cell cytokine response and bacterial burden of each granuloma, as well as granuloma and systemic responses in individual animals. Our results support that each granuloma within an individual host is independent with respect to total cell numbers, proportion of T cells, pattern of cytokine response, and bacterial burden. The spectrum of these components overlaps greatly amongst animals with different clinical status, indicating that a diversity of granulomas exists within an individual host. On average only about 8% of T cells from granulomas respond with cytokine production after stimulation with Mtb specific antigens, and few "multi-functional" T cells were observed. However, granulomas were found to be "multi-functional" with respect to the combinations of functional T cells that were identified among lesions from individual animals. Although the responses generally overlapped, sterile granulomas had modestly higher frequencies of T cells making IL-17, TNF and any of T-1 (IFN-γ, IL-2, or TNF and/or T-17 (IL-17 cytokines than non-sterile granulomas. An inverse correlation was observed between bacterial burden with TNF and T-1/T-17 responses in individual granulomas, and a combinatorial analysis of pair-wise cytokine responses indicated that granulomas with T cells producing both pro- and anti-inflammatory cytokines (e.g. IL-10 and IL-17 were associated with clearance of Mtb. Preliminary evaluation suggests that systemic responses in the blood do not

  10. Regulation of human cytokines by Cordyceps militaris.

    Science.gov (United States)

    Sun, Yong; Shao, Yani; Zhang, Zhiguo; Wang, Lianfen; Mariga, Alfred M; Pang, Guangchang; Geng, Chaoyu; Ho, Chi-Tang; Hu, Qiuhui; Zhao, Liyan

    2014-12-01

    Cordyceps (Cordyceps militaris) exhibits many biological activities including antioxidant, inhibition of inflammation, cancer prevention, hypoglycemic, and antiaging properties, etc. However, a majority of studies involving C. militaris have focused only on in vitro and animal models, and there is a lack of direct translation and application of study results to clinical practice (e.g., health benefits). In this study, we investigated the regulatory effects of C. militaris micron powder (3 doses) on the human immune system. The study results showed that administration of C. militaris at various dosages reduced the activity of cytokines such as eotaxin, fibroblast growth factor-2, GRO, and monocyte chemoattractant protein-1. In addition, there was a significant decrease in the activity of various cytokines, including GRO, sCD40L, and tumor necrosis factor-α, and a significant downregulation of interleukin-12(p70), interferon-γ inducible protein 10, and macrophage inflammatory protein-1β activities, indicating that C. militaris at all three dosages downregulated the activity of cytokines, especially inflammatory cytokines and chemokines. Different dosages of C. militaris produced different changes in cytokines. Copyright © 2014. Published by Elsevier B.V.

  11. Mechanisms underlying the anti-inflammatory effects of Clinacanthus nutans Lindau extracts: inhibition of cytokine production and Toll-like receptor-4 activation

    Directory of Open Access Journals (Sweden)

    Chun Wai eMai

    2016-02-01

    Full Text Available Clinacanthus nutans has had a long history of use in folk medicine in Malaysia and Southeast Asia; mostly in the relief of inflammatory conditions. In this study, we investigated the effects of different extracts of C. nutans upon lipopolysaccharide (LPS induced inflammation in order to identify its mechanism of action. Extracts of leaves and stem bark of C. nutans were prepared using polar and non-polar solvents to produce four extracts, namely polar leaf extract (LP, non-polar leaf extract (LN, polar stem extract (SP and non-polar stem extracts (SN. The extracts were standardized by determining its total phenolic and total flavonoid contents. Its anti-inflammatory effects were assessed on LPS induced nitrite release in RAW264.7 macrophages and Toll-like receptor (TLR-4 activation in TLR-4 transfected human embryonic kidney cells (HEK-BlueTM-hTLR4 cells. The levels of inflammatory cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-12p40 and IL-17 in treated RAW264.7 macrophages were quantified to verify its anti-inflammatory effects. Western blotting was used to investigate the effect of the most potent extract (LP on TLR-4 related inflammatory proteins (p65, p38, ERK, JNK, IRF3 in RAW264.7 macrophages. All four extracts produced a significant, concentration-dependent reduction in LPS-stimulated nitric oxide, LPS-induced TLR-4 activation in HEK-BlueTM-hTLR4 cells and LPS-stimulated cytokines production in RAW264.7 macrophages. The most potent extract, LP, also inhibited all LPS-induced TLR-4 inflammatory proteins. These results provide a basis for understanding the mechanisms underlying the previously demonstrated anti-inflammatory activity of C. nutans extracts.

  12. Single-cell multiplexed cytokine profiling of CD19 CAR-T cells reveals a diverse landscape of polyfunctional antigen-specific response.

    Science.gov (United States)

    Xue, Qiong; Bettini, Emily; Paczkowski, Patrick; Ng, Colin; Kaiser, Alaina; McConnell, Timothy; Kodrasi, Olja; Quigley, Máire F; Heath, James; Fan, Rong; Mackay, Sean; Dudley, Mark E; Kassim, Sadik H; Zhou, Jing

    2017-11-21

    It remains challenging to characterize the functional attributes of chimeric antigen receptor (CAR)-engineered T cell product targeting CD19 related to potency and immunotoxicity ex vivo, despite promising in vivo efficacy in patients with B cell malignancies. We employed a single-cell, 16-plex cytokine microfluidics device and new analysis techniques to evaluate the functional profile of CD19 CAR-T cells upon antigen-specific stimulation. CAR-T cells were manufactured from human PBMCs transfected with the lentivirus encoding the CD19-BB-z transgene and expanded with anti-CD3/anti-CD28 coated beads. The enriched CAR-T cells were stimulated with anti-CAR or control IgG beads, stained with anti-CD4 RPE and anti-CD8 Alexa Fluor 647 antibodies, and incubated for 16 h in a single-cell barcode chip (SCBC). Each SCBC contains ~12,000 microchambers, covered with a glass slide that was pre-patterned with a complete copy of a 16-plex antibody array. Protein secretions from single CAR-T cells were captured and subsequently analyzed using proprietary software and new visualization methods. We demonstrate a new method for single-cell profiling of CD19 CAR-T pre-infusion products prepared from 4 healthy donors. CAR-T single cells exhibited a marked heterogeneity of cytokine secretions and polyfunctional (2+ cytokine) subsets specific to anti-CAR bead stimulation. The breadth of responses includes anti-tumor effector (Granzyme B, IFN-γ, MIP-1α, TNF-α), stimulatory (GM-CSF, IL-2, IL-8), regulatory (IL-4, IL-13, IL-22), and inflammatory (IL-6, IL-17A) functions. Furthermore, we developed two new bioinformatics tools for more effective polyfunctional subset visualization and comparison between donors. Single-cell, multiplexed, proteomic profiling of CD19 CAR-T product reveals a diverse landscape of immune effector response of CD19 CAR-T cells to antigen-specific challenge, providing a new platform for capturing CAR-T product data for correlative analysis. Additionally, such high

  13. Cytokines and the neurodevelopmental basis of mental illness

    Directory of Open Access Journals (Sweden)

    Udani eRatnayake

    2013-10-01

    Full Text Available Epidemiological studies suggest that prenatal exposure to different types of viral or bacterial infections may be associated with similar outcomes; i.e., an increased risk of mental illness disorders in the offspring. Infections arising from various causes have similar debilitating effects in later life, suggesting that the exact pathogen may not be the critical factor in determining the neurological and cognitive outcome in the offspring. Instead, it is thought that response of the innate immune system, specifically the increased production of inflammatory cytokines, may be the critical mediator in altering fetal brain development pre-disposing the offspring to mental illness disorders later in life. Inflammatory cytokines are essential for normal brain development. Factors such as the site of cytokine production, a change in balance between anti- and pro- inflammatory cytokines, placental transfer of cytokines, the effects of cytokines on glial cells, and the effects of glucocorticoids are important when evaluating the impact of maternal infection on fetal brain development. Although it is clear that cytokines are altered in the fetal brain following maternal infection, further evidence is required to determine if cytokines are the critical factor that alters the trajectory of brain development, subsequently leading to postnatal behavioural and neurological abnormalities.

  14. Virally inactivated human platelet concentrate lysate induces regulatory T cells and immunosuppressive effect in a murine asthma model.

    Science.gov (United States)

    Lee, Yueh-Lun; Lee, Lin-Wen; Su, Chen-Yao; Hsiao, George; Yang, Yi-Yuan; Leu, Sy-Jye; Shieh, Ying-Hua; Burnouf, Thierry

    2013-09-01

    Platelet concentrate lysates (PCLs) are increasingly used in regenerative medicine. We have developed a solvent/detergent (S/D)-treated PCL. The functional properties of this preparation should be unveiled. We hypothesized that, due to transforming growth factor-β1 (TGF-β1) content, PCLs may exert immunosuppressive and anti-inflammatory functions. PCL was prepared by S/D treatment, oil extraction, and hydrophobic interaction chromatography. The content of TGF-β in PCL was determined by enzyme-linked immunosorbent assay. Cultured CD4+ T cells were used to investigate the effects of PCL on expression of transcription factor forkhead box P3 (Foxp3), the inhibition of T-cell proliferation, and cytokine production. The regulatory function of PCL-converted CD4+ T cells was analyzed by suppressive assay. The BALB/c mice were given PCL-converted CD4+ T cells before ovalbumin (OVA) sensitization and challenge using an asthma model. Inflammatory parameters, such as the level of immunoglobulin E (IgE), airway hyperresponsiveness (AHR), bronchial lavage fluid eosinophils, and cytokines were assayed. Recombinant human (rHu) TGF-β1 was used as control. PCL significantly enhanced the development of CD4+Foxp3+-induced regulatory T cells (iTregs). Converted iTregs produced neither Th1 nor Th2 cytokines and inhibited normal T-cell proliferation. PCL- and rHuTGF-β-converted CD4+ T cells prevented OVA-induced asthma. PCL- and rHuTGF-β-modified T cells both significantly reduced expression levels of OVA-specific IgE and significantly inhibited the development of AHR, airway eosinophilia, and Th2 responses in mice. S/D-treated PCL promotes Foxp3+ iTregs and exerts immunosuppressive and anti-inflammatory properties. This finding may help to understand the clinical properties of platelet lysates. © 2013 American Association of Blood Banks.

  15. Role of IL-38 and Its Related Cytokines in Inflammation

    Directory of Open Access Journals (Sweden)

    Xianli Yuan

    2015-01-01

    Full Text Available Interleukin- (IL- 38 is a recently discovered cytokine and is the tenth member of the IL-1 cytokine family. IL-38 shares structural features with IL-1 receptor antagonist (IL-1Ra and IL-36Ra. IL-36R is the specific receptor of IL-38, a partial receptor antagonist of IL-36. IL-38 inhibits the production of T-cell cytokines IL-17 and IL-22. IL-38 also inhibits the production of IL-8 induced by IL-36γ, thus inhibiting inflammatory responses. IL-38-related cytokines, including IL-1Ra and IL-36Ra, are involved in the regulation of inflammation and immune responses. The study of IL-38 and IL-38-related cytokines might provide new insights for developing anti-inflammatory treatments in the near future.

  16. Cytokines in human milk.

    Science.gov (United States)

    Garofalo, Roberto

    2010-02-01

    Epidemiologic studies conducted in the past 30 years to investigate the protective functions of human milk strongly support the notion that breastfeeding prevents infantile infections, particularly those affecting the gastrointestinal and respiratory tracts. However, more recent clinical and experimental observations also suggest that human milk not only provides passive protection, but also can directly modulate the immunological development of the recipient infant. The study of this remarkable defense system in human milk has been difficult because of its biochemical complexity, the small concentration of certain bioactive components, the compartmentalization of some of these agents, the dynamic quantitative and qualitative changes of milk during lactation, and the lack of specific reagents to quantify these agents. However, a host of bioactive substances, including hormones, growth factors, and immunological factors such as cytokines, have been identified in human milk. Cytokines are pluripotent polypeptides that act in autocrine/paracrine fashions by binding to specific cellular receptors. They operate in networks and orchestrate the development and functions of immune system. Several different cytokines and chemokines have been discovered in human milk in the past years, and the list is growing very rapidly. This article will review the current knowledge about the increasingly complex network of chemoattractants, activators, and anti-inflammatory cytokines present in human milk and their potential role in compensating for the developmental delay of the neonate immune system. Copyright 2010. Published by Mosby, Inc.

  17. Reduced Fc∊RI-Mediated Release of Asthma-Promoting Cytokines and Chemokines from Human Basophils during Omalizumab Therapy

    Science.gov (United States)

    Oliver, Janet M.; Tarleton, Christy A.; Gilmartin, Laura; Archibeque, Tereassa; Qualls, Clifford R.; Diehl, Lorena; Wilson, Bridget S.; Schuyler, Mark

    2010-01-01

    Background Treating asthmatics with the humanized IgE-scavenging antibody, omalizumab (rhuMAb-E25, Xolair®), reduces airways inflammation and asthma symptoms. Previously, omalizumab was shown to cause a dramatic and reversible loss of cell surface high-affinity IgE receptors, Fc∊RI, from the peripheral blood basophils of asthmatics. The consequences of receptor loss for the Fc∊RI-mediated synthesis and release of cytokines implicated in allergic asthma have not been examined. Methods Fifteen asthmatic volunteers each received omalizumab for 12 weeks. Peripheral blood basophils were isolated before, during, 2 weeks after and 6 months after omalizumab. Basophils were assayed for the basal and anti-IgE-stimulated release of cytokines, chemokines and histamine. Pooled data were analyzed by repeated measures ANOVA and by paired t tests. Results Anti-IgE-stimulated human basophils synthesize and release Th2 cytokines (IL-4, IL-13) and chemokines (IL-8, RANTES). The anti-IgE-stimulated release of IL-4, IL-13 and IL-8 was reduced during omalizumab treatment and returned to pretreatment levels after omalizumab withdrawal. Omalizumab did not alter basophil histamine levels or basal and anti-IgE-stimulated histamine release. Conclusions Omalizumab may reduce asthma symptoms in part by suppressing the Fc∊RI-mediated production by basophils of Th2 cytokines and selected chemokines. Anti-IgE-stimulated basophil cytokine synthesis appears more sensitive than histamine release to the loss of Fc∊RI caused by omalizumab treatment. PMID:19844128

  18. Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells

    International Nuclear Information System (INIS)

    Meyer-Siegler, Katherine L; Leifheit, Erica C; Vera, Pedro L

    2004-01-01

    The importance of various inflammatory cytokines in maintaining tumor cell growth and viability is well established. Increased expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) has previously been associated with various types of adenocarcinoma. MIF IHC was used to localize MIF in human bladder tissue. ELISA and Western blot analysis determined the synthesis and secretion of MIF by human bladder transitional cell carcinoma cells. The effects of MIF inhibitors (high molecular weight hyaluronate (HA), anti-MIF antibody or MIF anti-sense) on cell growth and cytokine expression were analyzed. Human bladder cancer cells (HT-1376) secrete detectable amounts of MIF protein. Treatment with HA, anti-MIF antibody and MIF anti-sense reduced HT-1376 cell proliferation, MIF protein secretion, MIF gene expression and secreted inflammatory cytokines. Our evidence suggests MIF interacts with the invariant chain, CD74 and the major cell surface receptor for HA, CD44. This study is the first to report MIF expression in the human bladder and these findings support a role for MIF in tumor cell proliferation. Since MIF participates in the inflammatory response and bladder cancer is associated with chronic inflammatory conditions, these new findings suggest that neutralizing bladder tumor MIF may serve as a novel therapeutic treatment for bladder carcinoma

  19. Bone Marrow Mononuclear Cell Transplantation Restores Inflammatory Balance of Cytokines after ST Segment Elevation Myocardial Infarction.

    Directory of Open Access Journals (Sweden)

    Kirsi Alestalo

    Full Text Available Acute myocardial infarction (AMI launches an inflammatory response and a repair process to compensate cardiac function. During this process, the balance between proinflammatory and anti-inflammatory cytokines is important for optimal cardiac repair. Stem cell transplantation after AMI improves tissue repair and increases the ventricular ejection fraction. Here, we studied in detail the acute effect of bone marrow mononuclear cell (BMMNC transplantation on proinflammatory and anti-inflammatory cytokines in patients with ST segment elevation myocardial infarction (STEMI.Patients with STEMI treated with thrombolysis followed by percutaneous coronary intervention (PCI were randomly assigned to receive either BMMNC or saline as an intracoronary injection. Cardiac function was evaluated by left ventricle angiogram during the PCI and again after 6 months. The concentrations of 27 cytokines were measured from plasma samples up to 4 days after the PCI and the intracoronary injection.Twenty-six patients (control group, n = 12; BMMNC group, n = 14 from the previously reported FINCELL study (n = 80 were included to this study. At day 2, the change in the proinflammatory cytokines correlated with the change in the anti-inflammatory cytokines in both groups (Kendall's tau, control 0.6; BMMNC 0.7. At day 4, the correlation had completely disappeared in the control group but was preserved in the BMMNC group (Kendall's tau, control 0.3; BMMNC 0.7.BMMNC transplantation is associated with preserved balance between pro- and anti-inflammatory cytokines after STEMI in PCI-treated patients. This may partly explain the favorable effect of stem cell transplantation after AMI.

  20. Analysis of the cytokine profile in spleen cells from dogs naturally infected by Leishmania chagasi.

    Science.gov (United States)

    Lage, R S; Oliveira, G C; Busek, S U; Guerra, L L; Giunchetti, R C; Corrêa-Oliveira, R; Reis, A B

    2007-01-15

    Recent studies suggest that asymptomatic dogs infected with canine visceral leishmaniasis (CVL) develop a Th1 immunological profile whilst oligosymptomatic and symptomatic CVL-infected animals present a Th2 profile. In the present study, an RT-PCR method has been standardised and employed to evaluate the frequency and the semi-quantitative level of expression of the cytokines IL-4, IL-10, IL-12, INF-gamma and TNF-alpha in splenocytes of 30 dogs naturally infected with Leishmania chagasi and of 7 non-infected dogs (NID). An increase in the level of expression of IL-12 (p=0.059) was detected in all CVL-infected dogs compared with NID. In dogs exhibiting high parasitism, the frequency of expression of IL-10 was higher (p=0.011) than in animals presenting low parasitism or medium parasitism (MP) and in NID animals, whilst the level of expression of IL-10 was higher (p=0.0094) than in animals exhibiting MP and in the NID group. Positive correlations between the levels of expression of IL-10 with respect to the progression of the disease (IL-10: r=0.3510; p=0.0337) and the levels of expression of IL-10 and INF-gamma increase in parasitism (IL-10: r=0.3428; p=0.0438 and INF-gamma: r=0.4690; p=0.0045) were observed. Such data suggest that CVL is marked by a balanced production of Th1 and Th2 cytokines, with a predominant accumulation of IL-10 as a consequence of an increase in parasitic load and progression of the disease, and INF-gamma was related with the increase in parasitic load.

  1. Pro-inflammatory Cytokine Response and Genetic Diversity in Merozoite Surface Protein 2 of Plasmodium falciparum Isolates from Nigeria.

    Science.gov (United States)

    Ajibaye, Olusola; Osuntoki, Akinniyi A; Ebuehi, Albert Ot; Iwalokun, Bamidele A; Balogun, Emmanuel O; Egbuna, Kathleen N

    2017-01-01

    Polymorphisms in Plasmodium falciparum merozoite surface protein-2 ( msp -2) and associated parasite genetic diversity which varies between malaria-endemic regions remain a limitation in malaria vaccine development. Pro-inflammatory cytokines are important in immunity against malaria, understanding the influence of genetic diversity on cytokine response is important for effective vaccine design. P. falciparum isolates obtained from 300 Nigerians with uncomplicated falciparum malaria at Ijede General Hospital, Ijede (IJE), General Hospital Ajeromi, Ajeromi (AJE) and Saint Kizito Mission Hospital, Lekki, were genotyped by nested polymerase chain reaction of msp -2 block 3 while ELISA was used to determine the pro-inflammatory cytokine response to describe the genetic diversity of P. falciparum . Eighteen alleles were observed for msp -2 loci. Of the 195 isolates, 61 (31.0%) had only FC27-type alleles, 38 (19.7%) had only 3D7-type alleles, and 49.3% had multiple parasite lines with both alleles. Band sizes were 275-625 bp for FC27 and 150-425 bp for 3D7. Four alleles were observed from LEK, 2 (375-425 bp) and 2 (275-325 bp) of FC27-and 3D7-types, respectively; 12 alleles from AJE, 9 (275-625 bp) and 3 (325-425 bp) of FC27-types and 3D7-types, respectively; while IJE had a total of 12 alleles, 9 (275-625 bp) and 3 (325-425 bp) of FC27-types and 3D7-types, respectively. Mean multiplicity of infection (MOI) was 1.54. Heterozygosity ( H E ) ranged from 0.77 to 0.87 and was highest for IJE (0.87). Cytokine response was higher among 0.05) but with neither parasite density nor infection type. P. falciparum genetic diversity is extensive in Nigeria, protection via pro-inflammatory cytokines have little or no interplay with infection multiplicity.

  2. A Short Peptide That Mimics the Binding Domain of TGF-β1 Presents Potent Anti-Inflammatory Activity.

    Directory of Open Access Journals (Sweden)

    Emília R Vaz

    Full Text Available The transforming growth factor beta 1 (TGF-β1 is a pleiotropic cytokine with multiple roles in development, wound healing, and immune regulation. TGF-β1-mediated immune dysfunction may lead to pathological conditions, such as inflammation. Chronic inflammatory process is characterized by a continuous release of pro-inflammatory cytokines, and the inhibition or the blockage of these cytokines signaling pathways are considered a target treatment. In this context, despite the high numbers of TGF-β-targeted pathways, the inducible regulatory T cells (iTreg to control inflammation seems to be a promising approach. Our aim was to develop novel peptides through phage display (PhD technology that could mimic TGF-β1 function with higher potency. Specific mimetic peptides were obtained through a PhD subtraction strategy from whole cell binding using TGF-β1 recombinant as a competitor during elution step. We have selected a peptide that seems to play an important role on cellular differentiation and modulation of TNF-α and IL-10 cytokines. The synthetic pm26TGF-β1 peptide tested in PBMC significantly down-modulated TNF-α and up-regulated IL-10 responses, leading to regulatory T cells (Treg phenotype differentiation. Furthermore, the synthetic peptide was able to decrease leukocytes rolling in BALB/C mice and neutrophils migration during inflammatory process in C57BL/6 mice. These data suggest that this peptide may be useful for the treatment of inflammatory diseases, especially because it displays potent anti-inflammatory properties and do not exhibit neutrophils' chemoattraction.

  3. Construction of a self-supporting tissue-equivalent dividing wall and operational characteristics of a coaxial double-cylindrical tissue-equivalent proportional counter

    International Nuclear Information System (INIS)

    Saion, E.B.; Watt, D.E.

    1994-01-01

    An additional feature incorporated in a coaxial double-cylindrical tissue-equivalent proportional counter, is the presence of a common tissue-equivalent dividing wall between the inner and outer counters of thickness equivalent to the corresponding maximum range of protons at the energy of interest. By appropriate use of an anti-coincidence arrangement with the outer counter, the inner counter could be used to discriminate microdosimetric spectra of neutrons at the desired low energy range from those of the faster neutrons. The construction of an A-150 self-supporting tissue-equivalent dividing wall and an anti-coincidence unit are described. Some operational characteristic tests have been performed to determine the operation of the new microdosimeter. (author)

  4. Effects of poor hygiene on cytokine phenotypes in children in the tropics

    Directory of Open Access Journals (Sweden)

    C. A. Figueiredo

    2016-11-01

    Full Text Available Abstract We describe immune phenotypes (innate and adaptive cytokines according to environmental exposure using latent class analysis. A total of 310 schoolchildren living in Ecuador were assayed for spontaneous cytokine production as well as mitogen (SEB-stimulated cytokines in whole blood cultures. We collected data on environmental exposures by questionnaire and on intestinal parasites by examination of stool samples. Latent class analysis (LCA was used to group children according to their innate (IL-6, IL-8, IL-10 and TNF-α and adaptive (IL-5, IL-13, IL-17, IFN-γ and IL-10 cytokine profile. We also conducted multiple-group LCA and LCA with covariates to evaluate the effect of predictors on profile membership. We identified both hyporesponsive and Th2-modified immune phenotypes produced by peripheral blood leukocytes (PBLs that were associated with intestinal worms and birth order, providing insights into how poor hygiene mediates immunologic effects on immune-mediated diseases.

  5. The Robust and Modulated Biomarker Network Elicited by the Plasmodium vivax Infection Is Mainly Mediated by the IL-6/IL-10 Axis and Is Associated with the Parasite Load

    Directory of Open Access Journals (Sweden)

    Allyson Guimarães da Costa

    2014-01-01

    Full Text Available Background. Recent studies have shown that the inflammatory process, including the biomarker production, and the intense activation of innate immune responses are greater in the malaria caused by Plasmodium vivax than other species. Here, we examined the levels of serum biomarkers and their interaction during acute malaria. Material and Methods. Blood samples were collected from P. vivax-infected patients at admission and from healthy donors. Levels of serum biomarkers were measured by Cytometric Bead Assay or ELISA. Results. P. vivax infection triggered the production of both inflammatory and regulatory biomarkers. Levels of IL-6, CXCL-8, IFN-γ, IL-5, and IL-10 were higher in P. vivax-infected patients than in healthy donors. On the other hand, malaria patients produced lower levels of TNF-α, IL-12p70, and IL-2 than healthy individuals. While the levels of IL-10 and IL-6 were found independent on the number of malaria episodes, higher levels of these cytokines were seen in patients with higher parasite load. Conclusion. A mixed pattern of proinflammatory and regulatory biomarkers is produced in P. vivax malaria. Analysis of biomarker network suggests that IL-10 and IL-6 are a robust axis in malaria patients and that this interaction seems to be associated with the parasite load.

  6. Developmental and Functional Control of Natural Killer Cells by Cytokines

    Directory of Open Access Journals (Sweden)

    Yang Wu

    2017-08-01

    Full Text Available Natural killer (NK cells are effective in combating infections and tumors and as such are tempting for adoptive transfer therapy. However, they are not homogeneous but can be divided into three main subsets, including cytotoxic, tolerant, and regulatory NK cells, with disparate phenotypes and functions in diverse tissues. The development and functions of such NK cells are controlled by various cytokines, such as fms-like tyrosine kinase 3 ligand (FL, kit ligand (KL, interleukin (IL-3, IL-10, IL-12, IL-18, transforming growth factor-β, and common-γ chain family cytokines, which operate at different stages by regulating distinct signaling pathways. Nevertheless, the specific roles of each cytokine that regulates NK cell development or that shapes different NK cell functions remain unclear. In this review, we attempt to describe the characteristics of each cytokine and the existing protocols to expand NK cells using different combinations of cytokines and feeder cells. A comprehensive understanding of the role of cytokines in NK cell development and function will aid the generation of better efficacy for adoptive NK cell treatment.

  7. An anti-interleukin-2 receptor drug attenuates T- helper 1 lymphocytes-mediated inflammation in an acute model of endotoxin-induced uveitis.

    Directory of Open Access Journals (Sweden)

    Salvador Mérida

    Full Text Available The aim of the present study was to evaluate the anti-inflammatory efficacy of Daclizumab, an anti-interleukin-2 receptor drug, in an experimental uveitis model upon a subcutaneous injection of lipopolysaccharide into Lewis rats, a valuable model for ocular acute inflammatory processes. The integrity of the blood-aqueous barrier was assessed 24 h after endotoxin-induced uveitis by evaluating two parameters: cell count and protein concentration in aqueous humors. The histopathology of all the ocular structures (cornea, lens, sclera, choroid, retina, uvea, and anterior and posterior chambers was also considered. Enzyme-linked immunosorbent assays of the aqueous humor samples were performed to quantify the levels of the different chemokine and cytokine proteins. Similarly, a biochemical analysis of oxidative stress-related markers was also assessed. The inflammation observed in the anterior chamber of the eyes when Daclizumab was administered with endotoxin was largely prevented since the aqueous humor protein concentration substantially lowered concomitantly with a significant reduction in the uveal and vitreous histopathological grading. Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon-γ, also significantly reduced with related anti-oxidant systems recovery. Daclizumab treatment in endotoxin-induced uveitis reduced Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon gamma, by about 60-70% and presented a preventive role in endotoxin-induced oxidative stress. This antioxidant protective effect of Daclizumab may be related to several of the observed Daclizumab effects in our study, including IL-6 cytokine regulatory properties and a substantial concomitant drop in INFγ. Concurrently, Daclizumab treatment triggered a significant reduction in both the uveal histopathological grading and protein concentration in aqueous humors, but not in cellular infiltration.

  8. Anti-inflammatory and anti-granuloma activity of Berberis aristata DC. in experimental models of inflammation

    Science.gov (United States)

    Kumar, Rohit; Gupta, Yogendra Kumar; Singh, Surender

    2016-01-01

    Objective: Berberis aristata (Berberidaceae) is an important medicinal plant used in traditional system of medicine for the treatment of rheumatoid arthritis and other inflammatory disorders. The aim of the present study is to scientifically validate the traditional use of BA in the treatment of inflammatory disorders. Materials and Methods: Anti-inflammatory and anti-granuloma activity of BA hydroalcoholic extract (BAHE) were evaluated in experimental models, viz., carrageenan-induced paw edema, cotton pellet-induced granuloma formation, and complete Freund's adjuvant-induced stimulation of peritoneal macrophages in rats. Expression of inflammatory mediators, viz., tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, TNF-R1, and cyclooxygenase-2 (COX-2) was carried out in serum and peritoneal macrophages to derive the plausible mechanism of BAHE in activated peritoneal macrophages. Results: Pretreatment with BAHE produced a dose-dependent reduction (P < 0.01) in carrageenan-induced paw edema and cotton pellet-induced granuloma model. BAHE treatment produced significant (P < 0.01) reduction in serum inflammatory cytokine levels as compared to control. Protein expression of pro-inflammatory markers, IL-1β, IL-6, TNF-R1, and COX-2, was found to be reduced in stimulated macrophages whereas anti-inflammatory cytokine, IL-10, was upregulated in peritoneal macrophages. Conclusion: The result of the present study thus demonstrates the anti-inflammatory and anti-granuloma activity of BAHE which may be attributed to its inhibitory activity on macrophage-derived cytokine and mediators. PMID:27114638

  9. Immune escape strategies of malaria parasites

    Directory of Open Access Journals (Sweden)

    Pollyanna Stephanie Gomes

    2016-10-01

    Full Text Available Malaria is one of the most life-threatening infectious diseases worldwide. Immunity to malaria is slow and short-lived despite the repeated parasite exposure in endemic areas. Malaria parasites have evolved refined machinery to evade the immune system based on a range of genetic changes that include allelic variation, biomolecular exposure of proteins and intracellular replication. All of these features increase the probability of survival in both mosquitoes and the vertebrate host. Plasmodium species escape from the first immunological trap in its invertebrate vector host, the Anopheles mosquitoes. The parasites have to pass through various immunological barriers within the mosquito such as anti-microbial molecules and the mosquito microbiota in order to achieve successful transmission to the vertebrate host. Within these hosts, Plasmodium species employ various immune evasion strategies during different life cycle stages. Parasite persistence against the vertebrate immune response depends on the balance among virulence factors, pathology, metabolic cost of the host immune response, and the parasites ability to evade the immune response. In this review we discuss the strategies that Plasmodium parasites use to avoid the vertebrate host immune system and how they promote successful infection and transmission.

  10. Timing of host feeding drives rhythms in parasite replication

    KAUST Repository

    Prior, Kimberley F.

    2018-02-26

    Circadian rhythms enable organisms to synchronise the processes underpinning survival and reproduction to anticipate daily changes in the external environment. Recent work shows that daily (circadian) rhythms also enable parasites to maximise fitness in the context of ecological interactions with their hosts. Because parasite rhythms matter for their fitness, understanding how they are regulated could lead to innovative ways to reduce the severity and spread of diseases. Here, we examine how host circadian rhythms influence rhythms in the asexual replication of malaria parasites. Asexual replication is responsible for the severity of malaria and fuels transmission of the disease, yet, how parasite rhythms are driven remains a mystery. We perturbed feeding rhythms of hosts by 12 hours (i.e. diurnal feeding in nocturnal mice) to desynchronise the host’s peripheral oscillators from the central, light-entrained oscillator in the brain and their rhythmic outputs. We demonstrate that the rhythms of rodent malaria parasites in day-fed hosts become inverted relative to the rhythms of parasites in night-fed hosts. Our results reveal that the host’s peripheral rhythms (associated with the timing of feeding and metabolism), but not rhythms driven by the central, light-entrained circadian oscillator in the brain, determine the timing (phase) of parasite rhythms. Further investigation reveals that parasite rhythms correlate closely with blood glucose rhythms. In addition, we show that parasite rhythms resynchronise to the altered host feeding rhythms when food availability is shifted, which is not mediated through rhythms in the host immune system. Our observations suggest that parasites actively control their developmental rhythms. Finally, counter to expectation, the severity of disease symptoms expressed by hosts was not affected by desynchronisation of their central and peripheral rhythms. Our study at the intersection of disease ecology and chronobiology opens up a new

  11. Timing of host feeding drives rhythms in parasite replication

    KAUST Repository

    Prior, Kimberley F

    2017-12-07

    Circadian rhythms enable organisms to synchronise the processes underpinning survival and reproduction to anticipate daily changes in the external environment. Recent work shows that daily (circadian) rhythms also enable parasites to maximise fitness in the context of ecological interactions with their hosts. Because parasite rhythms matter for their fitness, understanding how they are regulated could lead to innovative ways to reduce the severity and spread of diseases. Here, we examine how host circadian rhythms influence rhythms in the asexual replication of malaria parasites. Asexual replication is responsible for the severity of malaria and fuels transmission of the disease, yet, how parasite rhythms are driven remains a mystery. We perturbed feeding rhythms of hosts by 12 hours (i.e. diurnal feeding in nocturnal mice) to desynchronise the host\\'s peripheral oscillators from the central, light-entrained oscillator in the brain and their rhythmic outputs. We demonstrate that the rhythms of rodent malaria parasites in day-fed hosts become inverted relative to the rhythms of parasites in night-fed hosts. Our results reveal that the host\\'s peripheral rhythms (associated with the timing of feeding and metabolism), but not rhythms driven by the central, light-entrained circadian oscillator in the brain, determine the timing (phase) of parasite rhythms. Further investigation reveals that parasite rhythms correlate closely with blood glucose rhythms. In addition, we show that parasite rhythms resynchronise to the altered host feeding rhythms when food availability is shifted, which is not mediated through rhythms in the host immune system. Our observations suggest that parasites actively control their developmental rhythms. Finally, counter to expectation, the severity of disease symptoms expressed by hosts was not affected by desynchronisation of their central and peripheral rhythms. Our study at the intersection of disease ecology and chronobiology opens up a new

  12. Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells

    Directory of Open Access Journals (Sweden)

    Leifheit Erica C

    2004-07-01

    Full Text Available Abstract Background The importance of various inflammatory cytokines in maintaining tumor cell growth and viability is well established. Increased expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF has previously been associated with various types of adenocarcinoma. Methods MIF IHC was used to localize MIF in human bladder tissue. ELISA and Western blot analysis determined the synthesis and secretion of MIF by human bladder transitional cell carcinoma cells. The effects of MIF inhibitors (high molecular weight hyaluronate (HA, anti-MIF antibody or MIF anti-sense on cell growth and cytokine expression were analyzed. Results Human bladder cancer cells (HT-1376 secrete detectable amounts of MIF protein. Treatment with HA, anti-MIF antibody and MIF anti-sense reduced HT-1376 cell proliferation, MIF protein secretion, MIF gene expression and secreted inflammatory cytokines. Our evidence suggests MIF interacts with the invariant chain, CD74 and the major cell surface receptor for HA, CD44. Conclusions This study is the first to report MIF expression in the human bladder and these findings support a role for MIF in tumor cell proliferation. Since MIF participates in the inflammatory response and bladder cancer is associated with chronic inflammatory conditions, these new findings suggest that neutralizing bladder tumor MIF may serve as a novel therapeutic treatment for bladder carcinoma.

  13. Needle counter

    International Nuclear Information System (INIS)

    Fujita, Yuzo

    1977-01-01

    Needle counter had been devised by Geiger about 60 years ago before the present GM counter appeared. It is suitable for the detection of weak radiation because it is limited in effective volume, if the background due to mainly cosmic ray is proportional to the effective volume of the counter. Recently the very low β detector having a needle counter as the main detector has been developed. It showed highly excellent performance in the measurements of small area samples, about ten times sensitive as compared with other detectors. The counter is installed in the very low radiation measuring well at Nokogiriyama, Chiba Prefecture, using a NaI scintillator as its guard counter. D. H. Wilkinson first treated a gas amplification counter theoretically and quantitatively. The authors have obtained good results in the comparison with the experiments of the counter using a generalized form of Wilkinson theory. The findings obtained through this study seem to be applicable to the electrode arrangement which is important for the counter design. It was found that the excellent rise time of induced pulses in a gas amplification counter was achieved in larger amplification factor and smaller convolution effect. In the detection of charged particles with small obstructing capability such as γ ray, faster rise time and higher pulses can be obtained with needle counters than wire counters. (Wakatsuki, Y.)

  14. Withaferin A Associated Differential Regulation of Inflammatory Cytokines

    Directory of Open Access Journals (Sweden)

    Seema Dubey

    2018-02-01

    Full Text Available A role of inflammation-associated cytokines/chemokines has been implicated in a wide variety of human diseases. Here, we investigated the regulation of inflammatory cytokines released by monocyte-derived THP-1 cells following treatment with the dietary agent withaferin A (WFA. Membrane-based cytokine array profiling of the culture supernatant from adenosine triphosphate-stimulated WFA-treated THP-1 cells showed differential regulation of multiple cytokines/chemokines. A selected group of cytokines/chemokines [interleukin-1 beta (IL-1β, CCL2/MCP-1, granulocyte-macrophage colony stimulating factor, PDGF-AA, PTX3, cystatin-3, relaxin-2, TNFRSF8/CD30, and ACRP30] was validated at the transcription level using qPCR. In silico analysis for transcriptional binding factors revealed the presence of nuclear factor-kappa B (NF-κB in a group of downregulated cytokine gene promoters. WFA treatment of THP-1 cells blocks the nuclear translocation of NF-kB and corresponds with the reduced levels of cytokine secretion. To further understand the differential expression of cytokines/chemokines, we showed that WFA alters the nigericin-induced co-localization of NLRP3 and ASC proteins, thereby inhibiting caspase-1 activation, which is responsible for the cleavage and maturation of pro-inflammatory cytokines IL-1β and IL-18. These data suggest that dietary agent WFA concurrently targets NF-κB and the inflammasome complex, leading to inhibition of IL-1β and IL-18, respectively, in addition to differential expression of multiple cytokines/chemokines. Taken together, these results provide a rationale for using WFA to further explore the anti-inflammatory mechanism of cytokines/chemokines associated with inflammatory diseases.

  15. Deciphering RNA Regulatory Elements Involved in the Developmental and Environmental Gene Regulation of Trypanosoma brucei.

    Science.gov (United States)

    Gazestani, Vahid H; Salavati, Reza

    2015-01-01

    Trypanosoma brucei is a vector-borne parasite with intricate life cycle that can cause serious diseases in humans and animals. This pathogen relies on fine regulation of gene expression to respond and adapt to variable environments, with implications in transmission and infectivity. However, the involved regulatory elements and their mechanisms of actions are largely unknown. Here, benefiting from a new graph-based approach for finding functional regulatory elements in RNA (GRAFFER), we have predicted 88 new RNA regulatory elements that are potentially involved in the gene regulatory network of T. brucei. We show that many of these newly predicted elements are responsive to both transcriptomic and proteomic changes during the life cycle of the parasite. Moreover, we found that 11 of predicted elements strikingly resemble previously identified regulatory elements for the parasite. Additionally, comparison with previously predicted motifs on T. brucei suggested the superior performance of our approach based on the current limited knowledge of regulatory elements in T. brucei.

  16. Governing GMOs: The (Counter Movement for Mandatory and Voluntary Non-GMO Labels

    Directory of Open Access Journals (Sweden)

    Carmen Bain

    2014-12-01

    Full Text Available Since 2012 the anti-GMO (genetically modified organism movement has gained significant grassroots momentum in its efforts to require mandatory GMO food labels through state-level ballot and legislative efforts. Major food and agriculture corporations are opposed to mandatory GMO labels and have successfully defeated most of these initiatives. Nevertheless, these battles have garnered significant media attention and re-energized the debate over GMO crops and foods. In this paper, we argue that one of the most significant outcomes of this fight is efforts by food retailers and value-based food companies to implement voluntary non-GMO labels and brands. We draw on the governance and political consumerism literature to explore (counter movement efforts for mandatory labels and how these efforts are being institutionalized through private voluntary governance institutions. Our assessment is based on in-depth, semi-structured interviews with key informants from consumer and environmental organizations, agriculture and biotech companies, and government regulatory agencies, as well as a content analysis of food industry websites. A growing number of food retailers recognize the reputational and economic value that new niche markets for non-GMO foods can offer, while the anti-GMO movement views these efforts as a step in the direction of mandatory GMO labels. We conclude that voluntary labels may act to settle the labeling debate by mollifying agri-food industry concerns about mandatory labeling and meeting the desire of political consumers for greater choice and transparency but without addressing the broader social and environmental sustainability concerns that drives the anti-GMO movement in the first place.

  17. INTEGRAL EVALUATION OF THE CYTOKINE SYSTEM IN VIRAL MYOCARDITIS

    Directory of Open Access Journals (Sweden)

    Peremot S. D.

    2017-10-01

    -10, INF-γ, TNF-α in serum was measured by enzyme-linked immunosorbent assay using commercial enzyme immunoassay kits for Thermo Scientific ™ (IL-2R IL-4, IL-6, IL-10, TNF alpha, IFN gamma ELISA Kit, Human, USA and Stat Fax 303 Plus spectrophotometer. Statistical processing of all received data was carried out on a personal computer using the program Statistica, version 6.1 (StatSoft Inc., USA [1]. Results & discussion. Analysis of levels of pro- and anti-inflammatory cytokines in patients indicates an imbalance in their system, which is characterized primarily by a significant increase in the level of IL-6 prophylaxis to (134.09 ± 22.72 pg / ml (control level 11.83 ± 1, 64 pg / ml and a relatively moderate increase in IL-2 and TNF-α levels in subacute myocarditis. Such an increase in the level of IL-6, in our opinion, is due to the dualism of the action of this interleukin, the proinflammatory nature of its action at the final stage of inflammation changes to anti-inflammatory. As a consequence, in combination with IL-10, it limits the secretion of TNF-α. That is why its level remains high and with chronic herpesviral myocarditis and exceeds the level of the control group more than 8 times. In addition, in the chronic form of the course of herpesviral myocarditis, an increase in the levels of anti-inflammatory IL4 and IL-10 cytokines is observed in 2.9 and 3.1 times, respectively. And the level of IL-10 increased not only in comparison with the level of the control group, but also exceeded by 1.5 times the corresponding index for subacute myocarditis. In order to optimize the analysis of cytokine imbalance, an integral assessment of the levels of inflammatory mediators from opposing groups was carried out. Calculation of the integral indicator (II of the cytokine balance was performed by determining the values of cytokine indices as the ratios of the levels of proinflammatory and anti-inflammatory sera in the examined patients to the reference values of the

  18. Evaluation of TNF-α, IL-4, and IL-10 and parasite density in spleen and liver of L. (L.) chagasi naturally infected dogs.

    Science.gov (United States)

    DE F Michelin, A; Perri, S H V; De Lima, V M F

    2011-07-01

    Dogs are the main domestic reservoirs of L. (L.) chagasi. Once in the vertebrate host, the parasite can cause visceral leishmaniasis, which can also be transmitted to humans. Cytokines are key elements of the host immune response against Leishmania spp. To investigate whether tumor necrosis factor (TNF)-α, interleukin (IL)-4 and IL-10 are associated with pattern infection in dogs, these cytokines were quantified in the spleen and liver of dogs naturally infected with L. (L.) chagasi, with or without clinical manifestations, and their levels were correlated with the parasite load verified in these organs. A total of 40 adult dogs naturally infected with L. (L.) chagasi were assessed, together with 12 uninfected control dogs. Samples from spleen and liver were used to determine the cytokine levels by capture ELISA and for quantifying parasite load by real-time PCR. Statistical analysis was performed using the minimum Chi square method and group means were compared using the Tukey test. TNF-α, IL-4 and IL-10 levels in infected dogs were higher than in control groups; the liver was the main cytokine-producing organ during infection. The level of splenic TNF-α showed correlation with parasite load and may represent an important marker for infection process evolution, with the participation of IL-10. These results may contribute to a clearer understanding of the immune response in dogs infected with L. (L.) chagasi, which may lead to the development of prophylactic or preventive measures for these animals.

  19. Parasite-specific IL-4 responses in Ascaris suum and Trichuris suis-infected pigs evaluated by ELISPOT

    DEFF Research Database (Denmark)

    Steenhard, N. R.; Kringel, H.; Roepstorff, A.

    2007-01-01

    method is a valuable tool for future experimental settings as it enables repeated and parasite-specific measurement of IL-4 at protein level when investigating, for example, immunomodulatory properties of helminths. Furthermore, the method could be used to identify specific parasite antigens inducing IL......The objective of the present study was to develop an ELISPOT method to measure parasite-specific IL-4 producing cells during experimental Ascaris suum and Trichuris suis infections in pigs. In many experimental settings it is useful to be able to measure changes in specifically induced cytokines...

  20. Parasitic Helminths: New Weapons against Immunological Disorders

    OpenAIRE

    Osada, Yoshio; Kanazawa, Tamotsu

    2010-01-01

    The prevalence of allergic and autoimmune diseases is increasing in developed countries, possibly due to reduced exposure to microorganisms in childhood (hygiene hypothesis). Epidemiological and experimental evidence in support of this hypothesis is accumulating. In this context, parasitic helminths are now important candidates for antiallergic/anti-inflammatory agents. Here we summarize antiallergic/anti-inflammatory effects of helminths together along with our own study of the effects of Sc...

  1. Ethyl acetate extract from Asparagus cochinchinensis exerts anti-inflammatory effects in LPS-stimulated RAW264.7 macrophage cells by regulating COX-2/iNOS, inflammatory cytokine expression, MAP kinase pathways, the cell cycle and anti-oxidant activity

    Science.gov (United States)

    Lee, Hyun Ah; Koh, Eun Kyoung; Sung, Ji Eun; Kim, Ji Eun; Song, Sung Hwa; Kim, Dong Seob; Son, Hong Joo; Lee, Chung Yeoul; Lee, Hee Seob; Bae, Chang Joon; Hwang, Dae Youn

    2017-01-01

    Asparagus cochinchinesis (A. cochinchinesis) is a medicine traditionally used to treat fever, cough, kidney disease, breast cancer, inflammatory disease and brain disease in northeast Asian countries. Although numerous studies of the anti-inflammatory effects of A. cochinchinesis have been conducted, the underlying mechanisms of such effects in macrophages remain to be demonstrated. To investigate the mechanism of suppressive effects on the inflammatory response in macrophages, alterations of the nitric oxide (NO) level, the cell viability, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression levels, inflammatory cytokine expression, the mitogen-activated protein kinase (MAPK) signaling pathway, cell cycle arrest and reactive oxygen species (ROS) levels were measured in lipopolysaccharide (LPS)-activated RAW264.7 cells following treatment with ethyl acetate extract from A. cochinchinesis root (EaEAC). RAW264.7 cells pretreated two different concentrations of EaEAC prior to LPS treatment exhibited no significant toxicity. The concentration of NO was significantly decreased in the EaEAC + LPS treated group compared with the vehicle + LPS treated group. A similar decrease in mRNA transcript level of COX-2, iNOS, pro-inflammatory cytokines [tumor necrosis factor-α and interleukin (IL)-1β] and anti-inflammatory cytokines (IL-6 and IL-10) was detected in the EaEAC + LPS treated group compared with the vehicle + LPS treated group, although the decrease rate varied. Enhancement of the phosphorylation of MAPK family members following LPS treatment was partially rescued in the EaEAC pretreated group, and the cell cycle was arrested at the G2/M phase. Furthermore, the EaEAC pretreated group exhibited a reduced level of ROS generation compared with the vehicle + LPS treated group. Taken together, these results suggest that EaEAC suppresses inflammatory responses through inhibition of NO production, COX-2 expression and ROS production, as well as

  2. Cytokine profile determined by data-mining analysis set into clusters of non-small-cell lung cancer patients according to prognosis.

    Science.gov (United States)

    Barrera, L; Montes-Servín, E; Barrera, A; Ramírez-Tirado, L A; Salinas-Parra, F; Bañales-Méndez, J L; Sandoval-Ríos, M; Arrieta, Ó

    2015-02-01

    Immunoregulatory cytokines may play a fundamental role in tumor growth and metastases. Their effects are mediated through complex regulatory networks. Human cytokine profiles could define patient subgroups and represent new potential biomarkers. The aim of this study was to associate a cytokine profile obtained through data mining with the clinical characteristics of patients with advanced non-small-cell lung cancer (NSCLC). We conducted a prospective study of the plasma levels of 14 immunoregulatory cytokines by ELISA and a cytometric bead array assay in 110 NSCLC patients before chemotherapy and 25 control subjects. Cytokine levels and data-mining profiles were associated with clinical, quality of life and pathological outcomes. NSCLC patients had higher levels of interleukin (IL)-6, IL-8, IL-12p70, IL-17a and interferon (IFN)-γ, and lower levels of IL-33 and IL-29 compared with controls. The pro-inflammatory cytokines IL-1b, IL-6 and IL-8 were associated with lower hemoglobin levels, worse functional performance status (Eastern Cooperative Oncology Group, ECOG), fatigue and hyporexia. The anti-inflammatory cytokines IL-4, IL-10 and IL-33 were associated with anorexia and lower body mass index. We identified three clusters of patients according to data-mining analysis with different overall survival (OS; 25.4, 16.8 and 5.09 months, respectively, P = 0.0012). Multivariate analysis showed that ECOG performance status and data-mining clusters were significantly associated with OS (RR 3.59, [95% CI 1.9-6.7], P < 0.001 and 2.2, [1.2-3.8], P = 0.005). Our results provide evidence that complex cytokine networks may be used to identify patient subgroups with different prognoses in advanced NSCLC. These cytokines may represent potential biomarkers, particularly in the immunotherapy era in cancer research. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email

  3. Counter-insurgents of the blue revolution? Parasites and diseases affecting aquaculture and science.

    Science.gov (United States)

    Blaylock, Reginald B; Bullard, Stephen A

    2014-12-01

    Aquaculture is the fastest-growing segment of food production and is expected to supply a growing portion of animal protein for consumption by humans. Because industrial aquaculture developed only recently compared to industrial agriculture, its development occurred within the context of a growing environmental awareness and acknowledgment of environmental issues associated with industrial farming. As such, parasites and diseases have become central criticisms of commercial aquaculture. This focus on parasites and diseases, however, has created a nexus of opportunities for research that has facilitated considerable scientific advances in the fields of parasitology and aquaculture. This paper reviews Myxobolus cerebralis , Lepeophtheirus salmonis , white spot syndrome virus, and assorted flatworms as select marquee aquaculture pathogens, summarizes the status of the diseases caused by each and their impacts on aquaculture, and highlights some of the significant contributions these pathogens have made to the science of parasitology and aquaculture.

  4. Plasma cytokines do not reflect expression of pro- and anti-inflammatory cytokine mRNA at organ level after cardiopulmonary bypass in neonatal pigs

    DEFF Research Database (Denmark)

    Brix-Christensen, V.; Vestergaard, C.; Chew, M.

    2003-01-01

    Background: Plasma concentrations of inflammatory markers are increased in response to the trauma of cardiac surgery and cardiopulmonary bypass (CPB). It is, however, unknown whether the plasma cytokine levels and cytokine mRNA expression at organ level reflect each other. Methods: Twenty...

  5. Polypyridylruthenium(II complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases.

    Directory of Open Access Journals (Sweden)

    Madhu K Sundaraneedi

    2017-12-01

    Full Text Available Schistosomiasis affects over 200 million people and there are concerns whether the current chemotherapeutic control strategy (periodic mass drug administration with praziquantel (PZQ-the only licenced anti-schistosome compound is sustainable, necessitating the development of new drugs.We investigated the anti-schistosome efficacy of polypyridylruthenium(II complexes and showed they were active against all intra-mammalian stages of S. mansoni. Two compounds, Rubb12-tri and Rubb7-tnl, which were among the most potent in their ability to kill schistosomula and adult worms and inhibit egg hatching in vitro, were assessed for their efficacy in a mouse model of schistosomiasis using 5 consecutive daily i.v. doses of 2 mg/kg (Rubb12-tri and 10 mg/kg (Rubb7-tnl. Mice treated with Rubb12-tri showed an average 42% reduction (P = 0.009, over two independent trials, in adult worm burden. Liver egg burdens were not significantly decreased in either drug-treated group but ova from both of these groups showed significant decreases in hatching ability (Rubb12-tri-68%, Rubb7-tnl-56% and were significantly morphologically altered (Rubb12-tri-62% abnormal, Rubb7-tnl-35% abnormal. We hypothesize that the drugs exerted their activity, at least partially, through inhibition of both neuronal and tegumental acetylcholinesterases (AChEs, as worms treated in vitro showed significant decreases in activity of these enzymes. Further, treated parasites exhibited a significantly decreased ability to uptake glucose, significantly depleted glycogen stores and withered tubercules (a site of glycogen storage, implying drug-mediated interference in this nutrient acquisition pathway.Our data provide compelling evidence that ruthenium complexes are effective against all intra-mammalian stages of schistosomes, including schistosomula (refractory to PZQ and eggs (agents of disease transmissibility. Further, the results of this study suggest that schistosome AChE is a target of

  6. Heterogeneity in cytokine profiles of Babesia bovis-specific bovine CD4+ T cells clones activated in vitro.

    OpenAIRE

    Brown, W C; Woods, V M; Dobbelaere, D A; Logan, K S

    1993-01-01

    The central role of T cells in the immune response against hemoprotozoan parasites, both as helper cells for T cell-dependent antibody production and as effector cells acting on intracellular parasites through the elaboration of cytokines, has prompted an investigation of the bovine cellular immune response against Babesia bovis antigens. CD4+ T helper (Th) cell clones generated from four B. bovis-immune cattle by in vitro stimulation with a soluble or membrane-associated merozoite antigen we...

  7. Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

    Directory of Open Access Journals (Sweden)

    Avinaba Mukherjee

    2016-03-01

    Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

  8. In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Sampaio Guedes

    2018-02-01

    Full Text Available BACKGROUND Leishmaniasis, one of the most neglected diseases, is a serious public health problem in many countries, including Brazil. Currently available treatments require long-term use and have serious side effects, necessitating the development of new therapeutic interventions. Because translocator protein (TSPO levels are reduced in Leishmania amazonensis-infected cells and because this protein participates in apoptosis and immunomodulation, TSPO represents a potential target for Leishmania chemotherapy. The present study evaluated PK11195, a ligand of this protein, as an anti-leishmanial agent. OBJECTIVE To evaluate the leishmanicidal activity of PK11195 against L. amazonensis in infected CBA mouse macrophages in vitro. METHODS The viability of axenic L. amazonensis, Leishmania major, and Leishmania braziliensis promastigotes was assessed after 48 h treatment with PK11195 (0.2-400 µM. Additionally, intracellular parasite viability was evaluated to determine IC50 values and the number of viable parasites in infected macrophages treated with PK11195 (50-100 µM. Infected macrophages were then treated with PK11195 (25-100 µM to determine the percentage of L. amazonensis-infected cells and the number of parasites per infected cell. Electron microscopy was used to investigate morphological changes caused by PK11195. The production of free oxygen radicals, nitric oxide, and pro-inflammatory cytokines was also evaluated in infected macrophages treated with PK11195 and primed or not primed with IFN-γ. FINDINGS Median IC50 values for PK11195 were 14.2 µM for L. amazonensis, 8.2 µM for L. major, and 3.5 µM for L. braziliensis. The selective index value for L. amazonensis was 13.7, indicating the safety of PK11195 for future testing in mammals. Time- and dose-dependent reductions in the percentage of infected macrophages, the number of parasites per infected macrophage, and the number of viable intracellular parasites were observed. Electron

  9. Effects of Freshwater Clam Extract Supplementation on Time to Exhaustion, Muscle Damage, Pro/Anti-Inflammatory Cytokines, and Liver Injury in Rats after Exhaustive Exercise

    Directory of Open Access Journals (Sweden)

    Kuang-Wen Liao

    2013-03-01

    Full Text Available The potent anti-inflammatory activities and tissue-protective effects of freshwater clams (Corbicula fluminea have been well reported. The aim of this study was to determine the effects of freshwater clam extract (FCE supplementation on time to exhaustion, muscle damage, pro- and anti-inflammatory cytokines, and liver injury in rats after exhaustive exercise. Thirty-two rats were divided into four groups: sedentary control (SC; SC group with FCE supplementation (SC+FCE; exhaustive exercise (E; and E group with FCE supplementation (E+FCE. The SC+FCE and E+FCE groups were treated with gavage administration of 20 mg/kg for seven consecutive days. Blood samples were collected for the evaluation of biochemical parameters. The cytokine levels of TNF-α and IL-10 were also examined. Twenty-four hours after exhaustive exercise, the rat livers were removed for H & E staining. The FCE supplementation could extend the time to exhaustion in exercised rats. The levels of CPK, LDH, AST, ALT, lactate, TNF-α and H & E stains of the liver injury were significantly decreased in the E+FCE group, but the blood glucose and IL-10 were significantly higher in comparison with the E group. This study suggests that FCE supplementation may improve endurance performance and reduce exercise-induced muscle damage, inflammatory stress and liver injury.

  10. Cytokine, antibody and proliferative cellular responses elicited by Taenia solium calreticulin upon experimental infection in hamsters.

    Directory of Open Access Journals (Sweden)

    Fela Mendlovic

    Full Text Available Taenia solium causes two diseases in humans, cysticercosis and taeniosis. Tapeworm carriers are the main risk factor for neurocysticercosis. Limited information is available about the immune response elicited by the adult parasite, particularly the induction of Th2 responses, frequently associated to helminth infections. Calreticulin is a ubiquitous, multifunctional protein involved in cellular calcium homeostasis, which has been suggested to play a role in the regulation of immune responses. In this work, we assessed the effect of recombinant T. solium calreticulin (rTsCRT on the cytokine, humoral and cellular responses upon experimental infection in Syrian Golden hamsters (Mesocricetus auratus. Animals were infected with T. solium cysticerci and euthanized at different times after infection. Specific serum antibodies, proliferative responses in mesenteric lymph nodes and spleen cells, as well as cytokines messenger RNA (mRNA were analyzed. The results showed that one third of the infected animals elicited anti-rTsCRT IgG antibodies. Interestingly, mesenteric lymph node (MLN cells from either infected or non-infected animals did not proliferate upon in vitro stimulation with rTsCRT. Additionally, stimulation with a tapeworm crude extract resulted in increased expression of IL-4 and IL-5 mRNA. Upon stimulation, rTsCRT increased the expression levels of IL-10 in spleen and MLN cells from uninfected and infected hamsters. The results showed that rTsCRT favors a Th2-biased immune response characterized by the induction of IL-10 in mucosal and systemic lymphoid organs. Here we provide the first data on the cytokine, antibody and cellular responses to rTsCRT upon in vitro stimulation during taeniasis.

  11. The self-antigen, thyroglobulin, induces antigen-experienced CD4+ T cells from healthy donors to proliferate and promote production of the regulatory cytokine, interleukin-10, by monocytes

    DEFF Research Database (Denmark)

    Nielsen, Claus Kim Hostein; Galdiers, Marcel P; Hedegaard, Chris Juul

    2010-01-01

    Thyroglobulin (TG), as autoantigen, induces in vitro proliferation of T and B cells from normal individuals, but the cytokine production differs from that in patients with autoimmune thyroid disease. Here, we investigate whether normal T cells responding to TG are naive, or have previously....... Whereas TT induced pro-inflammatory cytokines [interleukin-2 (IL-2)/interferon-gamma (IFN-gamma)/IL-4/IL-5], TG evoked persistent release of the regulatory IL-10. Some donors, however, also responded with late IFN-gamma production, suggesting that the regulation by IL-10 could be overridden. Although...... monocytes were prime producers of IL-10 in the early TG response, a few IL-10-secreting CD4(+) T cells, primarily with CD45RO(+) memory phenotype, were also detected. Furthermore, T-cell depletion from the mononuclear cell preparation abrogated monocyte IL-10 production. Our findings indicate active...

  12. Trichomonas vaginalis exosomes deliver cargo to host cells and mediate host∶parasite interactions.

    Directory of Open Access Journals (Sweden)

    Olivia Twu

    Full Text Available Trichomonas vaginalis is a common sexually transmitted parasite that colonizes the human urogential tract where it remains extracellular and adheres to epithelial cells. Infections range from asymptomatic to highly inflammatory, depending on the host and the parasite strain. Here, we use a combination of methodologies including cell fractionation, immunofluorescence and electron microscopy, RNA, proteomic and cytokine analyses and cell adherence assays to examine pathogenic properties of T. vaginalis. We have found that T.vaginalis produces and secretes microvesicles with physical and biochemical properties similar to mammalian exosomes. The parasite-derived exosomes are characterized by the presence of RNA and core, conserved exosomal proteins as well as parasite-specific proteins. We demonstrate that T. vaginalis exosomes fuse with and deliver their contents to host cells and modulate host cell immune responses. Moreover, exosomes from highly adherent parasite strains increase the adherence of poorly adherent parasites to vaginal and prostate epithelial cells. In contrast, exosomes from poorly adherent strains had no measurable effect on parasite adherence. Exosomes from parasite strains that preferentially bind prostate cells increased binding of parasites to these cells relative to vaginal cells. In addition to establishing that parasite exosomes act to modulate host∶parasite interactions, these studies are the first to reveal a potential role for exosomes in promoting parasite∶parasite communication and host cell colonization.

  13. Proteomic analysis of Fasciola hepatica excretory and secretory products (FhESPs) involved in interacting with host PBMCs and cytokines by shotgun LC-MS/MS.

    Science.gov (United States)

    Liu, Qing; Huang, Si-Yang; Yue, Dong-Mei; Wang, Jin-Lei; Wang, Yujian; Li, Xiangrui; Zhu, Xing-Quan

    2017-02-01

    Fasciola hepatica is a helminth parasite with a worldwide distribution, which can cause chronic liver disease, fasciolosis, leading to economic losses in the livestock and public health in many countries. Control is mostly reliant on the use of drugs, and as a result, drug resistance has now emerged. The identification of F. hepatica genes involved in interaction between the parasite and host immune system is utmost important to elucidate the evasion mechanisms of the parasite and develop more effective strategies against fasciolosis. In this study, we aimed to identify molecules in F. hepatica excretory and secretory products (FhESPs) interacting with the host peripheral blood mononuclear cells (PBMCs), Th1-like cytokines (IL2 and IFN-γ), and Th17-like cytokines (IL17) by Co-IP combined with tandem mass spectrometry. The results showed that 14, 16, and 9 proteins in FhESPs could bind with IL2, IL17, and IFN-γ, respectively, which indicated that adult F. hepatica may evade the host immune responses through directly interplaying with cytokines. In addition, nine proteins in FhESPs could adhere to PBMCs. Our findings provided potential targets as immuno-regulators, and will be helpful to elucidate the molecular basis of host-parasite interactions and search for new potential proteins as vaccine and drug target candidates.

  14. Anti-parasite treatment and blood biochemistry in raptor nestlings

    DEFF Research Database (Denmark)

    Hanssen, Sveinn Are; Sonne, Christian; Bustnes, Jan Ove

    2017-01-01

    We investigated the effects of parasite removal on various blood clinical–chemical variables (BCCVs). BCCVs are indicators of health, reflecting, e.g., homeostasis of liver, kidney function, and bone metabolism. The study was conducted in Norway on chicks of two predatory birds: White-tailed Eagl...

  15. Plant Hormone Salicylic Acid Produced by a Malaria Parasite Controls Host Immunity and Cerebral Malaria Outcome.

    Directory of Open Access Journals (Sweden)

    Ryuma Matsubara

    Full Text Available The apicomplexan parasite Toxoplasma gondii produces the plant hormone abscisic acid, but it is unclear if phytohormones are produced by the malaria parasite Plasmodium spp., the most important parasite of this phylum. Here, we report detection of salicylic acid, an immune-related phytohormone of land plants, in P. berghei ANKA and T. gondii cell lysates. However, addition of salicylic acid to P. falciparum and T. gondii culture had no effect. We transfected P. falciparum 3D7 with the nahG gene, which encodes a salicylic acid-degrading enzyme isolated from plant-infecting Pseudomonas sp., and established a salicylic acid-deficient mutant. The mutant had a significantly decreased concentration of parasite-synthesized prostaglandin E2, which potentially modulates host immunity as an adaptive evolution of Plasmodium spp. To investigate the function of salicylic acid and prostaglandin E2 on host immunity, we established P. berghei ANKA mutants expressing nahG. C57BL/6 mice infected with nahG transfectants developed enhanced cerebral malaria, as assessed by Evans blue leakage and brain histological observation. The nahG-transfectant also significantly increased the mortality rate of mice. Prostaglandin E2 reduced the brain symptoms by induction of T helper-2 cytokines. As expected, T helper-1 cytokines including interferon-γ and interleukin-2 were significantly elevated by infection with the nahG transfectant. Thus, salicylic acid of Plasmodium spp. may be a new pathogenic factor of this threatening parasite and may modulate immune function via parasite-produced prostaglandin E2.

  16. A Comparative Study of Peripheral Immune Responses to Taenia solium in Individuals with Parenchymal and Subarachnoid Neurocysticercosis.

    Directory of Open Access Journals (Sweden)

    Iskra Tuero

    2015-10-01

    Full Text Available The ability of Taenia solium to modulate the immune system likely contributes to their longevity in the human host. We tested the hypothesis that the nature of the immune response is related to the location of parasite and clinical manifestations of infection.Peripheral blood mononuclear cells (PBMC were obtained from untreated patients with neurocysticercosis (NCC, categorized as having parenchymal or subarachnoid infection by the presence of cysts exclusively within the parenchyma or in subarachnoid spaces of the brain, and from uninfected (control individuals matched by age and gender to each patient. Using multiplex detection technology, sera from NCC patients and controls and cytokine production by PBMC after T. solium antigen (TsAg stimulation were assayed for levels of inflammatory and regulatory cytokines. PBMC were phenotyped by flow cytometry ex vivo and following in vitro stimulation with TsAg.Sera from patients with parenchymal NCC demonstrated significantly higher Th1 (IFN-γ/IL-12 and Th2 (IL-4/IL-13 cytokine responses and trends towards higher levels of IL-1β/IL-8/IL-5 than those obtained from patients with subarachnoid NCC. Also higher in vitro antigen-driven TNF-β secretion was detected in PBMC supernatants from parenchymal than in subarachnoid NCC. In contrast, there was a significantly higher IL-10 response to TsAg stimulation in patients with subarachnoid NCC compared to parenchymal NCC. Although no differences in regulatory T cells (Tregs frequencies were found ex vivo, there was a trend towards greater expansion of Tregs upon TsAg stimulation in subarachnoid than in parenchymal NCC when data were normalized for the corresponding controls.T. solium infection of the subarachnoid space is associated with an enhanced regulatory immune response compared to infection in the parenchyma. The resulting anti-inflammatory milieu may represent a parasite strategy to maintain a permissive environment in the host or diminish

  17. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy.

    LENUS (Irish Health Repository)

    O'Brien, Sinead M

    2012-02-03

    OBJECTIVE: Approximately 30% of patients with depression fail to respond to a selective serotonin reuptake inhibitor (SSRI). Few studies have attempted to define these patients from a biological perspective. Studies suggest that overall patients with depression show increased production of proinflammatory cytokines. We examined pro- and anti-inflammatory cytokine levels in patients who were SSRI resistant. METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in DSM-1V major depressives who were SSRI resistant, in formerly SSRI resistant patients currently euthymic and in healthy controls. RESULTS: Patients with SSRI-resistant depression had significantly higher production of the pro-inflammatory cytokines IL-6 (p=0.01) and TNF-alpha (p=0.004) compared to normal controls. Euthymic patients who were formerly SSRI resistant had proinflammatory cytokine levels which were similar to the healthy subject group. Anti-inflammatory cytokine levels did not differ across the 3 groups. CONCLUSION: Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery.

  18. Distributed performance counters

    Science.gov (United States)

    Davis, Kristan D; Evans, Kahn C; Gara, Alan; Satterfield, David L

    2013-11-26

    A plurality of first performance counter modules is coupled to a plurality of processing cores. The plurality of first performance counter modules is operable to collect performance data associated with the plurality of processing cores respectively. A plurality of second performance counter modules are coupled to a plurality of L2 cache units, and the plurality of second performance counter modules are operable to collect performance data associated with the plurality of L2 cache units respectively. A central performance counter module may be operable to coordinate counter data from the plurality of first performance counter modules and the plurality of second performance modules, the a central performance counter module, the plurality of first performance counter modules, and the plurality of second performance counter modules connected by a daisy chain connection.

  19. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production.

    LENUS (Irish Health Repository)

    Lynch, Lydia

    2012-09-21

    Invariant natural killer T (iNKT) cells are evolutionarily conserved innate T cells that influence inflammatory responses. We have shown that iNKT cells, previously thought to be rare in humans, were highly enriched in human and murine adipose tissue, and that as adipose tissue expanded in obesity, iNKT cells were depleted, correlating with proinflammatory macrophage infiltration. iNKT cell numbers were restored in mice and humans after weight loss. Mice lacking iNKT cells had enhanced weight gain, larger adipocytes, fatty livers, and insulin resistance on a high-fat diet. Adoptive transfer of iNKT cells into obese mice or in vivo activation of iNKT cells via their lipid ligand, alpha-galactocylceramide, decreased body fat, triglyceride levels, leptin, and fatty liver and improved insulin sensitivity through anti-inflammatory cytokine production by adipose-derived iNKT cells. This finding highlights the potential of iNKT cell-targeted therapies, previously proven to be safe in humans, in the management of obesity and its consequences.

  20. Distinct cytokines balance the development of regulatory T cells and interleukin-10-producing regulatory B cells

    Czech Academy of Sciences Publication Activity Database

    Holáň, Vladimír; Zajícová, Alena; Javorková, Eliška; Trošan, Peter; Chudíčková, Milada; Pavlíková, M.; Krulová, Magdaléna

    2014-01-01

    Roč. 141, č. 4 (2014), s. 577-586 ISSN 0019-2805 R&D Projects: GA MZd(CZ) NT14102; GA ČR(CZ) GAP301/11/1568; GA ČR GAP304/11/0653 Institutional support: RVO:68378041 Keywords : Autoregulation * B cells * Cytokines Subject RIV: FF - HEENT, Dentistry Impact factor: 3.795, year: 2014

  1. The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation

    Science.gov (United States)

    Zaiss, Mario M.; Rapin, Alexis; Lebon, Luc; Dubey, Lalit Kumar; Mosconi, Ilaria; Sarter, Kerstin; Piersigilli, Alessandra; Menin, Laure; Walker, Alan W.; Rougemont, Jacques; Paerewijck, Oonagh; Geldhof, Peter; McCoy, Kathleen D.; Macpherson, Andrew J.; Croese, John; Giacomin, Paul R.; Loukas, Alex; Junt, Tobias; Marsland, Benjamin J.; Harris, Nicola L.

    2015-01-01

    Summary Intestinal helminths are potent regulators of their host’s immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions. PMID:26522986

  2. Fasting metabolism modulates the interleukin-12/interleukin-10 cytokine axis.

    Directory of Open Access Journals (Sweden)

    Johannes J Kovarik

    Full Text Available A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR, is responsible for controlling the balance between pro-inflammatory interleukin (IL-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines. Cytokine release and protein expression in human and murine myeloid cells was assessed after toll-like receptor (TLR-activation and glucose-deprivation or co-treatment with 5'-adenosine monophosphate (AMP-activated protein kinase (AMPK activators. Additionally, the impact of metabolic interference was analysed in an in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10. Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation.

  3. Fasting metabolism modulates the interleukin-12/interleukin-10 cytokine axis

    Science.gov (United States)

    Kernbauer, Elisabeth; Hölzl, Markus A.; Hofer, Johannes; Gualdoni, Guido A.; Schmetterer, Klaus G.; Miftari, Fitore; Sobanov, Yury; Meshcheryakova, Anastasia; Mechtcheriakova, Diana; Witzeneder, Nadine; Greiner, Georg; Ohradanova-Repic, Anna; Waidhofer-Söllner, Petra; Säemann, Marcus D.; Decker, Thomas

    2017-01-01

    A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR), is responsible for controlling the balance between pro-inflammatory interleukin (IL)-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines. Cytokine release and protein expression in human and murine myeloid cells was assessed after toll-like receptor (TLR)-activation and glucose-deprivation or co-treatment with 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators. Additionally, the impact of metabolic interference was analysed in an in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG) increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10. Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation. PMID:28742108

  4. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile.

    Science.gov (United States)

    DeFuria, Jason; Belkina, Anna C; Jagannathan-Bogdan, Madhumita; Snyder-Cappione, Jennifer; Carr, Jordan David; Nersesova, Yanina R; Markham, Douglas; Strissel, Katherine J; Watkins, Amanda A; Zhu, Min; Allen, Jessica; Bouchard, Jacqueline; Toraldo, Gianluca; Jasuja, Ravi; Obin, Martin S; McDonnell, Marie E; Apovian, Caroline; Denis, Gerald V; Nikolajczyk, Barbara S

    2013-03-26

    Patients with type 2 diabetes (T2D) have disease-associated changes in B-cell function, but the role these changes play in disease pathogenesis is not well established. Data herein show B cells from obese mice produce a proinflammatory cytokine profile compared with B cells from lean mice. Complementary in vivo studies show that obese B cell-null mice have decreased systemic inflammation, inflammatory B- and T-cell cytokines, adipose tissue inflammation, and insulin resistance (IR) compared with obese WT mice. Reduced inflammation in obese/insulin resistant B cell-null mice associates with an increased percentage of anti-inflammatory regulatory T cells (Tregs). This increase contrasts with the sharply decreased percentage of Tregs in obese compared with lean WT mice and suggests that B cells may be critical regulators of T-cell functions previously shown to play important roles in IR. We demonstrate that B cells from T2D (but not non-T2D) subjects support proinflammatory T-cell function in obesity/T2D through contact-dependent mechanisms. In contrast, human monocytes increase proinflammatory T-cell cytokines in both T2D and non-T2D analyses. These data support the conclusion that B cells are critical regulators of inflammation in T2D due to their direct ability to promote proinflammatory T-cell function and secrete a proinflammatory cytokine profile. Thus, B cells are potential therapeutic targets for T2D.

  5. T-lymphocyte cytokine mRNA expression in cystic echinococcosis.

    Science.gov (United States)

    Fauser, S; Kern, P

    1997-04-01

    In the present study we investigated cytokine mRNA expression by peripheral blood mononuclear cells (PBMC) from patients with cystic echinococcosis (CE) after stimulation with different antigens. By using reverse transcriptase polymerase chain reaction (RT-PCR) we could demonstrate that restimulation with crude Echinococcus granulosus antigen (Eg-Ag) induced or enhanced Th2 cytokine mRNA expression, especially IL-5 (by using antigen from sheep cyst fluid) in 23 out of 26 investigated CE patients and IL-10 (by using antigen from camel cyst fluid) in 10 out of 10 investigated CE patients. In contrast, IL-5 mRNA expression was absent in PBMC of healthy controls after Eg-Ag stimulation. To determine the specificity of this reaction we stimulated PBMC from 11 CE patients with crude Echinococcus multilocularis antigen (Em-Ag) and PBMC from 8 CE patients with Toxocara canis antigen (Tc-Ag). We found that the PBMC of patients showed a similar mRNA cytokine pattern on stimulation with Em-Ag when compared with Eg-Ag stimulation. The cytokine mRNA pattern on stimulation with Tc-Ag, however, resembled the cytokine mRNA pattern of unstimulated PBMC. Furthermore, the stimulation of PBMC with crude Mycobacterium tuberculosis antigen (H37Ra) and purified protein derivative (PPD) of M. tuberculosis revealed distinct IL-5 mRNA expression in all investigated CE patients, whereas in healthy controls IL-5 mRNA expression was very weak or totally absent. Thus, our results indicate an induction of Th2 cytokine mRNA expression in CE patients, which is frequently observed in parasite infections. Interestingly, this response persists after stimulation with tuberculosis antigens, which normally induce Th1 response.

  6. Circulating levels of platelet α-granule cytokines in trauma patients

    DEFF Research Database (Denmark)

    Windeløv, Nis Agerlin; Ostrowski, Sisse Rye; Johansson, Per Ingemar

    2015-01-01

    p 4 (p = 0.02). GPVI and PMPs levels correlated with TGFβ1 and PF4 whereas we found no significant association between cytokine levels and measures of haemostasis. By multivariate regression, a high WBC count was associated with high levels of TGFβ1 (p = 0.01) and β......TGs (p 4 (p = 0.03). CONCLUSION: Severely injured patients had higher levels of βTGs and TGFβ1 but lower levels of the PF4; a high WBC count predicted this anti-inflammatory profile of platelet cytokines....

  7. Associations among serum pro- and anti-inflammatory cytokines, metabolic mediators, body condition, and uterine disease in postpartum dairy cows.

    Science.gov (United States)

    Kasimanickam, Ramanathan K; Kasimanickam, Vanmathy R; Olsen, Jesse R; Jeffress, Erin J; Moore, Dale A; Kastelic, John P

    2013-11-09

    body condition mediated increases in anti- and pro-inflammatory cytokines, whereas increased pro- and anti-inflammatory cytokines concentrations mediated body condition loss and thereby prolonged persistence of uterine inflammation in dairy cows.

  8. Depletion of Regulatory T Cells in Visceral Adipose Tissues Contributes to Insulin Resistance in Hashimoto's Thyroiditis

    Directory of Open Access Journals (Sweden)

    Min Yang

    2018-02-01

    Full Text Available Hashimoto's Thyroiditis (HT is a common organ-specific autoimmune disorder associated with a high incidence, and insulin resistance is highly related to autoimmune. Here, we examined the insulin sensitivity in HT patients and found decreased insulin sensitivity occurred in HT patients. To explore the relationship between impaired insulin sensitivity and immune status, we established HT model mice which showed similar pathological features and immune features to HT patients. In HT model mice, reinfusion of regulatory T cells (Tregs from peripheral blood of normal mice could improve insulin sensitivity and decrease the inflammation. Anti-CD25 antibodies blocked beneficial effects from reinfusion of Tregs, but delayed administration of anti-CD25 antibodies could not abolished the effect from Tregs. Delayed administration of anti-CD25 antibodies abolished exogenous Tregs in peripheral blood, but there were increased exogenous Tregs located to visceral adipose tissues (VATs which modulated the expression of cytokines in VATs. These findings suggest that insulin resistance exists in HT patients and it associates with the decreased Tregs and increased inflammation in the VATs.

  9. Secretory IgA in complex with Lactobacillus rhamnosus potentiates mucosal dendritic cell-mediated Treg cell differentiation via TLR regulatory proteins, RALDH2 and secretion of IL-10 and TGF-β.

    Science.gov (United States)

    Mikulic, Josip; Longet, Stéphanie; Favre, Laurent; Benyacoub, Jalil; Corthesy, Blaise

    2017-06-01

    The importance of secretory IgA in controlling the microbiota is well known, yet how the antibody affects the perception of the commensals by the local immune system is still poorly defined. We have previously shown that the transport of secretory IgA in complex with bacteria across intestinal microfold cells results in an association with dendritic cells in Peyer's patches. However, the consequences of such an interaction on dendritic cell conditioning have not been elucidated. In this study, we analyzed the impact of the commensal Lactobacillus rhamnosus, alone or associated with secretory IgA, on the responsiveness of dendritic cells freshly recovered from mouse Peyer's patches, mesenteric lymph nodes, and spleen. Lactobacillus rhamnosus-conditioned mucosal dendritic cells are characterized by increased expression of Toll-like receptor regulatory proteins [including single immunoglobulin interleukin-1 receptor-related molecule, suppressor of cytokine signaling 1, and Toll-interacting molecule] and retinaldehyde dehydrogenase 2, low surface expression of co-stimulatory markers, high anti- versus pro-inflammatory cytokine production ratios, and induction of T regulatory cells with suppressive function. Association with secretory IgA enhanced the anti-inflammatory/regulatory Lactobacillus rhamnosus-induced conditioning of mucosal dendritic cells, particularly in Peyer's patches. At the systemic level, activation of splenic dendritic cells exposed to Lactobacillus rhamnosus was partially dampened upon association with secretory IgA. These data suggest that secretory IgA, through coating of commensal bacteria, contributes to the conditioning of mucosal dendritic cells toward tolerogenic profiles essential for the maintenance of intestinal homeostasis.

  10. About the distribution of delays in G.M counters

    International Nuclear Information System (INIS)

    Picard, E.; Rogozinski, A.

    1954-01-01

    We measure, with an oscillograph method the global time that pass between the time that a particle in a determined region of the studied counter and the answer of the amplifier associated to the counter. This delay is composed of the latency time T l and the T q delay, that result from the rise time finished of the impulse and whose value depends of the sensitivity threshold of the amplifier. The selection of (cosmic) particles generating discharge in the studied counter is obtained thanks to a telescope of two meters in coincidence whose opening is limited by a group of four counters in anti-coincidence with the first. The meter is arranged so that the median plan of the telescope crosses to a variable distance d of his axial thread. The measures have been done for different securities of the distance d and of the over-voltage V s applied to the counter. The results show that the statistical distribution of the delays is more spread especially when d is bigger and V s more reduced. The average values of the observed delays vary of 7.10 -8 s for d = 0 and V s es = 200 V, to 90.10 -8 s for d = 1,9 cm and V s = 50 V. The mobility of an free electron within the gaseous mixture filling the counter under a pressure of 10 cm.Hg was found equal: (2,1 ±0,2).10 4 cm 2 .s -1 .V -1 . (author) [fr

  11. Counter-Hegemonic Regionalism and Higher Education for All: Venezuela and the ALBA

    Science.gov (United States)

    Muhr, Thomas

    2010-01-01

    This paper employs new regionalism theory and regulatory regionalism theory in its analysis and theorisation of the Bolivarian Alliance for the Peoples of Our America (ALBA) as a counter-hegemonic Latin American and Caribbean (LAC) regionalism. As (initially) the regionalisation of Venezuela's Bolivarian Revolution, ALBA is centred around the idea…

  12. Autoimmunity and Cytokine Imbalance in Inherited Epidermolysis Bullosa

    Directory of Open Access Journals (Sweden)

    Susanna Esposito

    2016-09-01

    Full Text Available In order to evaluate the serum anti-skin autoantibodies and cytokine concentrations in patients with different epidermolysis bullosa (EB types and severity, 42 EB patients and 38 controls were enrolled. Serum anti-skin antibodies were significantly higher in the patients than in the controls (p = 0.008, p < 0.001, p < 0.001, p < 0.001 and p < 0.001 for desmoglein 1 (DSG1 desmoglein 3 (DSG3, bullous pemphigoid 180 (BP180, BP230 and type VII collagen (COL7, respectively. The same trend was observed for interleukin (IL-1β, IL-2, IL-6, IL-10, tumor necrosis factor-β, and interferon-γ (p < 0.001, p < 0.001, p < 0.001, p = 0.008, p < 0.001 and p = 0.002, respectively. Increases in anti-skin antibodies and cytokine concentrations were higher in patients with recessive dystrophic EB than in those with different types of EB, in generalized cases than in localized ones, and in patients with higher Birmingham Epidermolysis Bullosa Severity (BEBS scores than in those with a lower score. The BEBS score was directly correlated with BP180, BP230, COL7 (p = 0.015, p = 0.008 and p < 0.001, respectively and IL-6 (p = 0.03, whereas IL-6 appeared significantly associated with DSG1, DSG3, BP180, BP230 and COL7 (p = 0.015, p = 0.023, p = 0.023, p = 0.015 and p = 0.005, respectively. This study showed that autoimmunity and inflammatory responses are frequently activated in EB, mainly in severe forms, suggesting the use of immunosuppressive drugs or biologicals that are active against pro-inflammatory cytokines to reduce clinical signs and symptoms of disease.

  13. Disease severity in patients with visceral leishmaniasis is not altered by co-infection with intestinal parasites.

    Science.gov (United States)

    Tajebe, Fitsumbrhan; Getahun, Mulusew; Adem, Emebet; Hailu, Asrat; Lemma, Mulualem; Fikre, Helina; Raynes, John; Tamiru, Aschalew; Mulugeta, Zemenay; Diro, Ermias; Toulza, Frederic; Shkedy, Ziv; Ayele, Tadesse; Modolell, Manuel; Munder, Markus; Müller, Ingrid; Takele, Yegnasew; Kropf, Pascale

    2017-07-01

    Visceral leishmaniasis (VL) is a neglected tropical disease that affects the poorest communities and can cause substantial morbidity and mortality. Visceral leishmaniasis is characterized by the presence of Leishmania parasites in the spleen, liver and bone marrow, hepatosplenomegaly, pancytopenia, prolonged fever, systemic inflammation and low body mass index (BMI). The factors impacting on the severity of VL are poorly characterized. Here we performed a cross-sectional study to assess whether co-infection of VL patients with intestinal parasites influences disease severity, assessed with clinical and haematological data, inflammation, cytokine profiles and BMI. Data from VL patients was similar to VL patients co-infected with intestinal parasites, suggesting that co-infection of VL patients with intestinal parasites does not alter disease severity.

  14. Disease severity in patients with visceral leishmaniasis is not altered by co-infection with intestinal parasites

    Science.gov (United States)

    Adem, Emebet; Hailu, Asrat; Lemma, Mulualem; Fikre, Helina; Raynes, John; Tamiru, Aschalew; Mulugeta, Zemenay; Diro, Ermias; Toulza, Frederic; Shkedy, Ziv; Ayele, Tadesse; Modolell, Manuel; Munder, Markus; Müller, Ingrid; Takele, Yegnasew

    2017-01-01

    Visceral leishmaniasis (VL) is a neglected tropical disease that affects the poorest communities and can cause substantial morbidity and mortality. Visceral leishmaniasis is characterized by the presence of Leishmania parasites in the spleen, liver and bone marrow, hepatosplenomegaly, pancytopenia, prolonged fever, systemic inflammation and low body mass index (BMI). The factors impacting on the severity of VL are poorly characterized. Here we performed a cross-sectional study to assess whether co-infection of VL patients with intestinal parasites influences disease severity, assessed with clinical and haematological data, inflammation, cytokine profiles and BMI. Data from VL patients was similar to VL patients co-infected with intestinal parasites, suggesting that co-infection of VL patients with intestinal parasites does not alter disease severity. PMID:28732017

  15. Effectiveness of Antihyperglycemic Effect of Momordica charantia: Implication of T-Cell Cytokines

    Directory of Open Access Journals (Sweden)

    Rufine Fachinan

    2017-01-01

    Full Text Available Background/Objective. We investigate the effect of antidiabetic Momordica charantia fruit juice on T cells’ differentiation, through plasmatic cytokine quantification in type 1 diabetic rats (T1D. Methods. Male Wistar rats were rendered diabetic by the injection of five low doses of streptozotocin. Then, animals were treated with Momordica charantia fruit juice for 28 consecutive days. Plasmatic levels of Th1 interleukin- (IL- 02 and interferon- (IFN- γ, Th2 (IL-4, and regulatory (IL-10 cytokines were determined in rats. Results. We observed that fruit juice induced a significant decrease in blood glucose of T1D rats. Besides, the concentrations of IL-2 and IFN-γ significantly increased while those of IL-4 and IL-10 diminished in diabetic rats compared to control animals. Interestingly, after treatment with Momordica charantia fruit juice, IL-4 and IL-10 levels significantly increased in diabetic rats, while IL-2 and IFN-γ concentrations decreased, suggesting a Th2 phenotype in these animals. Phytochemical analysis of the fruit juice revealed the presence of tannins, flavonoids, and coumarins, compounds which possess antioxidant activity. Conclusion. This study shows that Momordica charantia fruit juice, by lowering the hyperglycemia, induced a shift of proinflammatory Th1 phenotype in T1D rats towards a favorable anti-inflammatory Th2 status. These effects might be due to the presence of antioxidant compounds in the juice and confirms the use of this plant in the treatment of autoimmune type 1 diabetes.

  16. Effectiveness of Antihyperglycemic Effect of Momordica charantia: Implication of T-Cell Cytokines.

    Science.gov (United States)

    Fachinan, Rufine; Yessoufou, Akadiri; Nekoua, Magloire Pandoua; Moutairou, Kabirou

    2017-01-01

    We investigate the effect of antidiabetic Momordica charantia fruit juice on T cells' differentiation, through plasmatic cytokine quantification in type 1 diabetic rats (T1D). Male Wistar rats were rendered diabetic by the injection of five low doses of streptozotocin. Then, animals were treated with Momordica charantia fruit juice for 28 consecutive days. Plasmatic levels of Th1 interleukin- (IL-) 02 and interferon- (IFN-) γ , Th2 (IL-4), and regulatory (IL-10) cytokines were determined in rats. We observed that fruit juice induced a significant decrease in blood glucose of T1D rats. Besides, the concentrations of IL-2 and IFN- γ significantly increased while those of IL-4 and IL-10 diminished in diabetic rats compared to control animals. Interestingly, after treatment with Momordica charantia fruit juice, IL-4 and IL-10 levels significantly increased in diabetic rats, while IL-2 and IFN- γ concentrations decreased, suggesting a Th2 phenotype in these animals. Phytochemical analysis of the fruit juice revealed the presence of tannins, flavonoids, and coumarins, compounds which possess antioxidant activity. This study shows that Momordica charantia fruit juice, by lowering the hyperglycemia, induced a shift of proinflammatory Th1 phenotype in T1D rats towards a favorable anti-inflammatory Th2 status. These effects might be due to the presence of antioxidant compounds in the juice and confirms the use of this plant in the treatment of autoimmune type 1 diabetes.

  17. Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial [version 3; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Antony J. Cutler

    2017-10-01

    Full Text Available Background: The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen. Methods: Serial blood, serum and peripheral blood mononuclear cell (PBMC samples were collected pre-, and post-development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2 alone, samples from five non-infected participants administered similar doses were analysed in parallel. Results: Norovirus infection was self-limited and resolved within 24 hours, with the subsequent development of anti-norovirus antibodies. Serum pro- and anti-inflammatory cytokine levels, including IL-10, peaked during the symptomatic period of infection, coincident with increased frequencies of monocytes and neutrophils. At the same time, the frequency of regulatory CD4+ T cell (Treg, effector T cell (Teff CD4+ and CD8+ subsets were dynamically reduced, rebounding to baseline levels or above at the next sampling point 24 hours later.  NK cells and NKT cells transiently increased CD69 expression and classical monocytes expressed increased levels of CD40, HLA-DR and SIGLEC-1, biomarkers of an interferon response. We also observed activation and mobilisation of Teffs, where increased frequencies of CD69+ and Ki-67+ effector memory Teffs were followed by the emergence of memory CD8+ Teff expressing the mucosal tissue homing markers CD103 and β7 integrin. Treg responses were coincident with the innate cell, Teff and cytokine response. Key Treg molecules FOXP3, CTLA-4, and CD25 were upregulated following infection, alongside an increase in frequency of Tregs with the capacity to home to tissues. Conclusions: The results illustrate the innate, adaptive and counter-regulatory

  18. Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Antony J. Cutler

    2017-07-01

    Full Text Available Background: The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen. Methods: Serial blood, serum and peripheral blood mononuclear cell (PBMC samples were collected pre-, and post-development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2 alone, samples from five non-infected participants administered similar doses were analysed in parallel. Results: Norovirus infection was self-limited and resolved within 24 hours, with the subsequent development of anti-norovirus antibodies. Serum pro- and anti-inflammatory cytokine levels, including IL-10, peaked during the symptomatic period of infection, coincident with increased frequencies of monocytes and neutrophils. At the same time, the frequency of regulatory CD4+ T cell (Treg, effector T cell (Teff CD4+ and CD8+ subsets were dynamically reduced, rebounding to baseline levels or above at the next sampling point 24 hours later.  NK cells and NKT cells transiently increased CD69 expression and classical monocytes expressed increased levels of CD40, HLA-DR and SIGLEC-1, biomarkers of an interferon response. We also observed activation and mobilisation of Teffs, where increased frequencies of CD69+ and Ki-67+ effector memory Teffs were followed by the emergence of memory CD8+ Teff expressing the mucosal tissue homing markers CD103 and β7 integrin. Treg responses were coincident with the innate cell, Teff and cytokine response. Key Treg molecules FOXP3, CTLA-4, and CD25 were upregulated following infection, alongside an increase in frequency of Tregs with the capacity to home to tissues. Conclusions: The results illustrate the innate, adaptive and counter-regulatory

  19. Modulation of PBMC-decay accelerating factor (PBMC-DAF) and cytokines in rheumatoid arthritis.

    Science.gov (United States)

    Pahwa, Roma; Kumar, Uma; Das, Nibhriti

    2016-03-01

    Studies have suggested that abnormal expression of complement regulatory proteins and cytokines contribute significantly to the path-physiology of rheumatoid arthritis. In this context, Decay accelerating factor (DAF) a complement regulatory protein is gaining increased attention. With the notion that immune effecter mechanisms are all interlinked and circulating peripheral blood mononuclear cells (PBMCs) should have a role in a systemic disease like rheumatoid arthritis, we studied the modulation and significance of PBMC-DAF and cytokines in RA. Seventy-five RA patients and 75 healthy controls were recruited. Expression of DAF and cytokines (IFN-γ, IL-17A and IL-10) in the PBMCs of patients and controls was determined. Correlations among DAF, cytokines, and disease activity were evaluated by standard statistical methods. The effect of IFN-γ, IL-17A, and IL-10 on the expression of DAF in patients and controls was studied in vitro. Expression of PBMC-DAF declined in patients both at mRNA and surface level and correlated negatively with the disease activity. Expression of IFN-γ also declined in patients but correlated positively with DAF and negatively with disease activity. Expression of IL-17A and IL-10 was higher in patients. The levels correlated positively with disease activity and negatively with DAF both in patients and controls. In vitro studies indicated that IFN-γ up-regulated DAF expression in PBMCs, whereas IL-17A and IL-10 had negative effect on the same. The decline in the PBMC-DAF is a contributing factor in manifestations of RA. Cytokine environment contributes to this decline. These findings brought novel insights into the complement-cytokine axis in the path-physiology of RA.

  20. CYTOKINE PROFILE FEATURES IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

    Directory of Open Access Journals (Sweden)

    E. Р. Kalinina

    2012-01-01

    Full Text Available Abstract. We studied cytokine profile in blood and exhaled breath condensate (EBC in patients with chronic obstructive pulmonary disease (COPD being in remission state. It is shown that pro- and anti-inflammatory cytokine contents depended on the disease severity, both in whole blood and EBC of the COPD patients. We have revealed an increase in TNFα, s-TNFα RI, TGF-β1 and bFGF in EBC of patients with COPD manifestations, thus being indicative for progression of metabolic changes in lung tissue, and advanced stage of respiratory functional disturbances. Cytokine profile abnormalities in COPD patients resulting, in part, from systemic and local disorders of cellular immunity, represent a major pathogenetic mechanism determining the disease progression.

  1. Anti-VEGF drugs: evidence for effectiveness

    OpenAIRE

    Evans, Jennifer; Virgili, Gianni

    2014-01-01

    Anti-vascular endothelial growth factors (anti-VEGF) are targeted biological drugs (e.g. monoclonal antibodies) that prevent the growth of new vessels by inhibiting VEGF. VEGF is a cytokine (cell-signalling protein) that promotes the growth of, and leakage from, new vessels. Currently there are three anti-VEGF drugs licensed for use in eye disease: pegaptanib, aflibercept, ranibizumab and one that is not licensed but is commonly used off-label (bevacizumab).

  2. Cytokine gene expression profiles in chicken spleen and intestinal tissues during Ascaridia galli infection

    DEFF Research Database (Denmark)

    Pleidrup, Janne A.; Norup, Liselotte R.; Dalgaard, Tina S.

    2014-01-01

    In the poultry production industry, chickens with access to outdoor areas are exposed to a wide range of parasites e.g. the helminth Ascaridia galli. By real-time quantitative RTPCR, the relative gene expression of the T helper 1 (Th1) cytokine IFN-gamma, the T helper 2 (Th2) cytokine IL-13...... expression of jejunal IFN-gamma and IL-13 was observed. Finally, at the expected period of an adaptive immune response (days 14-21) a general decreased expression of IFN-gamma and TGF-beta 4 in spleen and IFN-gamma in jejunum was followed by a decreased expression of IFN-gamma and IL-10 at day 21 in caecal...

  3. BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Bo; Hu, Mintao [Department of Hepatology, Wuxi Infectious Diseases Hospital, Wuxi, Jiangsu (China); Zhang, Peng [Nanjing Medical University, Nanjing, Jiangsu (China); Cao, Hong [Department of Hepatology, Wuxi Infectious Diseases Hospital, Wuxi, Jiangsu (China); Wang, Yongzhen [The Second Hospital of Nanjing, Nanjing, Jiangsu (China); Wang, Zheng; Su, Tingting [Department of Hepatology, Wuxi Infectious Diseases Hospital, Wuxi, Jiangsu (China)

    2013-05-10

    Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs) play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF) is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment.

  4. Restoring Lost Anti-HER-2 Th1 Immunity in Breast Cancer: A Crucial Role for Th1 Cytokines in Therapy and Prevention.

    Science.gov (United States)

    Nocera, Nadia F; Lee, M Catherine; De La Cruz, Lucy M; Rosemblit, Cinthia; Czerniecki, Brian J

    2016-01-01

    The ErbB/B2 (HER-2/neu) oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy. Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast. Th1 cell production of the cytokines interferon gamma (IFNγ) and TNFα can enhance MHC class I expression, PD-L1 expression, augment apoptosis and tumor senescence, and enhances growth inhibition of many anti-breast cancer agents, including anti-estrogens and HER-2 targeted therapies. Recently, we have identified that a loss of anti-HER-2 CD4 Th1 in peripheral blood occurs during breast tumorigenesis and is dramatically diminished, even in Stage I breast cancers. The loss of anti-HER-2 Th1 response is specific and not readily reversed by standard therapies. In fact, this loss of anti-HER-2 Th1 response in peripheral blood correlates with lack of complete response to neoadjuvant therapy and diminished disease-free survival. This defect can be restored with HER-2 vaccinations in both DCIS and IBC. Correcting the anti-HER-2 Th1 response may have significant impact in improving response to HER-2 targeted therapies. Development of immune monitoring systems for anti-HER-2 Th1 to identify patients at risk for recurrence could be critical to improving outcomes, since the anti-HER-2 Th1 response can be restored by vaccination. Correction of the cellular immune response against HER-2 may prevent recurrence in high-risk patients with DCIS and IBC at risk of developing new or recurrent breast cancer.

  5. Anti-Inflammatory and Immune Regulatory Actions of Naja naja atra Venom

    Directory of Open Access Journals (Sweden)

    Shu-Zhi Wang

    2018-02-01

    Full Text Available Naja naja atra venom (NNAV is composed of various proteins, peptides, and enzymes with different biological and pharmacological functions. A number of previous studies have reported that NNAV exerts potent analgesic effects on various animal models of pain. The clinical studies using whole venom or active components have confirmed that NNAV is an effective and safe medicine for treatment of chronic pain. Furthermore, recent studies have demonstrated that NNAV has anti-inflammatory and immune regulatory actions in vitro and in vivo. In this review article, we summarize recent studies of NNAV and its components on inflammation and immunity. The main new findings in NNAV research show that it may enhance innate and humoral immune responses while suppressing T lymphocytes-mediated cellular immunity, thus suggesting that NNAV and its active components may have therapeutic values in the treatment of inflammatory and autoimmune diseases.

  6. Split2 Protein-Ligation Generates Active IL-6-Type Hyper-Cytokines from Inactive Precursors.

    Science.gov (United States)

    Moll, Jens M; Wehmöller, Melanie; Frank, Nils C; Homey, Lisa; Baran, Paul; Garbers, Christoph; Lamertz, Larissa; Axelrod, Jonathan H; Galun, Eithan; Mootz, Henning D; Scheller, Jürgen

    2017-12-15

    Trans-signaling of the major pro- and anti-inflammatory cytokines Interleukin (IL)-6 and IL-11 has the unique feature to virtually activate all cells of the body and is critically involved in chronic inflammation and regeneration. Hyper-IL-6 and Hyper-IL-11 are single chain designer trans-signaling cytokines, in which the cytokine and soluble receptor units are trapped in one complex via a flexible peptide linker. Albeit, Hyper-cytokines are essential tools to study trans-signaling in vitro and in vivo, the superior potency of these designer cytokines are accompanied by undesirable stress responses. To enable tailor-made generation of Hyper-cytokines, we developed inactive split-cytokine-precursors adapted for posttranslational reassembly by split-intein mediated protein trans-splicing (PTS). We identified cutting sites within IL-6 (E 134 /S 135 ) and IL-11 (G 116 /S 117 ) and obtained inactive split-Hyper-IL-6 and split-Hyper-IL-11 cytokine precursors. After fusion with split-inteins, PTS resulted in reconstitution of active Hyper-cytokines, which were efficiently secreted from transfected cells. Our strategy comprises the development of a background-free cytokine signaling system from reversibly inactivated precursor cytokines.

  7. Regulatory Lymphocytes Are Key Factors in MHC-Independent Resistance to EAE

    Science.gov (United States)

    Marín, Nieves; Mecha, Miriam; Espejo, Carmen; Mestre, Leyre; Eixarch, Herena; Montalban, Xavier; Álvarez-Cermeño, José C.; Guaza, Carmen; Villar, Luisa M.

    2014-01-01

    Background and Objectives. Resistant and susceptible mouse strains to experimental autoimmune encephalomyelitis (EAE), an inducible demyelinating experimental disease serving as animal model for multiple sclerosis, have been described. We aimed to explore MHC-independent mechanisms inducing resistance to EAE. Methods. For EAE induction, female C57BL/6 (susceptible strain) and CD1 (resistant outbred strain showing heterogeneous MHC antigens) mice were immunized with the 35–55 peptide of myelin oligodendrocyte glycoprotein (MOG35−55). We studied T cell proliferation, regulatory and effector cell subpopulations, intracellular and serum cytokine patterns, and titers of anti-MOG serum antibodies. Results. Upon immunization with MOG35−55, T lymphocytes from susceptible mice but not that of resistant strain were capable of proliferating when stimulated with MOG35−55. Accordingly, resistant mice experienced a rise in regulatory B cells (P = 0.001) and, to a lower extent, in regulatory T cells (P = 0.02) compared with C57BL/6 susceptible mice. As a consequence, MOG35−55-immunized C57BL/6 mice showed higher percentages of CD4+ T cells producing both IFN-gamma (P = 0.02) and IL-17 (P = 0.009) and higher serum levels of IL-17 (P = 0.04) than resistant mice. Conclusions. Expansion of regulatory B and T cells contributes to the induction of resistance to EAE by an MHC-independent mechanism. PMID:24868560

  8. Regulatory Lymphocytes Are Key Factors in MHC-Independent Resistance to EAE

    Directory of Open Access Journals (Sweden)

    Nieves Marín

    2014-01-01

    Full Text Available Background and Objectives. Resistant and susceptible mouse strains to experimental autoimmune encephalomyelitis (EAE, an inducible demyelinating experimental disease serving as animal model for multiple sclerosis, have been described. We aimed to explore MHC-independent mechanisms inducing resistance to EAE. Methods. For EAE induction, female C57BL/6 (susceptible strain and CD1 (resistant outbred strain showing heterogeneous MHC antigens mice were immunized with the 35–55 peptide of myelin oligodendrocyte glycoprotein (MOG35−55. We studied T cell proliferation, regulatory and effector cell subpopulations, intracellular and serum cytokine patterns, and titers of anti-MOG serum antibodies. Results. Upon immunization with MOG35−55, T lymphocytes from susceptible mice but not that of resistant strain were capable of proliferating when stimulated with MOG35−55. Accordingly, resistant mice experienced a rise in regulatory B cells (P=0.001 and, to a lower extent, in regulatory T cells (P=0.02 compared with C57BL/6 susceptible mice. As a consequence, MOG35−55-immunized C57BL/6 mice showed higher percentages of CD4+ T cells producing both IFN-gamma (P=0.02 and IL-17 (P=0.009 and higher serum levels of IL-17 (P=0.04 than resistant mice. Conclusions. Expansion of regulatory B and T cells contributes to the induction of resistance to EAE by an MHC-independent mechanism.

  9. Stress and sex in malaria parasites: Why does commitment vary?

    Science.gov (United States)

    Carter, Lucy M; Kafsack, Björn F C; Llinás, Manuel; Mideo, Nicole; Pollitt, Laura C; Reece, Sarah E

    2013-01-01

    For vector-borne parasites such as malaria, how within- and between-host processes interact to shape transmission is poorly understood. In the host, malaria parasites replicate asexually but for transmission to occur, specialized sexual stages (gametocytes) must be produced. Despite the central role that gametocytes play in disease transmission, explanations of why parasites adjust gametocyte production in response to in-host factors remain controversial. We propose that evolutionary theory developed to explain variation in reproductive effort in multicellular organisms, provides a framework to understand gametocyte investment strategies. We examine why parasites adjust investment in gametocytes according to the impact of changing conditions on their in-host survival. We then outline experiments required to determine whether plasticity in gametocyte investment enables parasites to maintain fitness in a variable environment. Gametocytes are a target for anti-malarial transmission-blocking interventions so understanding plasticity in investment is central to maximizing the success of control measures in the face of parasite evolution.

  10. GITR ligand-costimulation activates effector and regulatory functions of CD4+ T cells

    International Nuclear Information System (INIS)

    Igarashi, Hanna; Cao, Yujia; Iwai, Hideyuki; Piao, Jinhua; Kamimura, Yosuke; Hashiguchi, Masaaki; Amagasa, Teruo; Azuma, Miyuki

    2008-01-01

    Engagement of glucocorticoid-induced TNFR-related protein (GITR) enables the costimulation of both CD25 - CD4 + effector (Teff) and CD25 + CD4 + regulatory (Treg) cells; however, the effects of GITR-costimulation on Treg function remain controversial. In this study, we examined the effects of GITR ligand (GITRL) binding on the respective functions of CD4 + T cells. GITRL-P815 transfectants efficiently augmented anti-CD3-induced proliferation and cytokine production by Teff cells. Proliferation and IL-10 production in Treg were also enhanced by GITRL transfectants when exogenous IL-2 and stronger CD3 stimulation was provided. Concomitant GITRL-costimulation of Teff and Treg converted the anergic state of Treg into a proliferating state, maintaining and augmenting their function. Thus, GITRL-costimulation augments both effector and regulatory functions of CD4 + T cells. Our results suggest that highly activated and increased ratios of Treg reverse the immune-enhancing effects of GITRL-costimulation in Teff, which may be problematic for therapeutic applications using strong GITR agonists

  11. Targeting channels and transporters in protozoan parasite infections

    Science.gov (United States)

    Meier, Anna; Erler, Holger; Beitz, Eric

    2018-03-01

    Infectious diseases caused by pathogenic protozoa are among the most significant causes of death in humans. Therapeutic options are scarce and massively challenged by the emergence of resistant parasite strains. Many of the current anti-parasite drugs target soluble enzymes, generate unspecific oxidative stress, or act by an unresolved mechanism within the parasite. In recent years, collections of drug-like compounds derived from large-scale phenotypic screenings, such as the malaria or pathogen box, have been made available to researchers free of charge boosting the identification of novel promising targets. Remarkably, several of the compound hits have been found to inhibit membrane proteins at the periphery of the parasites, i.e. channels and transporters for ions and metabolites. In this review, we will focus on the progress made on targeting channels and transporters at different levels and the potential for use against infections with apicomplexan parasites mainly Plasmodium spp. (malaria) and Toxoplasma gondii (toxoplasmosis), with kinetoplastids Trypanosoma brucei (sleeping sickness), Trypanosoma cruzi (Chagas disease) and Leishmania ssp. (leishmaniasis), and the amoeba Entamoeba histolytica (amoebiasis).

  12. Regulatory T cell expansion in HTLV-1 and strongyloidiasis co-infection is associated with reduced IL-5 responses to Strongyloides stercoralis antigen.

    Directory of Open Access Journals (Sweden)

    Martin Montes

    2009-06-01

    Full Text Available Human strongyloidiasis varies from a chronic but limited infection in normal hosts to hyperinfection in patients treated with corticosteroids or with HTLV-1 co-infection. Regulatory T cells dampen immune responses to infections. How human strongyloidiasis is controlled and how HTLV-1 infection affects this control are not clear. We hypothesize that HTLV-1 leads to dissemination of Strongyloides stercoralis infection by augmenting regulatory T cell numbers, which in turn down regulate the immune response to the parasite.To measure peripheral blood T regulatory cells and Strongyloides stercoralis larval antigen-specific cytokine responses in strongyloidiasis patients with or without HTLV-1 co-infection.Peripheral blood mononuclear cells (PBMCs were isolated from newly diagnosed strongyloidiasis patients with or without HTLV-1 co-infection. Regulatory T cells were characterized by flow cytometry using intracellular staining for CD4, CD25 and FoxP3. PBMCs were also cultured with and without Strongyloides larval antigens. Supernatants were analyzed for IL-5 production.Patients with HTLV-1 and Strongyloides co-infection had higher parasite burdens. Eosinophil counts were decreased in the HTLV-1 and Strongyloides co-infected subjects compared to strongyloidiasis-only patients (70.0 vs. 502.5 cells/mm(3, p = 0.09, Mann-Whitney test. The proportion of regulatory T cells was increased in HTLV-1 positive subjects co-infected with strongyloidiasis compared to patients with only strongyloidiasis or asymptomatic HTLV-1 carriers (median = 17.9% vs. 4.3% vs. 5.9 p<0.05, One-way ANOVA. Strongyloides antigen-specific IL-5 responses were reduced in strongyloidiasis/HTLV-1 co-infected patients (5.0 vs. 187.5 pg/ml, p = 0.03, Mann-Whitney test. Reduced IL-5 responses and eosinophil counts were inversely correlated to the number of CD4+CD25+FoxP3+ cells.Regulatory T cell counts are increased in patients with HTLV-1 and Strongyloides stercoralis co-infection and

  13. Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite.

    Science.gov (United States)

    Das, Pronay; Babbar, Palak; Malhotra, Nipun; Sharma, Manmohan; Jachak, Gorakhnath R; Gonnade, Rajesh G; Shanmugam, Dhanasekaran; Harlos, Karl; Yogavel, Manickam; Sharma, Amit; Reddy, D Srinivasa

    2018-05-21

    The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332. Given that scores of anti-malarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of anti-microbial drug development.

  14. Seroprevalences of anti-Sarcocystis neurona and anti-Neospora hughesi antibodies among healthy equids in the United States.

    Science.gov (United States)

    James, Kaitlyn E; Smith, Woutrina A; Conrad, Patricia A; Packham, Andrea E; Guerrero, Leopoldo; Ng, Mitchell; Pusterla, Nicola

    2017-06-01

    OBJECTIVE To describe the general seroprevalence of anti-Sarcocystis neurona and anti-Neospora hughesi antibodies among healthy equids by use of indirect fluorescent antibody tests and determine potential risk factors for seropositivity. DESIGN Cross-sectional study. SAMPLE Whole blood samples collected from 5,250 equids (1 sample/animal) across 18 states in the United States during October 2013. PROCEDURES Information regarding potential risk factors (geographic region, breed, primary use, sex, and age) was collected along with the blood samples. For each equid, an indirect fluorescent antibody test was used to determine serum titers of antibody against each of the 2 protozoal parasites. Mixed-effects logistic regression models were created to determine ORs for seropositivity. RESULTS The overall seroprevalence of anti-S neurona and anti-N hughesi antibodies in the tested equids was 78% and 34%, respectively. Of the equids, 31% were seropositive and 18% were seronegative for antibodies against both parasites. Factors associated with equids being seropositive for anti-S neurona antibodies were residence in the South, warmblood breed, and age > 5 years. Seroprevalence of anti-N hughesi antibodies did not differ among equids in different states across the country, but warmblood breed and age > 5 years were associated with seropositivity. CONCLUSIONS AND CLINICAL RELEVANCE With regard to risk factors for S neurona and N hughesi exposure and antibody response among tested equids, older age was not unexpected; however, the influences of warmblood breed and geographic location on seropositivity for anti-S neurona antibody but not for anti-N hughesi antibody deserve further investigation.

  15. Morphological and Molecular Descriptors of the Developmental Cycle of Babesia divergens Parasites in Human Erythrocytes.

    Directory of Open Access Journals (Sweden)

    Ingrid Rossouw

    2015-05-01

    Full Text Available Human babesiosis, especially caused by the cattle derived Babesia divergens parasite, is on the increase, resulting in renewed attentiveness to this potentially life threatening emerging zoonotic disease. The molecular mechanisms underlying the pathophysiology and intra-erythrocytic development of these parasites are poorly understood. This impedes concerted efforts aimed at the discovery of novel anti-babesiacidal agents. By applying sensitive cell biological and molecular functional genomics tools, we describe the intra-erythrocytic development cycle of B. divergens parasites from immature, mono-nucleated ring forms to bi-nucleated paired piriforms and ultimately multi-nucleated tetrads that characterizes zoonotic Babesia spp. This is further correlated for the first time to nuclear content increases during intra-erythrocytic development progression, providing insight into the part of the life cycle that occurs during human infection. High-content temporal evaluation elucidated the contribution of the different stages to life cycle progression. Moreover, molecular descriptors indicate that B. divergens parasites employ physiological adaptation to in vitro cultivation. Additionally, differential expression is observed as the parasite equilibrates its developmental stages during its life cycle. Together, this information provides the first temporal evaluation of the functional transcriptome of B. divergens parasites, information that could be useful in identifying biological processes essential to parasite survival for future anti-babesiacidal discoveries.

  16. Effects of Curcuma comosa on the expression of atherosclerosis-related cytokine genes in rabbits fed a high-cholesterol diet.

    Science.gov (United States)

    Charoenwanthanang, Puttavee; Lawanprasert, Somsong; Phivthong-Ngam, Laddawal; Piyachaturawat, Pawinee; Sanvarinda, Yupin; Porntadavity, Sureerut

    2011-04-12

    Curcuma comosa has been known to have potential use in cardiovascular diseases, but its immunoregulatory role in atherosclerosis development and liver toxicity has not been well studied. We therefore investigated the effects of Curcuma comosa on the expression of atherosclerosis-related cytokine genes in rabbits fed a high-cholesterol diet. Twelve male New Zealand White rabbits were treated with 1.0% cholesterol for one month and were subsequently treated with 0.5% cholesterol either alone, or in combination with 5mg/kg/day of simvastatin or with 400mg/kg/day of Curcuma comosa powder for three months. The expression of IL-1, MCP-1, TNF-α, IL-10, and TGF-β in the isolated abdominal aorta and liver were determined by real-time RT-PCR. Liver toxicity was determined by hepatic enzyme activity. Curcuma comosa significantly decreased the expression of pro-inflammatory cytokines, leading to a stronger reduction in IL-1, MCP-1, and TNF-α expression compared to that was suppressed by simvastatin treatment. However, neither Curcuma comosa nor simvastatin affected the expression of anti-inflammation cytokines. In the liver, Curcuma comosa insignificantly decreased the expression of pro-inflammatory cytokines and significantly increased the expression of the anti-inflammatory cytokine IL-10 without altering the activity of hepatic enzymes. In contrast, simvastatin significantly increased the MCP-1 and TNF-α expressions and serum ALT level, without affecting the expression of anti-inflammatory cytokines. In this study, we demonstrated that Curcuma comosa exerts anti-inflammatory activity in the aorta and liver without causing liver toxicity, indicating that Curcuma comosa is a potential candidate as an alternative agent in cardiovascular disease therapy. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  17. Endoparasites of Stray Dogs in Mashhad, Khorasan Razavi Province, Northeast Iran with Special Reference to Zoonotic Parasites

    Directory of Open Access Journals (Sweden)

    Amir Adinezadeh

    2013-09-01

    Full Text Available Background: To find out different species of helminthes and blood/tissue proto­zoan parasites of stray dogs and their potential role for transmission of zoonotic species to human in Mashhad, Khorasan Razavi Province, northeast Iran, during 2008-2009.Methods: Totally, 100 stray dogs were selected among Mashhad municipal collection from different sites of the city. Internal organs were examined for any parasites. Helminthes were identified based on morphological characteristics. Smears prepared from peripheral blood as well as liver, spleen and any skin lesion were stained by Giemsa and examined microscopically. Samples obtained from spleen were aseptically cultured in three culture media including NNN, Schneider’s Drosophila (HIMEDIA and RPMI1640 (GIBCO for isolation of Leishmania spp. The titer of anti-Leishmania and anti-Toxoplasma antibodies were measured by direct agglutination test (DAT and indirect fluorescent antibody test (IFAT, respectively.Results: 84% of dogs were infected at least with one species of intestinal helminthes. The species of parasites and rate of infection were as follows: Taenia hydatigena (61%, Dipylidium caninum (46%, Mesocestoides lineatus (19%, Echinococcus granulosus (10%, Toxascaris leonina (53% and Toxocara canis (7%. Anti-Leishmania antibodies were detected by DAT in 8 dogs (8% at 1:320 titers and higher. Forty seven dogs (47% showed anti-Toxoplasma titer at 1:10 and 17 (17% showed titer of ≥1:100. No blood parasites were found in prepared blood smears.Conclusion: The high rate of parasitic infection and presence of zoonotic species

  18. Cytokine production in BALB/c mice immunized with radiation attenuated third stage larvae of the filarial nematode, Brugia pahangi

    International Nuclear Information System (INIS)

    Bancroft, A.J.; Devaney, E.; Grencis, R.K.; Else, K.J.

    1993-01-01

    BALB/c mice immunized with radiation-attenuated third stage larvae of the filarial nematode Brugia pahangi are strongly immune to challenge infection. Investigation of the profile of cytokines secreted by spleen cells from immune mice stimulated in vitro with either parasite Ag or with Con A revealed high levels of IL-5 and IL-9 and moderate levels of IL-4. In contrast, secretion of IFN-γ by spleen cells from immune animals was negligible. Spleen cells from control mice secreted low levels of all cytokines assayed. Levels of parasite-specific IgE were significantly elevated in immune animals and a peripheral blood eosinophilia was observed, which exhibited a biphasic distribution. Our results are consistent with the preferential expansion of Th2 cells in immune animals and provide the basis for dissecting the means by which radiation-attenuated larvae of filarial nematodes stimulate immunity. 5l refs., 3 figs., 3 tabs

  19. Antibody blockade of IL-17 family cytokines in immunity to acute murine oral mucosal candidiasis.

    Science.gov (United States)

    Whibley, Natasha; Tritto, Elaine; Traggiai, Elisabetta; Kolbinger, Frank; Moulin, Pierre; Brees, Dominique; Coleman, Bianca M; Mamo, Anna J; Garg, Abhishek V; Jaycox, Jillian R; Siebenlist, Ulrich; Kammüller, Michael; Gaffen, Sarah L

    2016-06-01

    Antibodies targeting IL-17A or its receptor, IL-17RA, are approved to treat psoriasis and are being evaluated for other autoimmune conditions. Conversely, IL-17 signaling is critical for immunity to opportunistic mucosal infections caused by the commensal fungus Candida albicans, as mice and humans lacking the IL-17R experience chronic mucosal candidiasis. IL-17A, IL-17F, and IL-17AF bind the IL-17RA-IL-17RC heterodimeric complex and deliver qualitatively similar signals through the adaptor Act1. Here, we used a mouse model of acute oropharyngeal candidiasis to assess the impact of blocking IL-17 family cytokines compared with specific IL-17 cytokine gene knockout mice. Anti-IL-17A antibodies, which neutralize IL-17A and IL-17AF, caused elevated oral fungal loads, whereas anti-IL-17AF and anti-IL-17F antibodies did not. Notably, there was a cooperative effect of blocking IL-17A, IL-17AF, and IL-17F together. Termination of anti-IL-17A treatment was associated with rapid C. albicans clearance. IL-17F-deficient mice were fully resistant to oropharyngeal candidiasis, consistent with antibody blockade. However, IL-17A-deficient mice had lower fungal burdens than anti-IL-17A-treated mice. Act1-deficient mice were much more susceptible to oropharyngeal candidiasis than anti-IL-17A antibody-treated mice, yet anti-IL-17A and anti-IL-17RA treatment caused equivalent susceptibilities. Based on microarray analyses of the oral mucosa during infection, only a limited number of genes were associated with oropharyngeal candidiasis susceptibility. In sum, we conclude that IL-17A is the main cytokine mediator of immunity in murine oropharyngeal candidiasis, but a cooperative relationship among IL-17A, IL-17AF, and IL-17F exists in vivo. Susceptibility displays the following hierarchy: IL-17RA- or Act1-deficiency > anti-IL-17A + anti-IL-17F antibodies > anti-IL-17A or anti-IL-17RA antibodies > IL-17A deficiency. © Society for Leukocyte Biology.

  20. Cytokine Gene Expression in Response to SnSAG1 in Horses with Equine Protozoal Myeloencephalitis

    Science.gov (United States)

    Spencer, Jennifer A.; Deinnocentes, Patricia; Moyana, Edith M.; Guarino, Anthony J.; Ellison, Siobhan E.; Bird, R. Curtis; Blagburn, Byron L.

    2005-01-01

    Equine protozoal myeloencephalitis (EPM) is a neurologic syndrome seen in horses from the Americas and is mainly caused by Sarcocystis neurona. Recently, a 29-kDa surface antigen from S. neurona merozoites was identified as being highly immunodominant on a Western blot. This antigen has been sequenced and cloned, and the expressed protein has been named SnSAG1. In a previous study, cell-mediated immune responses to SnSAG1 were shown to be statistically significantly reduced in horses with EPM in comparison to EPM-negative control horses. It therefore appears as though the parasite is able to induce immunosuppression towards parasite-derived antigens as parasite-specific responses are decreased. Isolated peripheral blood lymphocytes from 21 EPM (cerebrospinal fluid [CSF] Western blot)-negative horses with no clinical signs and 21 horses with clinical signs of EPM (CSF Western blot positive) were cocultured with SnSAG1 for 48 and 72 h, and the effect on cytokine production was investigated by means of reverse transcriptase PCR. Cytokines assayed include gamma interferon (IFN-γ), tumor necrosis factor alpha, interleukin (IL)-2, IL-4, and IL-6. β-Actin was used as the housekeeping gene. A Wilcoxon signed-rank test of the findings indicated that there was a statistically significant decrease in IFN-γ production after 48 h in culture for samples from horses with clinical disease. There was also a statistically significant increase in IL-4 production after 72 h in culture for samples from horses with EPM. These results further support the notion that this parasite is able to subvert the immune system in horses with clinical disease. PMID:15879026

  1. Retrospective investigation of serological finding in diagnosis of parasite agents caused mass in liver

    Directory of Open Access Journals (Sweden)

    Safinaz Demirkaya

    2014-06-01

    Full Text Available Objective: Many of parasite agent cause diseases damaging the liver. The parasite infections settled the liver give rise to focal mass named as reactive hyperplasia or granulomatous reactions in this organ. Some of parasites caused focal mass in liver are cystic echinococ, Fasciola hepatica and Entamoeba histolytica. The diagnoses of these parasites which are localized to liver have been carried out with serological methods (Indirect hemagglutination (IHA, Indirect Fluorescent Antibody Technic (IFAT and ELISA (Enzyme Linked Immunosorbent Assay and radiological imaging. In this study, we was aimed to investigating of prevalence with serological methods of parasite diseases like cystic echinococcosis, fascioliasis and amebic liver abscess in patients determined preliminary diagnosis mass with radiological imaging Methods: For this study, One hundred patient’s sera were included to investigation. It were investigated E.histolytica antibody with IHA method, anti-echinococcus IgG antibody with IFAT method and anti-fasciolia hepatica IgG antibody with ELISA method in sera of patient’s determined mass preliminary diagnosis with radiological imaging. Results: It were encountered these parasite in 27% of patients who determined mass preliminary diagnosis. It was determined in 1% E.histolytica, 13% Cystic echinococcus and 13% Fasciola hepatica seropositive of patients. Conclusion: The patients detected mass preliminary in liver should be evaluated for these parasites. We believe that will not be enough only radiological imaging in identification of these parasitic infections and should definitely need to be supported with a serological test.

  2. Pannexin-2-deficiency sensitizes pancreatic beta-cells to cytokine-induced apoptosis in vitro and impairs glucose tolerance in vivo

    DEFF Research Database (Denmark)

    Berchtold, Lukas A.; Miani, Michela; Diep, Thi A.

    2017-01-01

    -cells, and β-cell lines. The expression of Panx2, but not Panx1, was downregulated by interleukin-1β (IL-1β) plus interferon-γ (IFNγ), two pro-inflammatory cytokines suggested to contribute to β-cell demise in type 1 diabetes (T1D). siRNA-mediated knockdown (KD) of Panx2 aggravated cytokine-induced apoptosis...... in rat INS-1E cells and primary rat β-cells, suggesting anti-apoptotic properties of Panx2. An anti-apoptotic function of Panx2 was confirmed in isolated islets from Panx2-/- mice and in human EndoC-βH1 cells. Panx2 KD was associated with increased cytokine-induced activation of STAT3 and higher...

  3. Neuropathic pain and cytokines: current perspectives

    Directory of Open Access Journals (Sweden)

    Clark AK

    2013-11-01

    Full Text Available Anna K Clark, Elizabeth A Old, Marzia Malcangio Wolfson Centre for Age Related Diseases, King's College London, London, UK Abstract: Neuropathic pain represents a major problem in clinical medicine because it causes debilitating suffering and is largely resistant to currently available analgesics. A characteristic of neuropathic pain is abnormal response to somatic sensory stimulation. Thus, patients suffering peripheral neuropathies may experience pain caused by stimuli which are normally nonpainful, such as simple touching of the skin or by changes in temperature, as well as exaggerated responses to noxious stimuli. Convincing evidence suggests that this hypersensitivity is the result of pain remaining centralized. In particular, at the first pain synapse in the dorsal horn of the spinal cord, the gain of neurons is increased and neurons begin to be activated by innocuous inputs. In recent years, it has become appreciated that a remote damage in the peripheral nervous system results in neuronal plasticity and changes in microglial and astrocyte activity, as well as infiltration of macrophages and T cells, which all contribute to central sensitization. Specifically, the release of pronociceptive factors such as cytokines and chemokines from neurons and non-neuronal cells can sensitize neurons of the first pain synapse. In this article we review the current evidence for the role of cytokines in mediating spinal neuron–non-neuronal cell communication in neuropathic pain mechanisms following peripheral nerve injury. Specific and selective control of cytokine-mediated neuronal–glia interactions results in attenuation of the hypersensitivity to both noxious and innocuous stimuli observed in neuropathic pain models, and may represent an avenue for future therapeutic intervention. Keywords: anti-inflammatory cytokines, proinflammatory cytokines, microglia, astrocytes, first pain synapse

  4. Pitting of malaria parasites and spherocyte formation

    Directory of Open Access Journals (Sweden)

    Gichuki Charity W

    2006-07-01

    Full Text Available Abstract Background A high prevalence of spherocytes was detected in blood smears of children enrolled in a case control study conducted in the malaria holoendemic Lake Victoria basin. It was speculated that the spherocytes reflect intraerythrocytic removal of malarial parasites with a concurrent removal of RBC membrane through a process analogous to pitting of intraerythrocytic inclusion bodies. Pitting and re-circulation of RBCs devoid of malaria parasites could be a host mechanism for parasite clearance while minimizing the anaemia that would occur were the entire parasitized RBC removed. The prior demonstration of RBCs containing ring-infected erythrocyte surface antigen (pf 155 or RESA but no intracellular parasites, support the idea of pitting. Methods An in vitro model was developed to examine the phenomenon of pitting and spherocyte formation in Plasmodium falciparum infected RBCs (iRBC co-incubated with human macrophages. In vivo application of this model was evaluated using blood specimens from patients attending Kisumu Ditrict Hospital. RBCs were probed with anti-RESA monoclonal antibody and a DNA stain (propidium iodide. Flow cytometry and fluorescent microscopy was used to compare RBCs containing both the antigen and the parasites to those that were only RESA positive. Results Co-incubation of iRBC and tumor necrosis factor-alpha activated macrophages led to pitting (14% ± 1.31% macrophages with engulfed trophozoites as opposed to erythrophagocytosis (5.33% ± 0.95% (P Conclusion It is proposed that in malaria holoendemic areas where prevalence of asexual stage parasites approaches 100% in children, RBCs with pitted parasites are re-circulated and pitting may produce spherocytes.

  5. T helper-2 cytokine/regulatory T-cell gene polymorphisms and their relation with risk of psoriasis in a South Indian Tamil cohort.

    Science.gov (United States)

    Indhumathi, Sundar; Rajappa, Medha; Chandrashekar, Laxmisha; Ananthanarayanan, Palghat Hariharan; Thappa, Devinder Mohan; Negi, Vir Singh

    2017-02-01

    Psoriasis is known to be associated with an up-regulation of T-helper (Th)-1 & Th-17 cytokines and a relative down-regulation of Th-2 and T-regulatory (T-reg) cytokines. Certain allelic variants of these cytokine genes may alter Th1/Th17 and Th2/T-reg balance and may be associated with the risk of psoriasis. Hence we aimed to determine the association of IL-4 (rs2243250), IL-10 (rs1800871 and rs1800896) and FOXP3 (rs3761548) gene polymorphisms with risk of psoriasis in South Indian Tamils. A total of 360 cases of psoriasis and 360 healthy controls were recruited. The polymorphism in IL-4 (rs2243250) & IL-10 (rs1800871) were typed by ARMS-PCR and IL-10 (rs1800896) & FOXP3 (rs3761548) were typed by TaqMan 5'allele discrimination assay. We observed that IL-4 (rs2243250) had a reduced risk of psoriasis, while the IL-10 (rs1800871) conferred an increased susceptibility to psoriasis, as compared with controls. However, IL-10 (rs1800896) and FOXP3 (rs3761548) gene polymorphisms were not associated with psoriasis risk. The plasma IL-4 levels was not different between the cases and controls, however the heterozygous CT genotype demonstrated significant high IL-4 levels. Plasma IL-10 levels were significantly increased in cases compared to controls, however none of the genotypes were associated with the plasma IL-10 levels. Our results suggest that IL-4 (rs2243250) polymorphism is protective against psoriasis, while IL-10 (rs1800871) polymorphism confers increased risk of psoriasis in South Indian Tamils. Detection of these genetic variants as predictive risk factors may lead to the selection of patient-tailored therapy to maximize the effectiveness of therapy. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  6. Parasitic helminths: new weapons against immunological disorders.

    Science.gov (United States)

    Osada, Yoshio; Kanazawa, Tamotsu

    2010-01-01

    The prevalence of allergic and autoimmune diseases is increasing in developed countries, possibly due to reduced exposure to microorganisms in childhood (hygiene hypothesis). Epidemiological and experimental evidence in support of this hypothesis is accumulating. In this context, parasitic helminths are now important candidates for antiallergic/anti-inflammatory agents. Here we summarize antiallergic/anti-inflammatory effects of helminths together along with our own study of the effects of Schistosoma mansoni on Th17-dependent experimental arthritis. We also discuss possible mechanisms of helminth-induced suppression according to the recent advances of immunology.

  7. Parasitic Helminths: New Weapons against Immunological Disorders

    Directory of Open Access Journals (Sweden)

    Yoshio Osada

    2010-01-01

    Full Text Available The prevalence of allergic and autoimmune diseases is increasing in developed countries, possibly due to reduced exposure to microorganisms in childhood (hygiene hypothesis. Epidemiological and experimental evidence in support of this hypothesis is accumulating. In this context, parasitic helminths are now important candidates for antiallergic/anti-inflammatory agents. Here we summarize antiallergic/anti-inflammatory effects of helminths together along with our own study of the effects of Schistosoma mansoni on Th17-dependent experimental arthritis. We also discuss possible mechanisms of helminth-induced suppression according to the recent advances of immunology.

  8. Prevention of inflammation-mediated bone loss in murine and canine periodontal disease via recruitment of regulatory lymphocytes.

    Science.gov (United States)

    Glowacki, Andrew J; Yoshizawa, Sayuri; Jhunjhunwala, Siddharth; Vieira, Andreia E; Garlet, Gustavo P; Sfeir, Charles; Little, Steven R

    2013-11-12

    The hallmark of periodontal disease is the progressive destruction of gingival soft tissue and alveolar bone, which is initiated by inflammation in response to an invasive and persistent bacterial insult. In recent years, it has become apparent that this tissue destruction is associated with a decrease in local regulatory processes, including a decrease of forkhead box P3-expressing regulatory lymphocytes. Accordingly, we developed a controlled release system capable of generating a steady release of a known chemoattractant for regulatory lymphocytes, C-C motif chemokine ligand 22 (CCL22), composed of a degradable polymer with a proven track record of clinical translation, poly(lactic-co-glycolic) acid. We have previously shown that this sustained presentation of CCL22 from a point source effectively recruits regulatory T cells (Tregs) to the site of injection. Following administration of the Treg-recruiting formulation to the gingivae in murine experimental periodontitis, we observed increases in hallmark Treg-associated anti-inflammatory molecules, a decrease of proinflammatory cytokines, and a marked reduction in alveolar bone resorption. Furthermore, application of the Treg-recruiting formulation (fabricated with human CCL22) in ligature-induced periodontitis in beagle dogs leads to reduced clinical measures of inflammation and less alveolar bone loss under severe inflammatory conditions in the presence of a diverse periodontopathogen milieu.

  9. Reduced neonatal regulatory T cell response to microbial stimuli associates with subsequent eczema in high-risk infants.

    Science.gov (United States)

    Ismail, Intan H; Boyle, Robert J; Mah, Li-Jeen; Licciardi, Paul V; Tang, Mimi L K

    2014-11-01

    Regulatory T cells (Treg) play an essential role in early immune programming and shaping the immune response towards a pro-allergic or tolerant state. We evaluated cord blood Treg and cytokine responses to microbial and non-microbial stimuli in infants at high risk of allergic disease and their associations with development of allergic disease in the first year. Cord blood mononuclear cells from 72 neonates were cultured with toll-like receptors (TLR2) ligands: lipoteichoic acid (LTA) and heat-killed Lactobacillus rhamnosus GG (HKL); TLR4 ligand: lipopolysaccharide (LPS); ovalbumin (OVA); anti-CD3; or media for 48 h. Treg numbers and Treg cytokines were assessed in relation to allergic disease outcomes during the first year of life (eczema and atopic sensitization). Infants with eczema (n = 24) had reduced percentages of FoxP3(hi)CD25(hi) Treg in LTA (p = 0.01, adj p = 0.005) and HKL (p = 0.04, adj p = 0.02) stimulated cultures as well as reduced IL-10 (p = 0.01) production following HKL stimulation compared to those without eczema (n = 48). No differences in Treg or cytokine responses to LPS, OVA or anti-CD3 were seen. Infants who developed sensitization had lower percentages of Treg following TLR2 stimulation (but not other stimuli) compared to non-sensitized infants. High-risk children who develop allergic disease in the first year of life have deficient Treg responses to microbial stimuli but not allergen from the time of birth, which may contribute to failure of immune tolerance development in infancy. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Cytokine orchestration in post-operative peritoneal adhesion formation.

    LENUS (Irish Health Repository)

    Cahill, Ronan A

    2012-02-03

    Peritoneal adhesions are a near inevitable occurrence after laparotomy and a major cause of both patient and physician misery. To date, clinical attempts at their amelioration have concentrated on manipulating the physical factors that affect their development despite a wealth of experimental data elucidating the molecular mechanisms that underlie their initiation, development and maturation. However, the advent of targeted, specific anti-cytokine agents as directed therapy for inflammatory and neoplastic conditions raises the prospect of a new era for anti-adhesion strategies. To harness this potential will require considerable cross-disciplinary collaboration and that surgeon-scientists propel themselves to the forefront of this emerging field.

  11. Impaired Cytokine Responses to Epstein-Barr Virus Antigens in Systemic Lupus Erythematosus Patients

    DEFF Research Database (Denmark)

    Draborg, Anette Holck; Sandhu, Noreen; Larsen, Nanna

    2016-01-01

    We analyzed cytokine responses against latent and lytic Epstein-Barr virus (EBV) antigens in systemic lupus erythematosus (SLE) patients and healthy controls (HCs) to obtain an overview of the distinctive immune regulatory response in SLE patients and to expand the previously determined impaired...

  12. Cytokine changes in newborns with therapeutic hypothermia after hypoxic ischemic encephalopathy.

    Science.gov (United States)

    Moon, C J; Youn, Y A; Yum, S K; Sung, I K

    2016-12-01

    This study aimed to examine changes in cytokines according to therapeutic hypothermia (TH) for newborn hypoxic ischemic encephalopathy (HIE). We studied 20 neonates who were admitted with a diagnosis of HIE in the neonatal intensive care unit. Cytokine concentration assay was carried out for neonates (n=12) who received TH and neonates (n=8) who were not treated with hypothermia by collecting blood sample at 12, 48 and 120 h after birth. At 48 h after birth, interleukin (IL)-6 in the normothermia group was higher than that in the hypothermia group (P=0.010). At 48 h after birth, IL-10 was higher in the hypothermia group than in the normothermia group (P=0.038). This study confirmed that TH performs a role in the prevention of inflammatory process by way of maintaining proinflammatory cytokine IL-6 at low levels and anti-inflammatory cytokines IL-10 at high levels.

  13. Detection of immunotoxicity using T-cell based cytokine reporter cell lines ('Cell Chip')

    International Nuclear Information System (INIS)

    Ringerike, Tove; Ulleraas, Erik; Voelker, Rene; Verlaan, Bert; Eikeset, Aase; Trzaska, Dominika; Adamczewska, Violetta; Olszewski, Maciej; Walczak-Drzewiecka, Aurelia; Arkusz, Joanna; Loveren, Henk van; Nilsson, Gunnar; Lovik, Martinus; Dastych, Jaroslaw; Vandebriel, Rob J.

    2005-01-01

    Safety assessment of chemicals and drugs is an important regulatory issue. The evaluation of potential adverse effects of compounds on the immune system depends today on animal experiments. An increasing demand, however, exists for in vitro alternatives. Cytokine measurement is a promising tool to evaluate chemical exposure effects on the immune system. Fortunately, this type of measurement can be performed in conjunction with in vitro exposure models. We have taken these considerations as the starting point to develop an in vitro method to efficiently screen compounds for potential immunotoxicity. The T-cell lymphoma cell line EL-4 was transfected with the regulatory sequences of interleukin (IL)-2, IL-4, IL-10, interferon (IFN)-γ or actin fused to the gene for enhanced green fluorescent protein (EGFP) in either a stabile or a destabilised form. Consequently, changes in fluorescence intensity represent changes in cytokine expression with one cell line per cytokine. We used this prototype 'Cell Chip' to test, by means of flow cytometry, the immunomodulatory potential of 13 substances and were able to detect changes in cytokine expression in 12 cases (successful for cyclosporine, rapamycin, pentamidine, thalidomide, bis(tri-n-butyltin)oxide, house dust mite allergen (Der p I), 1-chloro-2,4-dinitrobenzene, benzocaine, tolylene 2,4-diisocyanate, potassium tetrachloroplatinate, sodium dodecyl sulphate and mercuric chloride; unsuccessful for penicillin G). In conclusion, this approach seems promising for in vitro screening for potential immunotoxicity, especially when additional cell lines besides T-cells are included

  14. Collective defence portfolios of ant hosts shift with social parasite pressure.

    Science.gov (United States)

    Jongepier, Evelien; Kleeberg, Isabelle; Job, Sylwester; Foitzik, Susanne

    2014-09-22

    Host defences become increasingly costly as parasites breach successive lines of defence. Because selection favours hosts that successfully resist parasitism at the lowest possible cost, escalating coevolutionary arms races are likely to drive host defence portfolios towards ever more expensive strategies. We investigated the interplay between host defence portfolios and social parasite pressure by comparing 17 populations of two Temnothorax ant species. When successful, collective aggression not only prevents parasitation but also spares host colonies the cost of searching for and moving to a new nest site. However, once parasites breach the host's nest defence, host colonies should resort to flight as the more beneficial resistance strategy. We show that under low parasite pressure, host colonies more likely responded to an intruding Protomognathus americanus slavemaker with collective aggression, which prevented the slavemaker from escaping and potentially recruiting nest-mates. However, as parasite pressure increased, ant colonies of both host species became more likely to flee rather than to fight. We conclude that host defence portfolios shift consistently with social parasite pressure, which is in accordance with the degeneration of frontline defences and the evolution of subsequent anti-parasite strategies often invoked in hosts of brood parasites. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  15. Sirtuins of parasitic protozoa: In search of function(s)

    Science.gov (United States)

    Religa, Agnieszka A.; Waters, Andrew P.

    2012-01-01

    The SIR2 family of NAD+-dependent protein deacetylases, collectively called sirtuins, has been of central interest due to their proposed roles in life-span regulation and ageing. Sirtuins are one group of environment sensors of a cell interpreting external information and orchestrating internal responses at the sub-cellular level, through participation in gene regulation mechanisms. Remarkably conserved across all kingdoms of life SIR2 proteins in several protozoan parasites appear to have both conserved and intriguing unique functions. This review summarises our current knowledge of the members of the sirtuin families in Apicomplexa, including Plasmodium, and other protozoan parasites such as Trypanosoma and Leishmania. The wide diversity of processes regulated by SIR2 proteins makes them targets worthy of exploitation in anti-parasitic therapies. PMID:22906508

  16. Cerenkov counters at ISABELLE

    International Nuclear Information System (INIS)

    Etkin, A.; Kostoulas, I.; Leith, D.W.G.S.; Thun, R.

    1977-01-01

    The Cherenkov counter described for use at Isabelle is a threshold counter in which light is focussed on phototubes. The counter is applicable in large-angle, small-aperture magnetic spectrometers for measurement of particle yields at large p/sub T/. Three of these counters will provide complete π-K-p separation in the range of 7-20 GeV/c. Other Cherenkov counters are discussed and a bibliography of relevant literature on the counters utilizing photoionization is included

  17. EVALUATION OF CYTOKINE GENE POLYMORPHISM IN B CELL LYMPHOID MALIGNANCIES

    Directory of Open Access Journals (Sweden)

    E. L. Nazarova

    2014-01-01

    Full Text Available Previous studies with some solid tumors has shown that polymorphisms of certain cytokine genes may be used as predictors of clinical outcome in the patients. It seemed important to evaluate potential correlations between production of certain pro- and anti-inflammatory cytokines and co-receptor molecules, and promoter polymorphism of the cytokine genes involved into regulation of cell proliferation, differentiation, apoptosis, lipid metabolism and blood clotting in the patients with hematological malignancies. The article contains our results concerning associations between of IL-1β, -2, -4, -10, -17, TNFα, and allelic polymorphisms of their genes in 62 patients with B cell lymphoid malignancies in an ethnically homogenous group (self-identified as Russians. We have shown that the GА and AA genotypes of the G-308A polymorphism in TNFα gene are significantly associated with increased production of this cytokine, being more common in aggressive non-Hodgkin lymphomas, more rare in multiple myeloma and in indolent non-Hodgkin lymphomas.

  18. Countering bullying at an australian secondary school with students as helpers.

    Science.gov (United States)

    Peterson, L; Rigby, K

    1999-08-01

    To counter bullying at an Australian coeducational secondary school, staff and students co-operated in developing and implementing appropriate policies and procedures. Questionnaires assessing the incidence of bullying and related attitudes were completed by students in Years 7, 9, 10 and 11 in 1995 and again in 1997. Significant reductions in levels of victimization were recorded for Year 7 students only. Significantly increased support for anti-bullying initiatives was found among senior students (Years 10 and 11). Anti-bullying activities directed and undertaken by students themselves received most approval from peers. Copyright 1999 The Association for Professionals in Services for Adolescents.

  19. The ecology of parasites of freshwater fishes: the search for patterns.

    Science.gov (United States)

    Kennedy, C R

    2009-10-01

    Developments in the study of the ecology of helminth parasites of freshwater fishes over the last half century are reviewed. Most research has of necessity been field based and has involved the search for patterns in population and community dynamics that are repeatable in space and time. Mathematical models predict that under certain conditions host and parasite populations can attain equilibrial levels through operation of regulatory factors. Such factors have been identified in several host-parasite systems and some parasite populations have been shown to persist over long time-periods. However, there is no convincing evidence that fish parasite populations are stable and regulated since in all cases alternative explanations are equally acceptable and it appears that they are non-equilibrial systems. It has proved particularly difficult to detect replicable patterns in parasite communities. Inter-specific competition, evidenced by functional and numerical responses, has been detected in several communities but its occurrence is erratic and its significance unclear. Some studies have failed to find any nested patterns in parasite community structure and richness, whereas others have identified such patterns although they are seldom constant over space and time. Departures from randomness appear to be the exception and then only temporary. It appears that parasite communities are non-equilibrial, stochastic assemblages rather than structured and organized.

  20. Effects of prebiotics on immune system and cytokine expression.

    Science.gov (United States)

    Shokryazdan, Parisa; Faseleh Jahromi, Mohammad; Navidshad, Bahman; Liang, Juan Boo

    2017-02-01

    Nowadays, use of prebiotics as feed and food additives has received increasing interest because of the beneficial effects of prebiotics on the health of animals and humans. One of the beneficial effects of prebiotics is stimulation of immune system, which can be direct or indirect through increasing population of beneficial microbes or probiotics, especially lactic acid bacteria and bifidobacteria, in the gut. An important mechanism of action of probiotics and prebiotics, by which they can affect the immune system, is changing the expression of cytokines. The present review tried to summarize the findings of studies that investigated the effects of prebiotics on immune system with focusing on their effects on cytokine expression. Generally, most of reviewed studies indicated beneficial effects for prebiotics in terms of improving immune system, by increasing the expression of anti-inflammatory cytokines, while reducing the expressions of proinflammatory cytokines. However, most of studies mainly considered the indirect effects of prebiotics on the immune system (through changing the composition and population of gut microbiota), and their direct effects still need to be further studied using prebiotics with different degree of polymerization in different hosts.

  1. Lemongrass and citral effect on cytokines production by murine macrophages.

    Science.gov (United States)

    Bachiega, Tatiana Fernanda; Sforcin, José Maurício

    2011-09-01

    Cymbopogon citratus (DC) Stapf (Poaceae-Gramineae), an herb commonly known as lemongrass (LG), is an important source of ethnomedicines as well as citral, the major constituent of Cymbopogon citratus, used in perfumery, cosmetic and pharmaceutical industries for controlling pathogens. Thus, the goal of this work was to analyze the effect of LG and citral on cytokines production (IL-1β, IL-6 and IL-10) in vitro, as well as before or after LPS incubation. Peritoneal macrophages from BALB/c mice were treated with LG or citral in different concentrations for 24h. The concentrations that inhibited cytokines production were tested before or after macrophages challenge with LPS, in order to evaluate a possible anti-inflammatory action. Supernatants of cell cultures were used for cytokines determination by ELISA. As to IL-1β, only citral inhibited its release, exerting an efficient action before LPS challenge. LG and citral inhibited IL-6 release. Cymbopogon citratus showed inhibitory effects only after LPS challenge, whereas citral prevented efficiently LPS effects before and after LPS addition. Citral inhibited IL-10 production and although LG did not inhibit its production, the concentration of 100 μg/well was tested in the LPS-challenge protocol, because it inhibited IL-6 production. LG inhibited LPS action after macrophages incubation with LPS, while citral counteracted LPS action when added before or after LPS incubation. LG exerted an anti-inflammatory action and citral may be involved in its inhibitory effects on cytokines production. We suggest that a possible mechanism involved in such results could be the inhibition of the transcription factor NF-κB. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  2. Nocardia brasiliensis Modulates IFN-gamma, IL-10, and IL-12 cytokine production by macrophages from BALB/c Mice.

    Science.gov (United States)

    Salinas-Carmona, Mario C; Zúñiga, Juan M; Pérez-Rivera, Luz I; Segoviano-Ramírez, Juan C; Vázquez-Marmolejo, Anna V

    2009-05-01

    Interferon-gamma (IFN-gamma) is a critical cytokine involved in control of different infections. Actinomycetoma is a chronic infectious disease mainly caused by the bacterium Nocardia brasiliensis, which destroys subcutaneous tissue, including bone. Currently, the mechanism of pathogenesis in N. brasiliensis infection is not known. Here, we demonstrate that N. brasiliensis induced an IFN-gamma response in serum after 24 h of infection, while, in infected tissue, positive cells to IFN-gamma appeared in 2 early peaks: the first was present only 3 h after infection, then transiently decreased; and the second peak appeared 12 h after infection and was independent of interleukin-10. Resident macrophages produced an immediate IFN-gamma response 1 h after in vitro infection, and spleen-positive cells began later. The phase of growth of N. brasiliensis affected cytokine production, and exposure of macrophages to Nocardia opsonized with either polyclonal anti-Nocardia antibodies or anti-P61 monoclonal antibody led to a suppression of cytokine production. Our report provides evidence that N. brasiliensis as an intracellular bacterium modulates macrophage cytokine production, which helps survival of the pathogen. Modulation of these cytokines may contribute to pathogenesis once this bacterium is inside the macrophage.

  3. Chronic infusion of epigallocatechin-3-O-gallate into the hypothalamic paraventricular nucleus attenuates hypertension and sympathoexcitation by restoring neurotransmitters and cytokines.

    Science.gov (United States)

    Yi, Qiu-Yue; Li, Hong-Bao; Qi, Jie; Yu, Xiao-Jing; Huo, Chan-Juan; Li, Xiang; Bai, Juan; Gao, Hong-Li; Kou, Bo; Liu, Kai-Li; Zhang, Dong-Dong; Chen, Wen-Sheng; Cui, Wei; Zhu, Guo-Qing; Shi, Xiao-Lian; Kang, Yu-Ming

    2016-11-16

    Reactive oxygen species (ROS) in the brain are involved in the pathogenesis of hypertension. Epigallocatechin-3-O-gallate (EGCG), one of the active compounds in green tea, has anti-oxidant, anti-inflammatory and vascular protective properties. This study was designed to determine whether chronic infusion of EGCG into the hypothalamic paraventricular nucleus (PVN) attenuates ROS and sympathetic activity and delays the progression of hypertension by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs) and decreasing nuclear factor-kappa B (NF-κB) activity, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar-Kyoto (WKY) rats and SHR received bilateral PVN infusion of EGCG (20μg/h) or vehicle via osmotic minipumps for 4 weeks. SHR showed higher mean arterial pressure, plasma proinflammatory cytokines and circulating norepinephrine (NE) levels compared with WKY rats. SHR also had higher PVN levels of the subunit of NAD(P)H oxidase (gp91 phox ), ROS, tyrosine hydroxylase, and PICs; increased NF-κB activity; and lower PVN levels of interleukin-10 (IL-10) and 67kDa isoform of glutamate decarboxylase (GAD67) than WKY rats. PVN infusion of EGCG attenuated all these changes in SHR. These findings suggest that SHR have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN. Chronic inhibition of ROS in the PVN restores the balance of neurotransmitters and cytokines in the PVN, thereby attenuating hypertensive response and sympathetic activity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. IRF4 Deficiency Abrogates Lupus Nephritis Despite Enhancing Systemic Cytokine Production

    Science.gov (United States)

    Lech, Maciej; Weidenbusch, Marc; Kulkarni, Onkar P.; Ryu, Mi; Darisipudi, Murthy Narayana; Susanti, Heni Eka; Mittruecker, Hans-Willi; Mak, Tak W.

    2011-01-01

    The IFN-regulatory factors IRF1, IRF3, IRF5, and IRF7 modulate processes involved in the pathogenesis of systemic lupus and lupus nephritis, but the contribution of IRF4, which has multiple roles in innate and adaptive immunity, is unknown. To determine a putative pathogenic role of IRF4 in lupus, we crossed Irf4-deficient mice with autoimmune C57BL/6-(Fas)lpr mice. IRF4 deficiency associated with increased activation of antigen-presenting cells in C57BL/6-(Fas)lpr mice, resulting in a massive increase in plasma levels of TNF and IL-12p40, suggesting that IRF4 suppresses cytokine release in these mice. Nevertheless, IRF4 deficiency completely protected these mice from glomerulonephritis and lung disease. The mice were hypogammaglobulinemic and lacked antinuclear and anti-dsDNA autoantibodies, revealing the requirement of IRF4 for the maturation of plasma cells. As a consequence, Irf4-deficient C57BL/6-(Fas)lpr mice neither developed immune complex disease nor glomerular activation of complement. In addition, lack of IRF4 impaired the maturation of Th17 effector T cells and reduced plasma levels of IL-17 and IL-21, which are cytokines known to contribute to autoimmune tissue injury. In summary, IRF4 deficiency enhances systemic inflammation and the activation of antigen-presenting cells but also prevents the maturation of plasma cells and effector T cells. Because these adaptive immune effectors are essential for the evolution of lupus nephritis, we conclude that IRF4 promotes the development of lupus nephritis despite suppressing antigen-presenting cells. PMID:21742731

  5. 76 FR 63333 - Sunshine Act Meeting

    Science.gov (United States)

    2011-10-12

    ... and settlement process, potential regulatory changes impacting the Over-The-Counter markets, and Anti-Money laundering concerns specific to microcap issuers. For further information, please contact the...

  6. Suppressor of cytokine signaling 4 (SOCS4 protects against severe cytokine storm and enhances viral clearance during influenza infection.

    Directory of Open Access Journals (Sweden)

    Lukasz Kedzierski

    2014-05-01

    Full Text Available Suppressor of cytokine signaling (SOCS proteins are key regulators of innate and adaptive immunity. There is no described biological role for SOCS4, despite broad expression in the hematopoietic system. We demonstrate that mice lacking functional SOCS4 protein rapidly succumb to infection with a pathogenic H1N1 influenza virus (PR8 and are hypersusceptible to infection with the less virulent H3N2 (X31 strain. In SOCS4-deficient animals, this led to substantially greater weight loss, dysregulated pro-inflammatory cytokine and chemokine production in the lungs and delayed viral clearance. This was associated with impaired trafficking of influenza-specific CD8 T cells to the site of infection and linked to defects in T cell receptor activation. These results demonstrate that SOCS4 is a critical regulator of anti-viral immunity.

  7. Interferon-Mediated Innate Immune Responses against Malaria Parasite Liver Stages

    Directory of Open Access Journals (Sweden)

    Jessica L. Miller

    2014-04-01

    Full Text Available Mosquito-transmitted malaria parasites infect hepatocytes and asymptomatically replicate as liver stages. Using RNA sequencing, we show that a rodent malaria liver-stage infection stimulates a robust innate immune response including type I interferon (IFN and IFNγ pathways. Liver-stage infection is suppressed by these infection-engendered innate responses. This suppression was abrogated in mice deficient in IFNγ, the type I IFN α/β receptor (IFNAR, and interferon regulatory factor 3. Natural killer and CD49b+CD3+ natural killer T (NKT cells increased in the liver after a primary infection, and CD1d-restricted NKT cells, which secrete IFNγ, were critical in reducing liver-stage burden of a secondary infection. Lack of IFNAR signaling abrogated the increase in NKT cell numbers in the liver, showing a link between type I IFN signaling, cell recruitment, and subsequent parasite elimination. Our findings demonstrate innate immune sensing of malaria parasite liver-stage infection and that the ensuing innate responses can eliminate the parasite.

  8. Trichomonas vaginalis α-Actinin 2 Modulates Host Immune Responses by Inducing Tolerogenic Dendritic Cells via IL-10 Production from Regulatory T Cells.

    Science.gov (United States)

    Lee, Hye-Yeon; Kim, Juri; Ryu, Jae-Sook; Park, Soon-Jung

    2017-08-01

    Trichomonas vaginalis is a pathogen that triggers severe immune responses in hosts. T. vaginalis α-actinin 2, Tvα-actinin 2, has been used to diagnose trichomoniasis. This study was undertaken to examine the role of Tvα-actinin 2 as an antigenic molecule to induce immune responses from humans. Western blot analysis using anti-Tvα-actinin 2 antibodies indicated its presence in the secreted proteins of T. vaginalis. ELISA was employed to measure cytokine production by vaginal epithelial cells, prostate cells, mouse dendritic cells (DCs), or T cells stimulated with T. vaginalis or Tvα-actinin 2 protein. Both T. vaginalis and rTvα-actinin 2 induced cytokine production from epithelial cell lines, including IL-10. Moreover, CD4+CD25- regulatory T cells (Treg cells) incubated with rTvα-actinin 2-treated DCs produced high levels of IL-10. These data indicate that Tvα-actinin 2 modulates immune responses via IL-10 production by Treg cells.

  9. Campylobacter jejuni induces diverse kinetics and profiles of cytokine genes in INT-407 cells

    International Nuclear Information System (INIS)

    Al-Amri, Ahlam I.; Bakhiet, Moiz O.; Botta, Giuseppe A.; Tabbara, Khaled S.; Ismaeel, Abdelrahman Y.; Al-Mahmeed, Ali E.; Bin Danya, Khalid M.

    2008-01-01

    Objective was to examine the kinetic ability of embryonic human epithelial INT-407 cells to express messenger ribonucleic acid (mRNA) for various cytokines and chemokines in response to Campylobacter jejuni (C. jejuni) stimulation. In an experimental single-blind study, cultured embryonic human epithelial INT-407 cells were treated with different concentrations of viable C. jejuni, its sonicated and filtered supernatant. A modified non-radioactive in situ hybridization using probe cocktails was used to measure mRNA levels for the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, interferon-gamma, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1 and IL-8 and the anti-inflammatory cytokines, IL-4 and IL-10. The study was carried out from September 2005 to March 2007 at the Department of Microbiology, Immunology and Infectious Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Bahrain. Viable C. jejuni sonicated bacteria and filtered supernatant induced high mRNA expression for the pro-inflammatory cytokines IL-1 beta, IL-6, IFN-gama, TNF-alpha, TGF-beta and IL-8 which peaked at the 12 hours post stimulation. Anti-inflammatory cytokine IL-4 and IL-10 mNRA expression were induced maximally at 3 hours post stimulation mainly by sonicated bacteria and filtrated supernatant, however, not with living bacteria and filtrated supernatant, however, not with living bacteria. Untreated embryonic human epithelial INT-407 cells expressed low amount of mNRA for the various cytokines and chemokines at all time points. For each cytokine, 4 samples were used per time hour. This study demonstrated that embryonic human epithelial INT-407 cells in response to viable C. jejuni or its cytotxins can alter cytokine and chemokine mNRA expression patterns and kinetics suggesting a potential role for these mediators in the immunopathogenesis of the infection caused by this pathogen, which might be relevant for future immunotherapeutic

  10. Cytokines and cytokine networks target neurons to modulate long-term potentiation.

    Science.gov (United States)

    Prieto, G Aleph; Cotman, Carl W

    2017-04-01

    Cytokines play crucial roles in the communication between brain cells including neurons and glia, as well as in the brain-periphery interactions. In the brain, cytokines modulate long-term potentiation (LTP), a cellular correlate of memory. Whether cytokines regulate LTP by direct effects on neurons or by indirect mechanisms mediated by non-neuronal cells is poorly understood. Elucidating neuron-specific effects of cytokines has been challenging because most brain cells express cytokine receptors. Moreover, cytokines commonly increase the expression of multiple cytokines in their target cells, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Here, we review evidence on both direct and indirect-mediated modulation of LTP by cytokines. We also describe novel approaches based on neuron- and synaptosome-enriched systems to identify cytokines able to directly modulate LTP, by targeting neurons and synapses. These approaches can test multiple samples in parallel, thus allowing the study of multiple cytokines simultaneously. Hence, a cytokine networks perspective coupled with neuron-specific analysis may contribute to delineation of maps of the modulation of LTP by cytokines. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. From topical antidote against skin irritants to a novel counter-irritating and anti-inflammatory peptide

    International Nuclear Information System (INIS)

    Brodsky, Berta; Erlanger-Rosengarten, Avigail; Proscura, Elena; Shapira, Elena; Wormser, Uri

    2008-01-01

    The primary purpose of the present study was to investigate the mechanism of the counter-irritating activity of topical iodine against skin lesions induced by chemical and thermal stimuli. The hypothesis that iodine exerts its activity by inducing an endogenous anti-inflammatory factor was confirmed by exposing guinea pig skin to heat stimulus followed by topical iodine treatment and skin extraction. Injection of the extract into naive guinea pigs reduced heat-induced irritation by 69%. The protective factor, identified as a new nonapeptide (histone H2A 36-44, H-Lys-Gly-Asn-Tyr-Ala-Glu-Arg-Ileu-Ala-OH), caused reduction of 40% in irritation score in heat-exposed guinea pigs. The murine analog (H-Lys-Gly-His-Tyr-Ala-Glu-Arg-Val-Gly-OH, termed IIIM1) reduced sulfur mustard (SM)-induced ear swelling at a dose-dependent bell-shape manner reaching peak activity of 1 mg/kg. Cultured keratinocytes transfected with the peptide were more resistant towards SM than the control cells. The peptide suppressed oxidative burst in activated neutrophils in a concentration-dependent manner. In addition, the peptide reduced glucose oxidase-induced skin edema in mice at a dose-dependent bell-shape manner. Apart from thermal and chemical-induced skin irritation this novel peptide might be of potential use in chronic dermal disorders such as psoriasis and pemphigus as well as non-dermal inflammatory diseases like multiple sclerosis, arthritis and colitis

  12. Multimode pulse counter

    International Nuclear Information System (INIS)

    Natanzon, D.D.

    1982-01-01

    A pulse counter with code conversion is described. The counter is based on the integrated circuits of direct-counting devices of medium integration. The counter ensures various modes of pulse counting depending on the logical control signals: reversible, two-channel summing, one-channel summing binary, summing with ''storage'' signal code fixation without interrupting pulse counting. Arrangement of the suggested structure as a microcircuit of medium integration might contribute to reduction in the counter type nomenclature in digital families of widely used integrated circuits

  13. 76 FR 63680 - Public Roundtable on Execution, Clearance and Settlement of Microcap Securities

    Science.gov (United States)

    2011-10-13

    ... clearance and settlement process, potential regulatory changes impacting the Over-The-Counter markets, and Anti-Money Laundering concerns specific to microcap issuers. DATES: The roundtable discussion will be...

  14. PROTON HEATING IN SOLAR WIND COMPRESSIBLE TURBULENCE WITH COLLISIONS BETWEEN COUNTER-PROPAGATING WAVES

    Energy Technology Data Exchange (ETDEWEB)

    He, Jiansen; Tu, Chuanyi; Wang, Linghua; Pei, Zhongtian [School of Earth and Space Sciences, Peking University, Beijing, 100871 (China); Marsch, Eckart [Institute for Experimental and Applied Physics, Christian-Albrechts-Universität zu Kiel, D-24118 Kiel (Germany); Chen, Christopher H. K. [Department of Physics, Imperial College London, London SW7 2AZ (United Kingdom); Zhang, Lei [Sate Key Laboratory of Space Weather, Chinese Academy of Sciences, Beijing 100190 (China); Salem, Chadi S.; Bale, Stuart D., E-mail: jshept@gmail.com [Space Sciences Laboratory, University of California, Berkeley, CA 94720 (United States)

    2015-11-10

    Magnetohydronamic turbulence is believed to play a crucial role in heating laboratory, space, and astrophysical plasmas. However, the precise connection between the turbulent fluctuations and the particle kinetics has not yet been established. Here we present clear evidence of plasma turbulence heating based on diagnosed wave features and proton velocity distributions from solar wind measurements by the Wind spacecraft. For the first time, we can report the simultaneous observation of counter-propagating magnetohydrodynamic waves in the solar wind turbulence. As opposed to the traditional paradigm with counter-propagating Alfvén waves (AWs), anti-sunward AWs are encountered by sunward slow magnetosonic waves (SMWs) in this new type of solar wind compressible turbulence. The counter-propagating AWs and SWs correspond, respectively, to the dominant and sub-dominant populations of the imbalanced Elsässer variables. Nonlinear interactions between the AWs and SMWs are inferred from the non-orthogonality between the possible oscillation direction of one wave and the possible propagation direction of the other. The associated protons are revealed to exhibit bi-directional asymmetric beams in their velocity distributions: sunward beams appear in short, narrow patterns and anti-sunward in broad extended tails. It is suggested that multiple types of wave–particle interactions, i.e., cyclotron and Landau resonances with AWs and SMWs at kinetic scales, are taking place to jointly heat the protons perpendicular and in parallel.

  15. Fish Suppressors of Cytokine Signaling (SOCS): Gene Discovery, Modulation of Expression and Function

    Science.gov (United States)

    Wang, Tiehui; Gorgoglione, Bartolomeo; Maehr, Tanja; Holland, Jason W.; Vecino, Jose L. González; Wadsworth, Simon; Secombes, Christopher J.

    2011-01-01

    The intracellular suppressors of cytokine signaling (SOCS) family members, including CISH and SOCS1 to 7 in mammals, are important regulators of cytokine signaling pathways. So far, the orthologues of all the eight mammalian SOCS members have been identified in fish, with several of them having multiple copies. Whilst fish CISH, SOCS3, and SOCS5 paralogues are possibly the result of the fish-specific whole genome duplication event, gene duplication or lineage-specific genome duplication may also contribute to some paralogues, as with the three trout SOCS2s and three zebrafish SOCS5s. Fish SOCS genes are broadly expressed and also show species-specific expression patterns. They can be upregulated by cytokines, such as IFN-γ, TNF-α, IL-1β, IL-6, and IL-21, by immune stimulants such as LPS, poly I:C, and PMA, as well as by viral, bacterial, and parasitic infections in member- and species-dependent manners. Initial functional studies demonstrate conserved mechanisms of fish SOCS action via JAK/STAT pathways. PMID:22203897

  16. Plant-parasitic nematodes: towards understanding molecular players in stress responses.

    Science.gov (United States)

    Gillet, François-Xavier; Bournaud, Caroline; Antonino de Souza Júnior, Jose Dijair; Grossi-de-Sa, Maria Fatima

    2017-03-01

    Plant-parasitic nematode interactions occur within a vast molecular plant immunity network. Following initial contact with the host plant roots, plant-parasitic nematodes (PPNs) activate basal immune responses. Defence priming involves the release in the apoplast of toxic molecules derived from reactive species or secondary metabolism. In turn, PPNs must overcome the poisonous and stressful environment at the plant-nematode interface. The ability of PPNs to escape this first line of plant immunity is crucial and will determine its virulence. Nematodes trigger crucial regulatory cytoprotective mechanisms, including antioxidant and detoxification pathways. Knowledge of the upstream regulatory components that contribute to both of these pathways in PPNs remains elusive. In this review, we discuss how PPNs probably orchestrate cytoprotection to resist plant immune responses, postulating that it may be derived from ancient molecular mechanisms. The review focuses on two transcription factors, DAF-16 and SKN-1 , which are conserved in the animal kingdom and are central regulators of cell homeostasis and immune function. Both regulate the unfolding protein response and the antioxidant and detoxification pathways. DAF-16 and SKN-1 target a broad spectrum of Caenorhabditis elegans genes coding for numerous protein families present in the secretome of PPNs. Moreover, some regulatory elements of DAF-16 and SKN-1 from C. elegans have already been identified as important genes for PPN infection. DAF-16 and SKN-1 genes may play a pivotal role in PPNs during parasitism. In the context of their hub status and mode of regulation, we suggest alternative strategies for control of PPNs through RNAi approaches. © The Author 2017. Published by Oxford University Press on behalf of the Annals of Botany Company.

  17. Production of cytokine and chemokines by human mononuclear cells and whole blood cells after infection with Trypanosoma cruzi

    Directory of Open Access Journals (Sweden)

    Karine Rezende-Oliveira

    2012-02-01

    Full Text Available INTRODUCTION: The innate immune response is the first mechanism of protection against Trypanosoma cruzi, and the interaction of inflammatory cells with parasite molecules may activate this response and modulate the adaptive immune system. This study aimed to analyze the levels of cytokines and chemokines synthesized by the whole blood cells (WBC and peripheral blood mononuclear cells (PBMC of individuals seronegative for Chagas disease after interaction with live T. cruzi trypomastigotes. METHODS: IL-12, IL-10, TNF-α, TGF-β, CCL-5, CCL-2, CCL-3, and CXCL-9 were measured by ELISA. Nitrite was determined by the Griess method. RESULTS: IL-10 was produced at high levels by WBC compared with PBMC, even after incubation with live trypomastigotes. Production of TNF-α by both PBMC and WBC was significantly higher after stimulation with trypomastigotes. Only PBMC produced significantly higher levels of IL-12 after parasite stimulation. Stimulation of cultures with trypomastigotes induced an increase of CXCL-9 levels produced by WBC. Nitrite levels produced by PBMC increased after the addition of parasites to the culture. CONCLUSIONS: Surface molecules of T. cruzi may induce the production of cytokines and chemokines by cells of the innate immune system through the activation of specific receptors not evaluated in this experiment. The ability to induce IL-12 and TNF-α contributes to shift the adaptive response towards a Th1 profile.

  18. The chronic blockade of angiotensin I-converting enzyme eliminates the sex differences of serum cytokine levels of spontaneously hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Dalpiaz, P.L.M.; Lamas, A.Z.; Caliman, I.F. [Departamento de Ciências Fisiológicas, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Medeiros, A.R.S. [Ciências Biológicas e da Saúde, Instituto Federal do Espírito Santo, Vitória, ES (Brazil); Abreu, G.R.; Moysés, M.R. [Departamento de Ciências Fisiológicas, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Andrade, T.U. [Departamento de Farmácia, Centro Universitário de Vila Velha, Vila Velha, ES (Brazil); Alves, M.F.; Carmona, A.K. [Departamento de Biofísica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP (Brazil); Bissoli, N.S. [Departamento de Ciências Fisiológicas, Universidade Federal do Espírito Santo, Vitória, ES (Brazil)

    2013-02-01

    Sex hormones modulate the action of both cytokines and the renin-angiotensin system. However, the effects of angiotensin I-converting enzyme (ACE) on the proinflammatory and anti-inflammatory cytokine levels in male and female spontaneously hypertensive rats (SHR) are unclear. We determined the relationship between ACE activity, cytokine levels and sex differences in SHR. Female (F) and male (M) SHR were divided into 4 experimental groups each (n = 7): sham + vehicle (SV), sham + enalapril (10 mg/kg body weight by gavage), castrated + vehicle, and castrated + enalapril. Treatment began 21 days after castration and continued for 30 days. Serum cytokine levels (ELISA) and ACE activity (fluorimetry) were measured. Male rats exhibited a higher serum ACE activity than female rats. Castration reduced serum ACE in males but did not affect it in females. Enalapril reduced serum ACE in all groups. IL-10 (FSV = 16.4 ± 1.1 pg/mL; MSV = 12.8 ± 1.2 pg/mL), TNF-α (FSV = 16.6 ± 1.2 pg/mL; MSV = 12.8 ± 1 pg/mL) and IL-6 (FSV = 10.3 ± 0.2 pg/mL; MSV = 7.2 ± 0.2 pg/mL) levels were higher in females than in males. Ovariectomy reduced all cytokine levels and orchiectomy reduced IL-6 but increased IL-10 concentrations in males. Castration eliminated the differences in all inflammatory cytokine levels (IL-6 and TNF-α) between males and females. Enalapril increased IL-10 in all groups and reduced IL-6 in SV rats. In conclusion, serum ACE inhibition by enalapril eliminated the sexual dimorphisms of cytokine levels in SV animals, which suggests that enalapril exerts systemic anti-inflammatory and anti-hypertensive effects.

  19. Cytokine expression in malaria-infected non-human primate placentas

    Directory of Open Access Journals (Sweden)

    M.M. Gicheru

    2012-06-01

    Full Text Available Malaria parasites are known to mediate the induction of inflammatory immune responses at the maternal-foetal interface during placental malaria (PM leading to adverse consequences like pre-term deliveries and abortions. Immunological events that take place within the malaria-infected placental micro-environment leading to retarded foetal growth and disruption of pregnancies are among the critical parameters that are still in need of further elucidation. The establishment of more animal models for studying placental malaria can provide novel ways of circumventing problems experienced during placental malaria research in humans such as inaccurate estimation of gestational ages. Using the newly established olive baboon (Papio anubis-Plasmodium knowlesi (P. knowlesi H strain model of placental malaria, experiments were carried out to determine placental cytokine profiles underlying the immunopathogenesis of placental malaria. Four pregnant olive baboons were infected with blood stage P. knowlesi H strain parasites on the one fiftieth day of gestation while four other uninfected pregnant olive baboons were maintained as uninfected controls. After nine days of infection, placentas were extracted from all the eight baboons through cesarean surgery and used for the processing of placental plasma and sera samples for cytokine sandwich enzyme linked immunosorbent assays (ELISA. Results indicated that the occurrence of placental malaria was associated with elevated concentrations of tumour necrosis factor alpha (TNF-α and interleukin 12 (IL-12. Increased levels of IL-4, IL-6 and IL-10 and interferon gamma (IFN-γ levels were detected in uninfected placentas. These findings match previous reports regarding immunity during PM thereby demonstrating the reliability of the olive baboon-P. knowlesi model for use in further studies.

  20. Effects of road salt on larval amphibian susceptibility to parasitism through behavior and immunocompetence.

    Science.gov (United States)

    Milotic, Dino; Milotic, Marin; Koprivnikar, Janet

    2017-08-01

    Large quantities of road salts are used for de-icing in temperate climates but often leach into aquatic ecosystems where they can cause harm to inhabitants, including reduced growth and survival. However, the implications of road salt exposure for aquatic animal susceptibility to pathogens and parasites have not yet been examined even though infectious diseases can significantly contribute to wildlife population declines. Through a field survey, we found a range of NaCl concentrations (50-560mg/L) in ponds known to contain larval amphibians, with lower levels found in sites close to gravel- rather than hard-surfaced roads. We then investigated how chronic exposure to environmentally-realistic levels of road salt (up to 1140mg/L) affected susceptibility to infection by trematode parasites (helminths) in larval stages of two amphibian species (Lithobates sylvaticus - wood frogs, and L. pipiens - northern leopard frogs) by considering effects on host anti-parasite behavior and white blood cell profiles. Wood frogs exposed to road salt had higher parasite loads, and also exhibited reduced anti-parasite behavior in these conditions. In contrast, infection intensity in northern leopard frogs had a non-monotonic response to road salts even though lymphocytes were only elevated at the highest concentration. Our results indicate the potential for chronic road salt exposure to affect larval amphibian susceptibility to pathogenic parasites through alterations of behavior and immunocompetence, with further studies needed at higher concentrations, as well as that of road salts on free-living parasite infectious stages. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Illicium verum Extract and Trans-Anethole Attenuate Ovalbumin-Induced Airway Inflammation via Enhancement of Foxp3+ Regulatory T Cells and Inhibition of Th2 Cytokines in Mice

    Directory of Open Access Journals (Sweden)

    Yoon-Young Sung

    2017-01-01

    Full Text Available Illicium verum is used in traditional medicine to treat inflammation. The study investigates the effects of IVE and its component, trans-anethole (AET, on airway inflammation in ovalbumin- (OVA- induced asthmatic mice. Asthma was induced in BALB/c mice by systemic sensitization to OVA, followed by intratracheal, intraperitoneal, and aerosol allergen challenges. IVE and AET were orally administered for four weeks. We investigated the effects of treatment on airway hyperresponsiveness, IgE production, pulmonary eosinophilic infiltration, immune cell phenotypes, Th2 cytokine production in bronchoalveolar lavage, Th1/Th2 cytokine production in splenocytes, forkhead box protein 3 (Foxp3 expression, and lung histology. IVE and AET ameliorated OVA-driven airway hyperresponsiveness (p<0.01, pulmonary eosinophilic infiltration (p<0.05, mucus hypersecretion (p<0.01, and IL-4, IL-5, IL-13, and CCR3 production (p<0.05, as well as IgE levels (p<0.01. IVE and AET increased Foxp3 expression in lungs (p<0.05. IVE and AET reduced IL-4 and increased IFN-γ production in the supernatant of splenocyte cultures (p<0.05. Histological studies showed that IVE and AET inhibited eosinophilia and lymphocyte infiltration in lungs (p<0.01. These results indicate that IVE and AET exert antiasthmatic effects through upregulation of Foxp3+ regulatory T cells and inhibition of Th2 cytokines, suggesting that IVE may be a potential therapeutic agent for allergic lung inflammation.

  2. Hairworm anti-predator strategy: a study of causes and consequences

    DEFF Research Database (Denmark)

    Ponton, Fleur; Lebarbenchon, Camille; Lefèvre, Thierry

    2006-01-01

    One of the most fascinating anti-predator responses displayed by parasites is that of hairworms (Nematomorpha). Following the ingestion of the insect host by fish or frogs, the parasitic worm is able to actively exit both its host and the gut of the predator. Using as a model the hairworm, Parago...

  3. Inhibition of Pro-inflammatory Mediators and Cytokines by Chlorella Vulgaris Extracts.

    Science.gov (United States)

    Sibi, G; Rabina, Santa

    2016-01-01

    The aim of this study was to determine the in vitro anti-inflammatory activities of solvent fractions from Chlorella vulgaris by inhibiting the production of pro-inflammatory mediators and cytokines. Methanolic extracts (80%) of C. vulgaris were prepared and partitioned with solvents of increasing polarity viz., n-hexane, chloroform, ethanol, and water. Various concentrations of the fractions were tested for cytotoxicity in RAW 264.7 cells using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and the concentrations inducing cell growth inhibition by about 50% (IC50) were chosen for further studies. Lipopolysaccharide (LPS) stimulated RAW 264.7 cells were treated with varying concentrations of C. vulgaris fractions and examined for its effects on nitric oxide (NO) production by Griess assay. The release of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) were quantified using enzyme-linked immunosorbent assay using Celecoxib and polymyxin B as positive controls. MTT assay revealed all the solvent fractions that inhibited cell growth in a dose-dependent manner. Of all the extracts, 80% methanolic extract exhibited the strongest anti-inflammatory activity by inhibiting NO production (P < 0.01), PGE2 (P < 0.05), TNF-α, and IL-6 (P < 0.001) release in LPS induced RAW 264.7 cells. Both hexane and chloroform fractions recorded a significant (P < 0.05) and dose-dependent inhibition of LPS induced inflammatory mediators and cytokines in vitro. The anti-inflammatory effect of ethanol and aqueous extracts was not significant in the study. The significant inhibition of inflammatory mediators and cytokines by fractions from C. vulgaris suggests that this microalga would be a potential source of developing anti-inflammatory agents and a good alternate for conventional steroidal and nonsteroidal anti-inflammatory drugs. C. vulgaris extracts have potential anti-inflammatory activitySolvent extraction using methanol

  4. Serial cytokine alterations and abnormal neuroimaging in newborn infants with encephalopathy.

    Science.gov (United States)

    O'Hare, Fiona M; Watson, R William G; O'Neill, Amanda; Segurado, Ricardo; Sweetman, Deirdre; Downey, Paul; Mooney, Eoghan; Murphy, John; Donoghue, Veronica; Molloy, Eleanor J

    2017-04-01

    Inflammatory cytokines may play a role in the final common pathway in the pathogenesis of hypoxic-ischaemic injury in experimental models. We aimed to profile the systemic pro-and anti-inflammatory response over the first week of life in term infants at risk of neonatal encephalopathy. In a tertiary referral university neonatal intensive care unit, serial blood samples were analysed from 41 term infants (requiring resuscitation at birth) in this prospective observational pilot study. Serum levels of 10 pro-and anti-inflammatory cytokines were evaluated including interleukin(IL)-1α, IL-1β, IL-6, IL-8, IL-10, tumour necrosis factor(TNF)-α, interferon (IFN)-γ, vascular endothelial growth factor (VEGF), granulocyte/colony-stimulating factor (G-CSF) and granulocyte macrophage/colony-stimulating factor (GM-CSF). Infants with neonatal encephalopathy and abnormal neuroimaging (n = 15) had significantly elevated granulocyte macrophage/colony-stimulating factor at 0-24 h and interleukin-8, interleukin-6 and interleukin-10 at 24-48 hour. Tumour necrosis factor-α and vascular endothelial growth factor levels were lower at 72-96 hour (p < 0.05). Significantly elevated levels of interleukin-10 were associated with mortality. Serum cytokine changes and innate immune dysregulation in the first week of life may be indicators of outcome in neonatal encephalopathy but require validation in larger studies. ©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  5. Cytokine Adsorption onto the Modified Carbon Sorbent Surface in vitro in Peritonitis

    Directory of Open Access Journals (Sweden)

    T. I. Dolgikh

    2009-01-01

    Full Text Available Objective: to evaluate the efficiency of cytokine sorption with carbon with a locally aminocaproic acid-modified surface from the plasma of patients with general purulent peritonitis. Materials and methods. The material of the investigation was the plasma obtained during plasmapheresis in 10 patients with acute pancreatitis complicated by pancreonecrosis and general purulent peritonitis, which was used to estimate before and after sorption the content of the cytokines: interleukin (IL-1/8, IL-4, and IL-8 by enzyme immunoassay. The sorption properties of carbon hemosor-bent and aminocaproic acid-modified sorbent were comparatively evaluated. Results. Aminocaproic acid-induced modification of the carbon adsorbent surface with its further polycondensation results in the higher content of superficial functional groups (oxygen- and nitrogen-containing that enhance the hydrophility of the surface and the specific pattern of sorption, thus acting as a means for controlling and regulating the plasma concentration of regulatory proteins, primarily the proinflammatory cytokine IL-1^3, the chemokine IL-8 and the T-helper cell clone cytokine IL-4.

  6. Florida's "truth" campaign: a counter-marketing, anti-tobacco media campaign.

    Science.gov (United States)

    Zucker, D; Hopkins, R S; Sly, D F; Urich, J; Kershaw, J M; Solari, S

    2000-05-01

    The "truth" campaign was created to change youth attitudes about tobacco and to reduce teen tobacco use throughout Florida by using youth-driven advertising, public relations, and advocacy. Results of the campaign include a 92 percent brand awareness rate among teens, a 15 percent rise in teens who agree with key attitudinal statements about smoking, a 19.4 percent decline in smoking among middle school students, and a 8.0 percent decline among high school students. States committed to results-oriented youth anti-tobacco campaigns should look to Florida's "truth" campaign as a model that effectively places youth at the helm of anti-tobacco efforts.

  7. Antiparasitic effects induced by polyclonal IgY antibodies anti-phospholipase A2 from Bothrops pauloensis venom.

    Science.gov (United States)

    Borges, Isabela Pacheco; Silva, Mariana Ferreira; Santiago, Fernanda Maria; de Faria, Lucas Silva; Júnior, Álvaro Ferreira; da Silva, Rafaela José; Costa, Mônica Soares; de Freitas, Vitor; Yoneyama, Kelly Aparecida Geraldo; Ferro, Eloísa Amália Vieira; Lopes, Daiana Silva; Rodrigues, Renata Santos; de Melo Rodrigues, Veridiana

    2018-06-01

    Activities of phospholipases (PLAs) have been linked to pathogenesis in various microorganisms, and implicated in cell invasion and so the interest in these enzymes as potential targets that could contribute to the control of parasite survival and proliferation. Chicken eggs immunized with BnSP-7, a Lys49 phospholipase A 2 (PLA 2 ) homologue from Bothrops pauloensis snake venom, represent an excellent source of polyclonal antibodies with potential inhibitory activity on parasite PLA s. Herein, we report the production, characterization and anti-parasitic effect of IgY antibodies from egg yolks of hens immunized with BnSP-7. Produced antibodies presented increasing avidity and affinity for antigenic toxin epitopes throughout immunization, attaining a plateau after 4weeks. Pooled egg yolks-purified anti-BnSP-7 IgY antibodies were able to specifically recognize different PLA 2 s from Bothrops pauloensis and Bothrops jararacussu venom. Antibodies also neutralized BnSP-7 cytotoxic activity in C2C12 cells. Also, the antibodies recognized targets in Leishmania (Leishmania) amazonensis and Toxoplasma gondii extracts by ELISA and immunofluorescence assays. Anti-BnSP-7 IgY antibodies were cytotoxic to T. gondii tachyzoite and L. (L.) amazonensis promastigotes, and were able to decrease proliferation of both parasites treated before infection. These data suggest that the anti-BnSP-7 IgY is an important tool for discovering new parasite targets and blocking parasitic effects. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Plasma cytokine profile in tropical endomyocardial fibrosis: predominance of TNF-a, IL-4 and IL-10.

    Directory of Open Access Journals (Sweden)

    Aline S Bossa

    Full Text Available BACKGROUND: The participation of immune/inflammatory mechanisms in the pathogenesis of tropical endomyocardial fibrosis (EMF has been suggested by the finding of early blood and myocardial eosinophilia. However, the inflammatory activation status of late-stage EMF patients is still unknown. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated pro- and anti-inflammatory cytokine levels in plasma samples from late stage EMF patients. Cytokine levels of Tumor Necrosis Factor (TNF-α, Interferon (IFN-γ, Interleukin (IL-2, IL-4, IL-6, and IL-10 were assayed in plasma samples from 27 EMF patients and compared with those of healthy control subjects. All EMF patients displayed detectable plasma levels of at least one of the cytokines tested. We found that TNF-α, IL-6, IL-4, and IL-10 were each detected in at least 74% of tested sera, and plasma levels of IL-10, IL-4, and TNF-α were significantly higher than those of controls. Plasma levels of such cytokines positively correlated with each other. CONCLUSIONS/SIGNIFICANCE: The mixed pro- and anti-inflammatory/Th2circulating cytokine profile in EMF is consistent with the presence of a persistent inflammatory stimulus. On the other hand, the detection of increased levels of TNF-α may be secondary to the cardiovascular involvement observed in these patients, whereas IL-4 and IL-10 may have been upregulated as a homeostatic mechanism to buffer both production and deleterious cardiovascular effects of pro-inflammatory cytokines. Further studies might establish whether these findings play a role in disease pathogenesis.

  9. Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and ω-3 PUFAs.

    Science.gov (United States)

    Leoncini, Silvia; De Felice, Claudio; Signorini, Cinzia; Zollo, Gloria; Cortelazzo, Alessio; Durand, Thierry; Galano, Jean-Marie; Guerranti, Roberto; Rossi, Marcello; Ciccoli, Lucia; Hayek, Joussef

    2015-01-01

    An involvement of the immune system has been suggested in Rett syndrome (RTT), a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2) or, more rarely, cyclin-dependent kinase-like 5 (CDKL5). To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg) response, as well as chemokines, were investigated in MECP2- (MECP2-RTT) (n = 16) and CDKL5-Rett syndrome (CDKL5-RTT) (n = 8), before and after ω-3 polyunsaturated fatty acids (PUFAs) supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. In MECP2-RTT, a Th2-shifted balance was evidenced, whereas in CDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4) were upregulated. In MECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced in CDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.

  10. Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and ω-3 PUFAs

    Directory of Open Access Journals (Sweden)

    Silvia Leoncini

    2015-01-01

    Full Text Available An involvement of the immune system has been suggested in Rett syndrome (RTT, a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2 or, more rarely, cyclin-dependent kinase-like 5 (CDKL5. To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg response, as well as chemokines, were investigated in MECP2- (MECP2-RTT (n=16 and CDKL5-Rett syndrome (CDKL5-RTT (n=8, before and after ω-3 polyunsaturated fatty acids (PUFAs supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. In MECP2-RTT, a Th2-shifted balance was evidenced, whereas in CDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4 were upregulated. In MECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced in CDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.

  11. Tributyltin Exposure Alters Cytokine Levels in Mouse Serum

    Science.gov (United States)

    Lawrence, Shanieek; Pellom, Samuel T.; Shanker, Anil; Whalen, Margaret M.

    2016-01-01

    Tributyltin (TBT), a toxic environmental contaminant, has been widely utilized for various industrial, agricultural and household purposes. Its usage has led to a global contamination and its bioaccumulation in aquatic organisms and terrestrial mammals. Previous studies suggest that TBT has debilitating effects on the overall immune function of animals, rendering them more vulnerable to diseases. TBT (at concentrations that have been detected in human blood) alters secretion of inflammatory cytokines from human lymphocytes ex vivo. Thus, it is important to determine if specified levels of TBT can alter levels of cytokines in an in vivo system. Mice were exposed to biologically relevant concentrations of TBT (200, 100 or 25 nM final concentrations). The quantitative determination of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL2, IL5, IL7, IL12βp40, IL13, IL15, KC, MIP1β, MIP2 and RANTES was performed in mouse sera by MAGPIX analysis and Western blot. Results indicated alterations (both decreases and increases) in several cytokines. The pro-inflammatory cytokines IFNγ, TNFα, IL-1β, IL-2, IL5, IL12βp40, and IL-15 were altered as were the chemokines MIP-1 and RANTES and the anti-inflammatory cytokine IL-13. Increases in IFNγ and TNFα were seen in serum of mice exposed to TBT for less than 24 hr. IL1-β, IL-12βp40, IL-5 and IL-15 were also modulated in mouse serum depending on the specific experiment and the exposure concentration. IL-2 was consistently decreased in mouse serum when animals were exposed to TBT. There were also TBT-induced increases in MIP-1β, RANTES, and IL-13. These results from human and murine samples clearly suggest that TBT exposures modulate the secretion inflammatory cytokines. PMID:27602597

  12. HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33.

    Science.gov (United States)

    Osbourn, Megan; Soares, Dinesh C; Vacca, Francesco; Cohen, E Suzanne; Scott, Ian C; Gregory, William F; Smyth, Danielle J; Toivakka, Matilda; Kemter, Andrea M; le Bihan, Thierry; Wear, Martin; Hoving, Dennis; Filbey, Kara J; Hewitson, James P; Henderson, Holly; Gonzàlez-Cìscar, Andrea; Errington, Claire; Vermeren, Sonja; Astier, Anne L; Wallace, William A; Schwarze, Jürgen; Ivens, Alasdair C; Maizels, Rick M; McSorley, Henry J

    2017-10-17

    Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine's activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  13. Human parasitic protozoan infection to infertility: a systematic review.

    Science.gov (United States)

    Shiadeh, Malihe Nourollahpour; Niyyati, Maryam; Fallahi, Shirzad; Rostami, Ali

    2016-02-01

    Protozoan parasitic diseases are endemic in many countries worldwide, especially in developing countries, where infertility is a major burden. It has been reported that such infections may cause infertility through impairment in male and female reproductive systems. We searched Medline, PubMed, and Scopus databases and Google scholar to identify the potentially relevant studies on protozoan parasitic infections and their implications in human and animal model infertility. Literature described that some of the protozoan parasites such as Trichomonas vaginalis may cause deformities of the genital tract, cervical neoplasia, and tubal and atypical pelvic inflammations in women and also non-gonoccocal urethritis, asthenozoospermia, and teratozoospermia in men. Toxopalasma gondii could cause endometritis, impaired folliculogenesis, ovarian and uterine atrophy, adrenal hypertrophy, vasculitis, and cessation of estrus cycling in female and also decrease in semen quality, concentration, and motility in male. Trypanosoma cruzi inhibits cell division in embryos and impairs normal implantation and development of placenta. Decrease in gestation rate, infection of hormone-producing glands, parasite invasion of the placenta, and overproduction of inflammatory cytokines in the oviducts and uterine horns are other possible mechanisms induced by Trypanosoma cruzi to infertility. Plasmodium spp. and Trypanosoma brucei spp. cause damage in pituitary gland, hormonal disorders, and decreased semen quality. Entamoeba histolytica infection leads to pelvic pain, salpingitis, tubo-ovarian abscess, and genital ulcers. Cutaneous and visceral leishmaniasis can induce genital lesion, testicular amyloidosis, inflammation of epididymis, prostatitis, and sperm abnormality in human and animals. In addition, some epidemiological studies have reported that rates of protozoan infections in infertile patients are higher than healthy controls. The current review indicates that protozoan parasitic

  14. Parasitic manipulation and neuroinflammation: Evidence from the system Microphallus papillorobustus (Trematoda - Gammarus (Crustacea

    Directory of Open Access Journals (Sweden)

    Thomas Frederic

    2010-04-01

    Full Text Available Abstract Background Neuropathological consequences of neuroinflammatory processes have been implicated in a wide range of diseases affecting the central nervous system (CNS. Glial cells, the resident immune cells of the CNS, respond to tissue injury by releasing proinflammatory cytokines and free radicals such as nitric oxide. We explored the possibility that neuroimmune responses are involved in parasitic manipulation of host behavior in a trematode-crustacean association. The cerebral larva of the flatworm Microphallus papillorobustus alters responses to environmental stimuli - and thus reflex pathways - in the crustacean Gammarus insensibilis, in a way that enhances predation of the crustacean by birds, definitive hosts of the parasite. Results Immunocytochemical experiments followed by confocal microscopy were performed to study the distribution of glutamine synthetase, a glial cell marker, and nitric oxide synthase in the brain of gammarids. Astrocyte-like glia and their processes were abundant at the surface of the parasites while levels of nitric oxide synthase were elevated at the host-parasite interface in the brain of gammarids harboring mature cerebral larvae and demonstrating altered behavior. Conclusion Taken together these results lend support to the neuroinflammation hypothesis whereby a chronic CNS specific immune response induced by the parasite plays a role in the disruption of neuromodulation, neuronal integrity, and behavior in infected hosts.

  15. Effects of aerobic and resistance training of long duration on pro- and anti-inflammatory cytokines in rats

    Directory of Open Access Journals (Sweden)

    C.M.S. Silva

    2017-12-01

    Full Text Available Objective: To determine possible changes in serum concentrations of pro- and anti-inflammatory cytokines of eutrophic rats subjected to aerobic or resistance physical training. Methods: This study examined serum concentrations of TNF-α, IFN-γ, IL-6, IL-10 and IL-1-β in rats that performed aerobic or resistance training for 16 weeks. Thirty-five Wistar rats (male adult were divided into three groups: Control Group (CG, Aerobic Group (AG and Resistance Group (RG. Rats were sacrificed 48 h after the final training session. Serum concentrations of cytokines were analysed by ELISA. Results: TNF-α levels were higher in the RG, followed by the AG and CG groups (p < 0.001. IFN-γ and IL-10 levels were not significantly different between groups (p = 0.097 and p = 0.17, respectively. The levels of IL6 and IL1-β were higher in AG compared to RG and CG (p = 0.0004 and p = 0.003, respectively. In general, our results indicate a higher pro-inflammatory profile in AG and probably RG animals. Conclusion: Further studies are required in order to better clarify the effects of aerobic and resistance exercise training on pro- and anti-inflammatory cytokines. Additionally, future studies should address the metabolic and molecular pathways involved in these responses. Resumen: Objetivo: Determinar posibles cambios en las concentraciones séricas de citoquinas pro y antiinflamatorias de ratas eutróficas sometidas a entrenamiento físico aérobico y de resistencia. Método: Se examinaron las concentraciones séricas de TNF-α, IFN-γ, IL-6, IL-10 e IL-1-β en ratas sometidas a entrenamiento aeróbico o de resistencia de 16 semanas de duración. Treinta y cinco ratas Wistar (macho adulto fueron divididas en 3 grupos: Grupo Control (GC, Grupo Aeróbico (GA y Grupo Resistencia (GR. Las ratas se sacrificaron 48 horas después de la sesión de entrenamiento final. Las concentraciones s

  16. Anti-Plasmodium activity of ceramide analogs

    Directory of Open Access Journals (Sweden)

    Gatt Shimon

    2004-12-01

    Full Text Available Abstract Background Sphingolipids are key molecules regulating many essential functions in eukaryotic cells and ceramide plays a central role in sphingolipid metabolism. A sphingolipid metabolism occurs in the intraerythrocytic stages of Plasmodium falciparum and is associated with essential biological processes. It constitutes an attractive and potential target for the development of new antimalarial drugs. Methods The anti-Plasmodium activity of a series of ceramide analogs containing different linkages (amide, methylene or thiourea linkages between the fatty acid part of ceramide and the sphingoid core was investigated in culture and compared to the sphingolipid analog PPMP (d,1-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol. This analog is known to inhibit the parasite sphingomyelin synthase activity and block parasite development by preventing the formation of the tubovesicular network that extends from the parasitophorous vacuole to the red cell membrane and delivers essential extracellular nutrients to the parasite. Results Analogs containing methylene linkage showed a considerably higher anti-Plasmodium activity (IC50 in the low nanomolar range than PPMP and their counterparts with a natural amide linkage (IC50 in the micromolar range. The methylene analogs blocked irreversibly P. falciparum development leading to parasite eradication in contrast to PPMP whose effect is cytostatic. A high sensitivity of action towards the parasite was observed when compared to their effect on the human MRC-5 cell growth. The toxicity towards parasites did not correlate with the inhibition by methylene analogs of the parasite sphingomyelin synthase activity and the tubovesicular network formation, indicating that this enzyme is not their primary target. Conclusions It has been shown that ceramide analogs were potent inhibitors of P. falciparum growth in culture. Interestingly, the nature of the linkage between the fatty acid part and the

  17. Anti-Inflammatory and Gastroprotective Roles of Rabdosia inflexa through Downregulation of Pro-Inflammatory Cytokines and MAPK/NF-κB Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Md Rashedunnabi Akanda

    2018-02-01

    Full Text Available Globally, gastric ulcer is a vital health hazard for a human. Rabdosia inflexa (RI has been used in traditional medicine for inflammatory diseases. The present study aimed to investigate the protective effect and related molecular mechanism of RI using lipopolysaccharide (LPS-induced inflammation in RAW 246.7 cells and HCl/EtOH-induced gastric ulcer in mice. We applied 3-(4,5-dimethyl-thiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT, nitric oxide (NO, reactive oxygen species (ROS, histopathology, malondialdehyde (MDA, quantitative real-time polymerase chain reaction (qPCR, immunohistochemistry (IHC, and Western blot analyses to evaluate the protective role of RI. Study revealed that RI effectively attenuated LPS-promoted NO and ROS production in RAW 246.7 cells. In addition, RI mitigated gastric oxidative stress by inhibiting lipid peroxidation, elevating NO, and decreasing gastric inflammation. RI significantly halted elevated gene expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α, interleukin-1β (IL-1β, interleukin-6 (IL-6, inducible nitric oxide synthetase (iNOS, and cyclooxygenase-2 (COX-2 in gastric tissue. Likewise, RI markedly attenuated the mitogen-activated protein kinases (MAPKs phosphorylation, COX-2 expression, phosphorylation and degradation of inhibitor kappa B (IκBα and activation of nuclear factor kappa B (NF-κB. Thus, experimental findings suggested that the anti-inflammatory and gastroprotective activities of RI might contribute to regulating pro-inflammatory cytokines and MAPK/NF-κB signaling pathways.

  18. Protein kinase C-dependent signaling controls the midgut epithelial barrier to malaria parasite infection in anopheline mosquitoes.

    Directory of Open Access Journals (Sweden)

    Nazzy Pakpour

    Full Text Available Anopheline mosquitoes are the primary vectors of parasites in the genus Plasmodium, the causative agents of malaria. Malaria parasites undergo a series of complex transformations upon ingestion by the mosquito host. During this process, the physical barrier of the midgut epithelium, along with innate immune defenses, functionally restrict parasite development. Although these defenses have been studied for some time, the regulatory factors that control them are poorly understood. The protein kinase C (PKC gene family consists of serine/threonine kinases that serve as central signaling molecules and regulators of a broad spectrum of cellular processes including epithelial barrier function and immunity. Indeed, PKCs are highly conserved, ranging from 7 isoforms in Drosophila to 16 isoforms in mammals, yet none have been identified in mosquitoes. Despite conservation of the PKC gene family and their potential as targets for transmission-blocking strategies for malaria, no direct connections between PKCs, the mosquito immune response or epithelial barrier integrity are known. Here, we identify and characterize six PKC gene family members--PKCδ, PKCε, PKCζ, PKD, PKN, and an indeterminate conventional PKC--in Anopheles gambiae and Anopheles stephensi. Sequence and phylogenetic analyses of the anopheline PKCs support most subfamily assignments. All six PKCs are expressed in the midgut epithelia of A. gambiae and A. stephensi post-blood feeding, indicating availability for signaling in a tissue that is critical for malaria parasite development. Although inhibition of PKC enzymatic activity decreased NF-κB-regulated anti-microbial peptide expression in mosquito cells in vitro, PKC inhibition had no effect on expression of a panel of immune genes in the midgut epithelium in vivo. PKC inhibition did, however, significantly increase midgut barrier integrity and decrease development of P. falciparum oocysts in A. stephensi, suggesting that PKC

  19. Peroxisomes in parasitic protists.

    Science.gov (United States)

    Gabaldón, Toni; Ginger, Michael L; Michels, Paul A M

    Representatives of all major lineages of eukaryotes contain peroxisomes with similar morphology and mode of biogenesis, indicating a monophyletic origin of the organelles within the common ancestor of all eukaryotes. Peroxisomes originated from the endoplasmic reticulum, but despite a common origin and shared morphological features, peroxisomes from different organisms show a remarkable diversity of enzyme content and the metabolic processes present can vary dependent on nutritional or developmental conditions. A common characteristic and probable evolutionary driver for the origin of the organelle is an involvement in lipid metabolism, notably H 2 O 2 -dependent fatty-acid oxidation. Subsequent evolution of the organelle in different lineages involved multiple acquisitions of metabolic processes-often involving retargeting enzymes from other cell compartments-and losses. Information about peroxisomes in protists is still scarce, but available evidence, including new bioinformatics data reported here, indicate striking diversity amongst free-living and parasitic protists from different phylogenetic supergroups. Peroxisomes in only some protists show major involvement in H 2 O 2 -dependent metabolism, as in peroxisomes of mammalian, plant and fungal cells. Compartmentalization of glycolytic and gluconeogenic enzymes inside peroxisomes is characteristic of kinetoplastids and diplonemids, where the organelles are hence called glycosomes, whereas several other excavate parasites (Giardia, Trichomonas) have lost peroxisomes. Amongst alveolates and amoebozoans patterns of peroxisome loss are more complicated. Often, a link is apparent between the niches occupied by the parasitic protists, nutrient availability, and the absence of the organelles or their presence with a specific enzymatic content. In trypanosomatids, essentiality of peroxisomes may be considered for use in anti-parasite drug discovery. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Manipulating small ruminant parasite epidemiology through the combination of nutritional strategies.

    Science.gov (United States)

    Houdijk, Jos G M; Kyriazakis, Ilias; Kidane, Alemayehu; Athanasiadou, Spiridoula

    2012-05-04

    It is increasingly being recognized that non-chemical parasite control strategies may need to be combined to control more effectively gastrointestinal parasitism, result in resilient production systems and reduce reliance on anthelmintics. Here, we consider if and how metabolizable protein (MP) supplementation and anti-parasitic plant secondary metabolites (PSM) may modulate parasite epidemiology through intervention in pasture contamination, development of infection on pasture and larval challenge as target processes. We then propose that combining two or more non-chemical parasite control strategies may have additive effects on host resistance, especially if the individual strategies target different drivers of parasite epidemiology, different processes in the parasite life cycle or different phases of acquired immunity to parasites. This epidemiological framework is used to review recent findings on combining maternal MP supplementation and grazing the PSM-rich bioactive forage chicory as an example of combining nutritional treatments to manipulate parasite epidemiology in a temperate production system. In the absence of available data for combined nutritional strategies in tropical production systems, we make predictions on the consequences of combining such strategies in these systems. We conclude that currently published studies on combining nutritional strategies under temperate conditions show potential to improve additively host resilience and reduce reliance on anthelmintics; however, effects on epidemiology have to date not shown the additive results hypothesized. The framework developed may assist further in evaluating combined (nutritional) strategies to manipulate parasite epidemiology. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. Foxo4- and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis

    Science.gov (United States)

    Fu, Wenyu; Hu, Wenhuo; Shi, Lei; Mundra, Jyoti Joshi; Xiao, GuoZhi; Dustin, Michael L.; Liu, Chuan-ju

    2017-01-01

    Progranulin (PGRN) restrains inflammation and is therapeutic against inflammatory arthritis; however, the underlying immunological mechanism remains unknown. In this study, we demonstrated that anti-inflammatory cytokine IL-10 was a critical mediator for PGRN-mediated anti-inflammation in collagen-induced arthritis by using PGRN and IL-10 genetically modified mouse models. IL-10 green fluorescent protein reporter mice revealed that regulatory T (Treg) cells were the predominant source of IL-10 in response to PGRN. In addition, PGRN-mediated expansion and activation of Treg cells, as well as IL-10 production, depends on JNK signaling, but not on known PGRN-activated ERK and PI3K pathways. Furthermore, microarray and chromatin immunoprecipitation sequencing screens led to the discovery of forkhead box protein O4 and signal transducer and activator of transcription 3 as the transcription factors required for PGRN induction of IL-10 in Treg cells. These findings define a previously unrecognized signaling pathway that underlies IL-10 production by PGRN in Treg cells and present new insights into the mechanisms by which PGRN resolves inflammation in inflammatory conditions and autoimmune diseases, particularly inflammatory arthritis.—Fu, W., Hu, W., Shi, L., Mundra, J. J. Xiao, G., Dustin, M. L., Liu, C. Foxo4- and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis. PMID:28011648

  2. Apicomplexa-specific tRip facilitates import of exogenous tRNAs into malaria parasites.

    Science.gov (United States)

    Bour, Tania; Mahmoudi, Nassira; Kapps, Delphine; Thiberge, Sabine; Bargieri, Daniel; Ménard, Robert; Frugier, Magali

    2016-04-26

    The malaria-causing Plasmodium parasites are transmitted to vertebrates by mosquitoes. To support their growth and replication, these intracellular parasites, which belong to the phylum Apicomplexa, have developed mechanisms to exploit their hosts. These mechanisms include expropriation of small metabolites from infected host cells, such as purine nucleotides and amino acids. Heretofore, no evidence suggested that transfer RNAs (tRNAs) could also be exploited. We identified an unusual gene in Apicomplexa with a coding sequence for membrane-docking and structure-specific tRNA binding. This Apicomplexa protein-designated tRip (tRNA import protein)-is anchored to the parasite plasma membrane and directs import of exogenous tRNAs. In the absence of tRip, the fitness of the parasite stage that multiplies in the blood is significantly reduced, indicating that the parasite may need host tRNAs to sustain its own translation and/or as regulatory RNAs. Plasmodium is thus the first example, to our knowledge, of a cell importing exogenous tRNAs, suggesting a remarkable adaptation of this parasite to extend its reach into host cell biology.

  3. Anti-trypanosomal activity of cationic N-heterocyclic carbene gold(I) complexes.

    Science.gov (United States)

    Winter, Isabel; Lockhauserbäumer, Julia; Lallinger-Kube, Gertrud; Schobert, Rainer; Ersfeld, Klaus; Biersack, Bernhard

    2017-06-01

    Two gold(I) N-heterocyclic carbene complexes 1a and 1b were tested for their anti-trypanosomal activity against Trypanosoma brucei parasites. Both gold compounds exhibited excellent anti-trypanosomal activity (IC 50 =0.9-3.0nM). The effects of the gold complexes 1a and 1b on the T. b. brucei cytoskeleton were evaluated. Rapid detachment of the flagellum from the cell body occurred after treatment with the gold complexes. In addition, a quick and complete degeneration of the parasitic cytoskeleton was induced by the gold complexes, only the microtubules of the detached flagellum remained intact. Both gold compounds 1a and 1b feature selective anti-trypanosomal agents and were distinctly more active against T. b. brucei cells than against human HeLa cells. Thus, the gold complexes 1a and 1b feature promising drug candidates for the treatment of trypanosome infections such as sleeping sickness (human African Trypanosomiasis caused by Trypanosoma brucei parasites). Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Cytokine profiling in Chagas disease: towards understanding the association with infecting Trypanosoma cruzi discrete typing units (a BENEFIT TRIAL sub-study.

    Directory of Open Access Journals (Sweden)

    Cristina Poveda

    Full Text Available Chagas disease caused by the protozoan Trypanosoma cruzi is an important public health problem in Latin America. The immunological mechanisms involved in Chagas disease pathogenesis remain incompletely elucidated. The aim of this study was to explore cytokine profiles and their possible association to the infecting DTU and the pathogenesis of Chagas disease.109 sero-positive T. cruzi patients and 21 negative controls from Bolivia and Colombia, were included. Flow cytometry assays for 13 cytokines were conducted on human sera. Patients were divided into two groups: in one we compared the quantification of cytokines between patients with and without chronic cardiomyopathy; in second group we compared the levels of cytokines and the genetic variability of T. cruzi.Significant difference in anti-inflammatory and pro-inflammatory cytokines profiles was observed between the two groups cardiac and non-cardiac. Moreover, serum levels of IFN-γ, IL-12, IL-22 and IL-10 presented an association with the genetic variability of T.cruzi, with significant differences in TcI and mixed infections TcI/TcII.Expression of anti-inflammatory and pro-inflammatory cytokines may play a relevant role in determining the clinical presentation of chronic patients with Chagas disease and suggests the occurrence of specific immune responses, probably associated to different T. cruzi DTUs.

  5. Cytokine profiling in Chagas disease: towards understanding the association with infecting Trypanosoma cruzi discrete typing units (a BENEFIT TRIAL sub-study).

    Science.gov (United States)

    Poveda, Cristina; Fresno, Manuel; Gironès, Núria; Martins-Filho, Olindo A; Ramírez, Juan David; Santi-Rocca, Julien; Marin-Neto, José A; Morillo, Carlos A; Rosas, Fernando; Guhl, Felipe

    2014-01-01

    Chagas disease caused by the protozoan Trypanosoma cruzi is an important public health problem in Latin America. The immunological mechanisms involved in Chagas disease pathogenesis remain incompletely elucidated. The aim of this study was to explore cytokine profiles and their possible association to the infecting DTU and the pathogenesis of Chagas disease. 109 sero-positive T. cruzi patients and 21 negative controls from Bolivia and Colombia, were included. Flow cytometry assays for 13 cytokines were conducted on human sera. Patients were divided into two groups: in one we compared the quantification of cytokines between patients with and without chronic cardiomyopathy; in second group we compared the levels of cytokines and the genetic variability of T. cruzi. Significant difference in anti-inflammatory and pro-inflammatory cytokines profiles was observed between the two groups cardiac and non-cardiac. Moreover, serum levels of IFN-γ, IL-12, IL-22 and IL-10 presented an association with the genetic variability of T.cruzi, with significant differences in TcI and mixed infections TcI/TcII. Expression of anti-inflammatory and pro-inflammatory cytokines may play a relevant role in determining the clinical presentation of chronic patients with Chagas disease and suggests the occurrence of specific immune responses, probably associated to different T. cruzi DTUs.

  6. Bee Venom Inhibits Porphyromonas gingivalis Lipopolysaccharides-Induced Pro-Inflammatory Cytokines through Suppression of NF-κB and AP-1 Signaling Pathways.

    Science.gov (United States)

    Kim, Woon-Hae; An, Hyun-Jin; Kim, Jung-Yeon; Gwon, Mi-Gyeong; Gu, Hyemin; Park, Jae-Bok; Sung, Woo Jung; Kwon, Yong-Chul; Park, Kyung-Duck; Han, Sang Mi; Park, Kwan-Kyu

    2016-11-10

    Periodontitis is a chronic inflammatory disease that leads to destruction of tooth supporting tissues. Porphyromonas gingivalis ( P. gingivalis ), especially its lipopolysaccharides (LPS), is one of major pathogens that cause periodontitis. Bee venom (BV) has been widely used as a traditional medicine for various diseases. Previous studies have demonstrated the anti-inflammatory, anti-bacterial effects of BV. However, a direct role and cellular mechanism of BV on periodontitis-like human keratinocytes have not been explored. Therefore, we investigated the anti-inflammatory mechanism of BV against P. gingivalis LPS (PgLPS)-induced HaCaT human keratinocyte cell line. The anti-inflammatory effect of BV was demonstrated by various molecular biological methods. The results showed that PgLPS increased the expression of Toll-like receptor (TLR)-4 and pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, and interferon (IFN)-γ. In addition, PgLPS induced activation of the signaling pathways of inflammatory cytokines-related transcription factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1). BV effectively inhibited those pro-inflammatory cytokines through suppression of NF-κB and AP-1 signaling pathways. These results suggest that administration of BV attenuates PgLPS-induced inflammatory responses. Furthermore, BV may be a useful treatment to anti-inflammatory therapy for periodontitis.

  7. Differential tolerances to ocean acidification by parasites that share the same host.

    Science.gov (United States)

    MacLeod, C D; Poulin, R

    2015-06-01

    Ocean acidification is predicted to cause major changes in marine ecosystem structure and function over the next century, as species-specific tolerances to acidified seawater may alter previously stable relationships between coexisting organisms. Such differential tolerances could affect marine host-parasite associations, as either host or parasite may prove more susceptible to the stressors associated with ocean acidification. Despite their important role in many ecological processes, parasites have not been studied in the context of ocean acidification. We tested the effects of low pH seawater on the cercariae and, where possible, the metacercariae of four species of marine trematode parasite. Acidified seawater (pH 7.6 and 7.4, 12.5 °C) caused a 40-60% reduction in cercarial longevity and a 0-78% reduction in metacercarial survival. However, the reduction in longevity and survival varied distinctly between parasite taxa, indicating that the effects of reduced pH may be species-specific. These results suggest that ocean acidification has the potential to reduce the transmission success of many trematode species, decrease parasite abundance and alter the fundamental regulatory role of multi-host parasites in marine ecosystems. Copyright © 2015 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

  8. Interleukin-1 antagonists and other cytokine blockade strategies for type 1 diabetes

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, Thomas

    2012-01-01

    Proinflammatory cytokines stimulate adaptive immunity and attenuate T cell regulation and tolerance induction. They also profoundly impair β-cell function, proliferation, and viability, activities of similar importance in the context of type 1 diabetes (T1D). Detailed knowledge of the molecular...... mechanisms of β-cell toxicity has been gathered within the last 2-3 decades. However, the efficacy of individual proinflammatory cytokine blockade in animal models of T1D has been inconsistent and generally modest, except in the context of islet transplantation. This suggests that the timing of the cytokine...... blockade relative to anti-β-cell immune activation is critical, and that combination therapy may be required. In randomized, placebo-controlled, clinical trials of limited power, TNF-α (but not IL-1) blockade has yielded moderate but significant improvements in glycemia, insulin requirement, and β...

  9. Spectrum-Effect Relationships between Fingerprints of Caulophyllum robustum Maxim and Inhabited Pro-Inflammation Cytokine Effects.

    Science.gov (United States)

    Lü, Shaowa; Dong, Shuyu; Xu, Dan; Duan, Jixin; Li, Guoyu; Guo, Yuyan; Kuang, Haixue; Wang, Qiuhong

    2017-10-26

    Caulophyllum robustum Maxim (CRM) is a Chinese folk medicine with significant effect on treatment of rheumatoid arthritis (RA). This study was designed to explore the spectrum-effect relationships between high-performance liquid chromatography (HPLC) fingerprints and the anti-inflammatory effects of CRM. Seventeen common peaks were detected by fingerprint similarity evaluation software. Among them, 15 peaks were identified by Liquid Chromatography-Mass Spectrometry (LC-MS). Pharmacodynamics experiments were conducted in collagen-induced arthritis (CIA) mice to obtain the anti-inflammatory effects of different batches of CRM with four pro-inflammation cytokines (TNF-α, IL-β, IL-6, and IL-17) as indicators. These cytokines were suppressed at different levels according to the different batches of CRM treatment. The spectrum-effect relationships between chemical fingerprints and the pro-inflammation effects of CRM were established by multiple linear regression (MLR) and gray relational analysis (GRA). The spectrum-effect relationships revealed that the alkaloids ( N -methylcytisine, magnoflorine), saponins (leiyemudanoside C, leiyemudanoside D, leiyemudanoside G, leiyemudanoside B, cauloside H, leonticin D, cauloside G, cauloside D, cauloside B, cauloside C, and cauloside A), sapogenins (oleanolic acid), β-sitosterols, and unknown compounds (X3, X17) together showed anti-inflammatory efficacy. The results also showed that the correlation between saponins and inflammatory factors was significantly closer than that of alkaloids, and saponins linked with less sugar may have higher inhibition effect on pro-inflammatory cytokines in CIA mice. This work provided a general model of the combination of HPLC and anti-inflammatory effects to study the spectrum-effect relationships of CRM, which can be used to discover the active substance and to control the quality of this treatment.

  10. JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells.

    Science.gov (United States)

    Keohane, Clodagh; Kordasti, Shahram; Seidl, Thomas; Perez Abellan, Pilar; Thomas, Nicholas S B; Harrison, Claire N; McLornan, Donal P; Mufti, Ghulam J

    2015-10-01

    CD4(+) T cells maintain cancer surveillance and immune tolerance. Chronic inflammation has been proposed as a driver of clonal evolution in myeloproliferative neoplasms (MPN), suggesting that T cells play an important role in their pathogenesis. Treatment with JAK inhibitors (JAKi) results in improvements in MPN-associated constitutional symptoms as well as reductions in splenomegaly. However, effects of JAKi on T cells in MPN are not well established and the baseline immune signature remains unclear. We investigated the frequency and function of CD4(+) T cell subsets in 50 MPN patients at baseline as well as during treatment with either ruxolitinib or fedratinib in a subset. We show that CD4(+)  CD127(low)  CD25(high)  FOXP3(+) T regulatory cells are reduced in MPN patients compared to healthy controls and that this decrease is even more pronounced following JAKi therapy. Moreover, we show that after 6 months of treatment the number of T helper (Th)-17 cells increased. We also describe a functional 'silencing' of T helper cells both in vivo and in vitro and a blockade of pro-inflammatory cytokines from these cells. This profound effect of JAKi on T cell function may underlay augmented rates of atypical infections that have been reported with use of these drugs. © 2015 John Wiley & Sons Ltd.

  11. Norisoboldine ameliorates collagen-induced arthritis through regulating the balance between Th17 and regulatory T cells in gut-associated lymphoid tissues.

    Science.gov (United States)

    Tong, Bei; Dou, Yannong; Wang, Ting; Yu, Juntao; Wu, Xin; Lu, Qian; Chou, Guixin; Wang, Zhengtao; Kong, Lingyi; Dai, Yue; Xia, Yufeng

    2015-01-01

    Norisoboldine (NOR), the main active ingredient of the dry root of Lindera aggregata, was previously proven to have substantial therapeutic effects on collagen-induced arthritis (CIA) in mice by oral administration. However, it exhibited a very poor bioavailability in normal rats. The pharmacokinetic-pharmacodynamics disconnection attracts us to explore its anti-arthritic mechanism in more detail. In this study, NOR, administered orally, markedly attenuated the pathological changes in CIA rats, which was accompanied by the down-regulation of pro-inflammatory cytokines and the up-regulation of anti-inflammatory cytokine IL-10. Pharmacokinetic studies demonstrated that the plasma concentration of NOR was moderately elevated in CIA rats compared with normal rats, but it was still far lower than the minimal effective concentration required for inhibiting the proliferation and activation of T lymphocytes in vitro. Interestingly, NOR was shown to regulate the balance between Th17 and regulatory T (Treg) cells in the intestinal lymph nodes more strikingly than in other tissues. It could increase the expression of Foxp3 mRNA in both gut and joints, and markedly up-regulate the number of integrin α4β7 (a marker of gut source)-positive Foxp3(+) cells in the joints of CIA rats. These results suggest that the gut might be the primary action site of NOR, and NOR exerts anti-arthritis effect through regulating the balance between Th17 and Treg cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from the gut to joint. The findings of the present study also provide a plausible explanation for the anti-arthritic effects of poorly absorbed compounds like NOR. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Do mechanical strain and TNF-α interact to amplify pro-inflammatory cytokine production in human annulus fibrosus cells?

    Science.gov (United States)

    Likhitpanichkul, Morakot; Torre, Olivia M; Gruen, Jadry; Walter, Benjamin A; Hecht, Andrew C; Iatridis, James C

    2016-05-03

    During intervertebral disc (IVD) injury and degeneration, annulus fibrosus (AF) cells experience large mechanical strains in a pro-inflammatory milieu. We hypothesized that TNF-α, an initiator of IVD inflammation, modifies AF cell mechanobiology via cytoskeletal changes, and interacts with mechanical strain to enhance pro-inflammatory cytokine production. Human AF cells (N=5, Thompson grades 2-4) were stretched uniaxially on collagen-I coated chambers to 0%, 5% (physiological) or 15% (pathologic) strains at 0.5Hz for 24h under hypoxic conditions with or without TNF-α (10ng/mL). AF cells were treated with anti-TNF-α and anti-IL-6. ELISA assessed IL-1β, IL-6, and IL-8 production and immunocytochemistry measured F-actin, vinculin and α-tubulin in AF cells. TNF-α significantly increased AF cell pro-inflammatory cytokine production compared to basal conditions (IL-1β:2.0±1.4-84.0±77.3, IL-6:10.6±9.9-280.9±214.1, IL-8:23.9±26.0-5125.1±4170.8pg/ml for basal and TNF-α treatment, respectively) as expected, but mechanical strain did not. Pathologic strain in combination with TNF-α increased IL-1β, and IL-8 but not IL-6 production of AF cells. TNF-α treatment altered F-actin and α-tubulin in AF cells, suggestive of altered cytoskeletal stiffness. Anti-TNF-α (infliximab) significantly inhibited pro-inflammatory cytokine production while anti-IL-6 (atlizumab) did not. In conclusion, TNF-α altered AF cell mechanobiology with cytoskeletal remodeling that potentially sensitized AF cells to mechanical strain and increased TNF-α-induced pro-inflammatory cytokine production. Results suggest an interaction between TNF-α and mechanical strain and future mechanistic studies are required to validate these observations. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. The role of cytokine deficiencies and cytokine autoantibodies in clinical dermatology

    DEFF Research Database (Denmark)

    Liszewski, Walter; Gniadecki, Robert

    2016-01-01

    due to a downregulation or absence of cytokines. Here, we review the diagnosis and clinical management of cytokine deficiency syndromes in dermatology. We will review the biology of cytokines, and the current approved indications for recombinant cytokines and anticytokine antibodies. We will also...

  14. Pattern of cytokine (IL-6 and IL-10) level as inflammation and anti-inflammation mediator of multiple organ dysfunction syndrome (MODS) in polytrauma.

    Science.gov (United States)

    Sapan, Heber Bombang; Paturusi, Idrus; Jusuf, Irawan; Patellongi, Ilhamjaya; Massi, Muh Nasrum; Pusponegoro, Aryono Djuned; Arief, Syafrie Kamsul; Labeda, Ibrahim; Islam, Andi Asadul; Rendy, Leo; Hatta, Mochammad

    2016-01-01

    Massive injury remains the most common cause of death for productive age group globally. The current immune, inflammatory paradigm, based on an incomplete understanding of the functional integration of the complex host response, remains a major impediment to the development of effective innovative diagnostic and therapeutic effort. This study attempt to investigate the pattern of inflammatory and anti-inflammatory cytokines such as interleukin-6 and 10 (IL-6 and IL-10) and their interaction in severe injury condition with its major complication as multiple organ dysfunction syndrome (MODS) and failure (MOF) after polytrauma. This is multicenter study held at 4 academic Level-1 Trauma center included 54 polytrauma participants. Inclusion criteria were age between 16-60 years old, had new acute episode of polytrauma which defined as injury in ≥2 body region with Injury Severity Score (ISS) ≥16, and the presence of Systemic Inflammation Response Syndrome (SIRS). Serum level of IL-6 and IL-10 were taken on day 2, 3, and 5 after trauma. During hospitalization, samples were observed for the occurrence of MODS or MOF using Sequential Organ Failure Assessment (SOFA) and mortality rate were also noted. Participant were mostly male with mean of age of 35, 9 years old, endured polytrauma caused by traffic accident. Elevation of cytokines (IL-6, IL-10, and IL-6/IL-10 ratio) had directly proportional with MODS and mortality. Threshold level of compensation for severe trauma is IL-6 of 50 pg/mL and trauma load of ISS ≥30. Inflammation reaction greater than this threshold level would result in downhill level of IL-6, IL-10, or IL-6/IL-10 ratio which associated with poor outcome (MODS and death). The elevation of these cytokines level were represent as compensation/adaptive immune system and its fall represent decompensating/failure of immune system after severe trauma. The pattern of IL-6 and IL-10 after polytrauma represent immune system effort to restore homeostasis

  15. Detection of Signal Regulatory Protein α in Saimiri sciureus (Squirrel Monkey) by Anti-Human Monoclonal Antibody

    Science.gov (United States)

    de Souza, Hugo Amorim dos Santos; Costa-Correa, Edmar Henrique; Bianco-Junior, Cesare; Andrade, Márcia Cristina Ribeiro; Lima-Junior, Josué da Costa; Pratt-Riccio, Lilian Rose; Daniel-Ribeiro, Cláudio Tadeu; Totino, Paulo Renato Rivas

    2017-01-01

    Non-human primates (NHP) are suitable models for studying different aspects of the human system, including pathogenesis and protective immunity to many diseases. However, the lack of specific immunological reagents for neo-tropical monkeys, such as Saimiri sciureus, is still a major factor limiting studies in these models. An alternative strategy to circumvent this obstacle has been the selection of immunological reagents directed to humans, which present cross-reactivity with NHP molecules. In this context and considering the key role of inhibitory immunoreceptors—such as the signal regulatory protein α (SIRPα)—in the regulation of immune responses, in the present study, we attempted to evaluate the ability of anti-human SIRPα monoclonal antibodies to recognize SIRPα in antigen-presenting S. sciureus peripheral blood mononuclear cells (PBMC). As shown by flow cytometry analysis, the profile of anti-SIRPα staining as well as the levels of SIRPα-positive cells in PBMC from S. sciureus were similar to those observed in human PBMC. Furthermore, using anti-SIRPα monoclonal antibody, it was possible to detect a decrease of the SIRPα levels on surface of S. sciureus cells after in vitro stimulation with lipopolysaccharides. Finally, using computed-based analysis, we observed a high degree of conservation of SIRPα across six species of primates and the presence of shared epitopes in the extracellular domain between humans and Saimiri genus that could be targeted by antibodies. In conclusion, we have identified a commercially available anti-human monoclonal antibody that is able to detect SIRPα of S. sciureus monkeys and that, therefore, can facilitate the study of the immunomodulatory role of SIRPα when S. sciureus is used as a model. PMID:29312325

  16. Detection of Signal Regulatory Protein α in Saimiri sciureus (Squirrel Monkey by Anti-Human Monoclonal Antibody

    Directory of Open Access Journals (Sweden)

    Hugo Amorim dos Santos de Souza

    2017-12-01

    Full Text Available Non-human primates (NHP are suitable models for studying different aspects of the human system, including pathogenesis and protective immunity to many diseases. However, the lack of specific immunological reagents for neo-tropical monkeys, such as Saimiri sciureus, is still a major factor limiting studies in these models. An alternative strategy to circumvent this obstacle has been the selection of immunological reagents directed to humans, which present cross-reactivity with NHP molecules. In this context and considering the key role of inhibitory immunoreceptors—such as the signal regulatory protein α (SIRPα—in the regulation of immune responses, in the present study, we attempted to evaluate the ability of anti-human SIRPα monoclonal antibodies to recognize SIRPα in antigen-presenting S. sciureus peripheral blood mononuclear cells (PBMC. As shown by flow cytometry analysis, the profile of anti-SIRPα staining as well as the levels of SIRPα-positive cells in PBMC from S. sciureus were similar to those observed in human PBMC. Furthermore, using anti-SIRPα monoclonal antibody, it was possible to detect a decrease of the SIRPα levels on surface of S. sciureus cells after in vitro stimulation with lipopolysaccharides. Finally, using computed-based analysis, we observed a high degree of conservation of SIRPα across six species of primates and the presence of shared epitopes in the extracellular domain between humans and Saimiri genus that could be targeted by antibodies. In conclusion, we have identified a commercially available anti-human monoclonal antibody that is able to detect SIRPα of S. sciureus monkeys and that, therefore, can facilitate the study of the immunomodulatory role of SIRPα when S. sciureus is used as a model.

  17. Flavanol-Rich Cocoa Powder Interacts with Lactobacillus rhamnossus LGG to Alter the Antibody Response to Infection with the Parasitic Nematode Ascaris suum.

    Science.gov (United States)

    Jang, Saebyeol; Lakshman, Sukla; Beshah, Ethiopia; Xie, Yue; Molokin, Aleksey; Vinyard, Bryan T; Urban, Joseph F; Davis, Cindy D; Solano-Aguilar, Gloria I

    2017-10-12

    Consumption of the probiotic bacteria Lactobacillus rhamnosus LGG and flavanol-rich cocoa have purported immune modulating effects. This study compared the host response to infection with Ascaris suum in three-month-old pigs fed a standard growth diet supplemented with a vehicle control: LGG, cocoa powder (CP) or LGG + CP. Pigs were inoculated with infective A . suum eggs during Week 5 of dietary treatment and euthanized 17 days later. Lactobacillus abundance was increased in pigs fed LGG or LGG + CP. Specific anti- A . suum IgG2 antibodies were decreased ( p < 0.05) in LGG + CP-fed pigs compared to pigs fed CP alone. Pigs fed LGG had significantly reduced expression ( p < 0.05) of Eosinophil peroxidase ( EPX) , Interleukin 13 ( IL-13) , Eotaxin 3 ( CCL26) , Toll-like receptor 2 ( TLR2 ), TLR4, and TLR9 and Interleukin-1Beta ( IL1B ) in the tracheal-bronchial lymph node (TBLN) independent of CP treatment. These results suggested that feeding LGG significantly reduced the localized prototypical Th2-related markers of infection with A . suum in the TBLN. Although feeding CP does not appear to affect the A . suum- induced Th2-associated cytokine response, feeding LGG + CP reduced anti- A . suum antibodies and delayed intestinal expulsion of parasitic larvae from the intestine.

  18. Effects of Mind-Body Training on Cytokines and Their Interactions with Catecholamines.

    Science.gov (United States)

    Jang, Joon Hwan; Park, Hye Yoon; Lee, Ui Soon; Lee, Kyung-Jun; Kang, Do-Hyung

    2017-07-01

    Mind-body training (MBT) may control reactions to stress and regulate the nervous and immune systems. The present study was designed to assess the effects of MBT on plasma cytokines and their interactions with catecholamines. The study group consisted of 80 subjects who practice MBT and a control group of 62 healthy subjects. Plasma catecholamine (norepinephrine, NE; epinephrine, E; and dopamine, DA) and cytokine (TNF-alpha, IL-6, IFN-gamma, and IL-10) levels were measured, and the differences between the MBT and control groups and the interactions of cytokines with catecholamines were investigated. A significant increase in IL-10+IFN-gamma was found in females of the MBT group compared with controls. Also, a significant increase of IL-10 (anti-inflammatory cytokine) in the MBT group was shown in a specific condition in which TNF-alpha and IL-6 (pro-inflammatory cytokines) are almost absent (≤1 ng/L) compared with controls. In the MBT group, significant positive correlations were found between IL-10 and the NE/E ratio and between IL-10 and the DA/E ratio, whereas the control group did not show any such correlations. MBT may increase IL-10, under specific conditions such as a decrease of pro-inflammatory cytokines or E, which may regulate the stress response and possibly contribute to effective and beneficial interactions between the nervous and immune systems.

  19. Fitness of Leishmania donovani parasites resistant to drug combinations.

    Directory of Open Access Journals (Sweden)

    Raquel García-Hernández

    2015-04-01

    Full Text Available Drug resistance represents one of the main problems for the use of chemotherapy to treat leishmaniasis. Additionally, it could provide some advantages to Leishmania parasites, such as a higher capacity to survive in stress conditions. In this work, in mixed populations of Leishmania donovani parasites, we have analyzed whether experimentally resistant lines to one or two combined anti-leishmanial drugs better support the stress conditions than a susceptible line expressing luciferase (Luc line. In the absence of stress, none of the Leishmania lines showed growth advantage relative to the other when mixed at a 1:1 parasite ratio. However, when promastigotes from resistant lines and the Luc line were mixed and exposed to different stresses, we observed that the resistant lines are more tolerant of different stress conditions: nutrient starvation and heat shock-pH stress. Further to this, we observed that intracellular amastigotes from resistant lines present a higher capacity to survive inside the macrophages than those of the control line. These results suggest that resistant parasites acquire an overall fitness increase and that resistance to drug combinations presents significant differences in their fitness capacity versus single-drug resistant parasites, particularly in intracellular amastigotes. These results contribute to the assessment of the possible impact of drug resistance on leishmaniasis control programs.

  20. The Effects of Post-Mating Administration of Anti-IL-10 and Anti-TGFß on Conception Rates in Mice

    Directory of Open Access Journals (Sweden)

    Ali Risvanli

    2015-04-01

    Full Text Available Background: In fertility studies, it has been shown that transforming growth factor β (TGFβ and interlukin 10 (IL-10 play very important roles in implantation, maternal immune tolerance, placentation and fetal development, and the release beginning of release for fetal and postnatal death. The present study aims to determine the effects of the postmating administration of neutralizing antibodies against IL-10 and TGFβ, which significantly impact pregnancy in females and the conception rates in mice via assessments of blood serum and uterine fluid concentrations of IL-2, IL-4, IL-6, IL-10, IL-17, interferon γ (IFNγ, Tumor necrosis factor α (TNFα, and TGFβ. Materials and Methods: In this experimental study, 21 BALB/c strain female mice were mated and randomly divided into three groups. The mice in the first group were selected as the control group. The second group of animals was injected with 0.5 mg of anti-IL-10 after mating, while those in the third group were intraperitoneally injected with 0.5 mg of anti-TGFβ. The animals in all groups were decapitated on the 13th day after mating and their blood samples were taken. The uteri were removed to determine pregnancy. The mice’s uterine irrigation fluids were also obtained. We used the multiplex immunoassay technique to determine the cytokine concentrations in uterine fluid and blood serum of the mice. Results: We observed no intergroup difference with respect to conception rates. A comparison of the cytokine concentrations in the uterine fluids of pregnant mice revealed higher TGFβ concentrations (p<0.01 in the second group injected with the anti-IL-10 antibody compared with the other groups. There was no difference detected in pregnant animals with regards to both uterine fluid and blood serum concentrations of the other cytokines. Conclusion: Post-mating administration of anti-IL-10 and anti-TGFβ antibodies in mice may not have any effect on conception rates.

  1. Secondary Defense Chemicals in Milkweed Reduce Parasite Infection in Monarch Butterflies, Danaus plexippus.

    Science.gov (United States)

    Gowler, Camden D; Leon, Kristoffer E; Hunter, Mark D; de Roode, Jacobus C

    2015-06-01

    In tri-trophic systems, herbivores may benefit from their host plants in fighting parasitic infections. Plants can provide parasite resistance in two contrasting ways: either directly, by interfering with the parasite, or indirectly, by increasing herbivore immunity or health. In monarch butterflies, the larval diet of milkweed strongly influences the fitness of a common protozoan parasite. Toxic secondary plant chemicals known as cardenolides correlate strongly with parasite resistance of the host, with greater cardenolide concentrations in the larval diet leading to lower parasite growth. However, milkweed cardenolides may covary with other indices of plant quality including nutrients, and a direct experimental link between cardenolides and parasite performance has not been established. To determine if the anti-parasitic activity of milkweeds is indeed due to secondary chemicals, as opposed to nutrition, we supplemented the diet of infected and uninfected monarch larvae with milkweed latex, which contains cardenolides but no nutrients. Across three experiments, increased dietary cardenolide concentrations reduced parasite growth in infected monarchs, which consequently had longer lifespans. However, uninfected monarchs showed no differences in lifespan across treatments, confirming that cardenolide-containing latex does not increase general health. Our results suggest that cardenolides are a driving force behind plant-derived resistance in this system.

  2. Nitric oxide-releasing agents enhance cytokine-induced tumor necrosis factor synthesis in human mononuclear cells

    NARCIS (Netherlands)

    Eigler, A; Sinha, B; Endres, S

    1993-01-01

    In septic shock tumor necrosis factor (TNF) leads to increased nitric oxide (NO) production by induction of NO synthase. An inverse regulatory effect, the influence of NO on cytokine synthesis, has rarely been investigated. The present study assessed the influence of NO-releasing agents on TNF

  3. Proinflammatory and anti-inflammatory cytokine profile in pediatric patients with irritable bowel syndrome

    Directory of Open Access Journals (Sweden)

    R. Vázquez-Frias

    2015-01-01

    Conclusions: This study suggests that children with IBS have a state of altered immune regulation. This is consistent with the theory of low-grade inflammatory state in these patients. Further studies are needed to elucidate the role played by these cytokines, specifically TGF-β in the pathogenesis of IBS.

  4. Thioredoxin ameliorates cutaneous inflammation by regulating the epithelial production and release of pro-Inflammatory cytokines

    Directory of Open Access Journals (Sweden)

    Hai eTian

    2013-09-01

    Full Text Available Human thioredoxin-1 (TRX is a 12-kDa protein with redox-active dithiol in the active site -Cys-Gly-Pro-Cys-. It has been demonstrated that systemic administration and transgenic overexpression of TRX ameliorate inflammation in various animal models, but its anti-inflammatory mechanism is not well characterized. We investigated the anti-inflammatory effects of topically applied recombinant human TRX (rhTRX in a murine irritant contact dermatitis (ICD induced by croton oil. Topically applied rhTRX was distributed only in the skin tissues under both non-inflammatory and inflammatory conditions, and significantly suppressed the inflammatory response by inhibiting the production of cytokines and chemokines, such as TNF-α, Il-1β, IL-6, CXCL-1, and MCP-1. In an in vitro study, rhTRX also significantly inhibited the formation of cytokines and chemokines produced by keratinocytes after exposure to croton oil and phorbol 12-myristate 13-acetate. These results indicate that TRX prevents skin inflammation via the inhibition of local formation of inflammatory cytokines and chemokines. As a promising new approach, local application of TRX may be useful for the treatment of various skin and mucosal inflammatory disorders.

  5. Identification of Lactobacillus plantarum genes modulating the cytokine response of human peripheral blood mononuclear cells

    Directory of Open Access Journals (Sweden)

    Molenaar Douwe

    2010-11-01

    Full Text Available Abstract Background Modulation of the immune system is one of the most plausible mechanisms underlying the beneficial effects of probiotic bacteria on human health. Presently, the specific probiotic cell products responsible for immunomodulation are largely unknown. In this study, the genetic and phenotypic diversity of strains of the Lactobacillus plantarum species were investigated to identify genes of L. plantarum with the potential to influence the amounts of cytokines interleukin 10 (IL-10 and IL-12 and the ratio of IL-10/IL-12 produced by peripheral blood mononuclear cells (PBMCs. Results A total of 42 Lactobacillus plantarum strains isolated from diverse environmental and human sources were evaluated for their capacity to stimulate cytokine production in PBMCs. The L. plantarum strains induced the secretion of the anti-inflammatory cytokine IL-10 over an average 14-fold range and secretion of the pro-inflammatory cytokine IL-12 over an average 16-fold range. Comparisons of the strain-specific cytokine responses of PBMCs to comparative genome hybridization profiles obtained with L. plantarum WCFS1 DNA microarrays (also termed gene-trait matching resulted in the identification of 6 candidate genetic loci with immunomodulatory capacities. These loci included genes encoding an N-acetyl-glucosamine/galactosamine phosphotransferase system, the LamBDCA quorum sensing system, and components of the plantaricin (bacteriocin biosynthesis and transport pathway. Deletion of these genes in L. plantarum WCFS1 resulted in growth phase-dependent changes in the PBMC IL-10 and IL-12 cytokine profiles compared with wild-type cells. Conclusions The altered PBMC cytokine profiles obtained with the L. plantarum WCFS1 mutants were in good agreement with the predictions made by gene-trait matching for the 42 L. plantarum strains. This study therefore resulted in the identification of genes present in certain strains of L. plantarum which might be responsible for

  6. Comparison of Effect of Two-Hour Exposure to Forest and Urban Environments on Cytokine, Anti-Oxidant, and Stress Levels in Young Adults.

    Science.gov (United States)

    Im, Su Geun; Choi, Han; Jeon, Yo-Han; Song, Min-Kyu; Kim, Won; Woo, Jong-Min

    2016-06-23

    The purpose of this study was to investigate the effect of two-hour exposure to a forest environment on cytokine, anti-oxidant and stress levels among university students and to compare the results to those measured in urban environments. Forty-one subjects were recruited. For our crossover design, subjects were divided into two groups based on similar demographic characteristics. Group A remained in the urban environment and was asked to perform regular breathing for 2 h. Blood samples were collected and the serum levels of cytokines including interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), and glutathione peroxidase (GPx) were examined. Subjects were moved to a small town in a rural area for an equal amount of time to exclude carryover effects, and then remained for another 2 h in a forest environment. The second set of blood samples was collected to assess the effect of exposure to the forest environment. Using the same method, Group B was first exposed to the forest environment, followed by exposure to the urban environment. Blood samples collected after the subjects were exposed to the forest environment showed significantly lower levels of IL-8 and TNF-α compared to those in samples collected after urban environment exposure (10.76 vs. 9.21, t = 4.559, p forest environment (LnGPx = 5.09 vs. LnGPx = 5.21, t = -2.039, p < 0.05).

  7. Ghrelin’s Effects on Proinflammatory Cytokine Mediated Apoptosis and Their Impact on β-Cell Functionality

    Directory of Open Access Journals (Sweden)

    Antonia Diaz-Ganete

    2015-01-01

    Full Text Available Ghrelin is a peptidic hormone, which stimulates cell proliferation and inhibits apoptosis in several tissues, including pancreas. In preclinical stage of type 1 diabetes, proinflammatory cytokines generate a destructive environment for β-cells known as insulitis, which results in loss of β-cell mass and impaired insulin secretion, leading to diabetes. Our aim was to demonstrate that ghrelin could preserve β-cell viability, turnover rate, and insulin secretion acting as a counter balance of cytokines. In the present work we reproduced proinflammatory milieu found in insulitis stage by treating murine cell line INS-1E and rat islets with a cytokine cocktail including IL-1β, IFNγ, and TNFα and/or ghrelin. Several proteins involved in survival pathways (ERK 1/2 and Akt/PKB and apoptosis (caspases and Bcl-2 protein family and endoplasmic reticulum stress markers as well as insulin secretion were analyzed. Our results show that ghrelin alone has no remarkable effects on β-cells in basal conditions, but interestingly it activates cell survival pathways, downregulates apoptotic mediators and endoplasmic reticulum stress, and restores insulin secretion in response to glucose when beta-cells are cytokine-exposed. These data suggest a potential role of ghrelin in preventing or slowing down the transition from a preclinical to clinically established diabetes by ameliorating the effects of insulitis on β-cells.

  8. IBS, NERD and functional dyspepsia are immuno-neuronal disorders of mucosal cytokine imbalances clinically reversible with high potency sucralfate.

    Science.gov (United States)

    McCullough, Ricky W

    2013-03-01

    Irritable bowel syndrome (IBS), non-erosive reflux disorder (NERD), and functional dyspepsia (FD) are best classified as immuno-neuronal disorders of the mucosa or functional mucosal syndromes (FMS). Each appears to be clinically reversible using high potency sucralfate (HPS). In FMS of the GI tract, postprandial nausea, altered motility, discordant peristalsis, vomiting, diarrhea, and hyperalgesia are the clinical expressions of a mucosal imbalance between pro-inflammatory cytokines of up-regulated intra-epithelial lymphocytes (IELs) and feedback anti-inflammatory cytokines tasked with moderating the antigenic response of IELs. Normal functioning GI tract requires an operative balance between pro-inflammatory and anti-inflammatrory cytokines, a balance governed by locally expressed growth factors. The surface concentration of sucralfate can be enhanced 7-23-fold by suspending it in a select concentration of cations and multi-dentate cationic chelators. Increased surface concentration of sucralfate facilitates novel dose effects which include efficient activation of growth factors, quiescence of gated-nociceptor firing and resultant restoration of normal GI function. Published by Elsevier Ltd.

  9. Bovine lactoferricin is anti-inflammatory and anti-catabolic in human articular cartilage and synovium.

    Science.gov (United States)

    Yan, Dongyao; Chen, Di; Shen, Jie; Xiao, Guozhi; van Wijnen, Andre J; Im, Hee-Jeong

    2013-02-01

    Bovine lactoferricin (LfcinB) is a multi-functional peptide derived from proteolytic cleavage of bovine lactoferrin. LfcinB was found to antagonize the biological effects mediated by angiogenic growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) in endothelial cells. However, the effect of LfcinB on human articular cartilage remained unknown. Here, our findings demonstrate that LfcinB restored the proteoglycan loss promoted by catabolic factors (interleukin-1β) IL-1β and FGF-2 in vitro and ex vivo. Mechanistically, LfcinB attenuated the effects of IL-1β and FGF-2 on the expression of cartilage-degrading enzymes (MMP-1, MMP-3, and MMP-13), destructive cytokines (IL-1β and IL-6), and inflammatory mediators (iNOS and TLR2). LfcinB induced protective cytokine expression (IL-4 and IL-10), and downregulated aggrecanase basal expression. LfcinB specifically activated ERK MAPK and Akt signaling pathways, which may account for its anti-inflammatory activity. We also revealed that LfcinB exerted similar protective effects on human synovial fibroblasts challenged by IL-1β, with minimal cytotoxicity. Collectively, our results suggest that LfcinB possesses potent anti-catabolic and anti-inflammatory bioactivities in human articular tissues, and may be utilized for the prevention and/or treatment of OA in the future. Copyright © 2012 Wiley Periodicals, Inc.

  10. Reactive oxygen species-dependent Toll/NF-κB activation in the Drosophila hematopoietic niche confers resistance to wasp parasitism.

    Science.gov (United States)

    Louradour, Isabelle; Sharma, Anurag; Morin-Poulard, Ismael; Letourneau, Manon; Vincent, Alain; Crozatier, Michèle; Vanzo, Nathalie

    2017-11-01

    Hematopoietic stem/progenitor cells in the adult mammalian bone marrow ensure blood cell renewal. Their cellular microenvironment, called 'niche', regulates hematopoiesis both under homeostatic and immune stress conditions. In the Drosophila hematopoietic organ, the lymph gland, the posterior signaling center (PSC) acts as a niche to regulate the hematopoietic response to immune stress such as wasp parasitism. This response relies on the differentiation of lamellocytes, a cryptic cell type, dedicated to pathogen encapsulation and killing. Here, we establish that Toll/NF-κB pathway activation in the PSC in response to wasp parasitism non-cell autonomously induces the lymph gland immune response. Our data further establish a regulatory network where co-activation of Toll/NF-κB and EGFR signaling by ROS levels in the PSC/niche controls lymph gland hematopoiesis under parasitism. Whether a similar regulatory network operates in mammals to control emergency hematopoiesis is an open question.

  11. Tributyltin exposure alters cytokine levels in mouse serum.

    Science.gov (United States)

    Lawrence, Shanieek; Pellom, Samuel T; Shanker, Anil; Whalen, Margaret M

    2016-11-01

    Tributyltin (TBT), a toxic environmental contaminant, has been widely utilized for various industrial, agricultural and household purposes. Its usage has led to a global contamination and its bioaccumulation in aquatic organisms and terrestrial mammals. Previous studies suggest that TBT has debilitating effects on the overall immune function of animals, rendering them more vulnerable to diseases. TBT (at concentrations that have been detected in human blood) alters secretion of inflammatory cytokines from human lymphocytes ex vivo. Thus, it is important to determine if specified levels of TBT can alter levels of cytokines in an in vivo system. Mice were exposed to biologically relevant concentrations of TBT (200, 100 or 25 nM final concentrations). The quantitative determination of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL2, IL5, IL7, IL12βp40, IL13, IL15, keratinocyte chemoattractant (KC), macrophage inflammatory protein 1β (MIP), MIP2 and regulated on activation normal T-cell-expressed and secreted (RANTES) was performed in mouse sera by MAGPIX analysis and Western blot. Results indicated alterations (both decreases and increases) in several cytokines. The pro-inflammatory cytokines IFNγ, TNFα, IL-1β, IL-2, IL5, IL12βp40 and IL-15 were altered as were the chemokines MIP-1 and RANTES and the anti-inflammatory cytokine IL-13. Increases in IFNγ and TNFα were seen in the serum of mice exposed to TBT for less than 24 h. Levels of IL1β, IL-12 βp40, IL-5 and IL-15 were also modulated in mouse serum, depending on the specific experiment and exposure level. IL-2 was consistently decreased in mouse serum when animals were exposed to TBT. There were also TBT-induced increases in MIP-1β, RANTES and IL-13. These results from human and murine samples clearly suggest that TBT exposures modulate the secretion inflammatory cytokines.

  12. Th17-Related Cytokines in Systemic Lupus Erythematosus Patients with Dilated Cardiomyopathies: A Possible Linkage to Parvovirus B19 Infection

    Science.gov (United States)

    Chen, Der-Yuan; Chen, Yi-Ming; Lan, Joung-Liang

    2014-01-01

    Dilated cardiomyopathies (DCM) are a major cause of mortality in patients with systemic lupus erythematosus (SLE). Immune responses induced by human parvovirus B19 (B19) are considered an important pathogenic mechanism in myocarditis or DCM. However, little is known about Th17-related cytokines in SLE patients with DCM about the linkage with B19 infection. IgM and IgG against B19 viral protein, and serum levels of Th17-related cytokines were determined using ELISA in eight SLE patients with DCM and six patients with valvular heart disease (VHD). Humoral responses of anti-B19-VP1u and anti-B19-NS1 antibody were assessed using Western blot and B19 DNA was detected by nested Polymerase Chain Reaction (PCR). Levels of interleukin (IL)-17, IL-6, IL-1β, and tumor necrosis factor (TNF)-α were significantly higher in SLE patients with DCM (mean ± SEM, 390.99±125.48 pg/ml, 370.24±114.09 pg/ml, 36.01±16.90 pg/ml, and 183.84±82.94 pg/ml, respectively) compared to healthy controls (51.32±3.04 pg/ml, pB19-NS1 IgG and four (50.0%) of them had anti-B19-VP1u IgG, whereas only one (16.7%) of VHD patients had detectable anti-B19-NS1 IgG and anti-B19-VP1u IgG. Serum levels of IL-17, IL-6 and IL-1β were markedly higher in SLE patients with anti-B19-VP1u IgG and anti-B19-NS1 IgG compared to those without anti-B19-VP1u IgG or anti-B19-NS1 IgG, respectively. These suggest a potential association of B19 with DCM and Th17-related cytokines implicated in the pathogenesis of DCM in SLE patients. PMID:25462010

  13. Dichotomy in the human CD4+ T-cell response to Leishmania parasites

    DEFF Research Database (Denmark)

    Kemp, M; Kurtzhals, J A; Kharazmi, A

    1994-01-01

    Leishmania parasites cause human diseases ranging from self-healing cutaneous ulcers to fatal systemic infections. In addition, many individuals become infected without developing disease. In mice the two subsets of CD4+ T cells, Th1 and Th2, have different effects on the outcome of experimental...... in humans, and that the balance between subsets of parasite-specific T cells may play an important regulatory role in determining the outcome of the infections....

  14. Suppression of LPS-induced inflammatory responses in macrophages infected with Leishmania

    Directory of Open Access Journals (Sweden)

    Kelly Ben L

    2010-02-01

    Full Text Available Abstract Background Chronic inflammation activated by macrophage innate pathogen recognition receptors such as TLR4 can lead to a range of inflammatory diseases, including atherosclerosis, Crohn's disease, arthritis and cancer. Unlike many microbes, the kinetoplastid protozoan pathogen Leishmania has been shown to avoid and even actively suppress host inflammatory cytokine responses, such as LPS-induced IL-12 production. The nature and scope of Leishmania-mediated inflammatory cytokine suppression, however, is not well characterized. Advancing our knowledge of such microbe-mediated cytokine suppression may provide new avenues for therapeutic intervention in inflammatory disease. Methods We explored the kinetics of a range of cytokine and chemokine responses in primary murine macrophages stimulated with LPS in the presence versus absence of two clinically distinct species of Leishmania using sensitive multiplex cytokine analyses. To confirm that these effects were parasite-specific, we compared the effects of Leishmania uptake on LPS-induced cytokine expression with uptake of inert latex beads. Results Whilst Leishmania uptake alone did not induce significant levels of any cytokine analysed in this study, Leishmania uptake in the presence of LPS caused parasite-specific suppression of certain LPS-induced pro-inflammatory cytokines, including IL-12, IL-17 and IL-6. Interestingly, L. amazonensis was generally more suppressive than L. major. We also found that other LPS-induced proinflammatory cytokines, such as IL-1α, TNF-α and the chemokines MIP-1α and MCP-1 and also the anti-inflammatory cytokine IL-10, were augmented during Leishmania uptake, in a parasite-specific manner. Conclusions During uptake by macrophages, Leishmania evades the activation of a broad range of cytokines and chemokines. Further, in the presence of a strong inflammatory stimulus, Leishmania suppresses certain proinflammatory cytokine responses in a parasite

  15. Intradermal Immunization of Leishmania donovani Centrin Knock-Out Parasites in Combination with Salivary Protein LJM19 from Sand Fly Vector Induces a Durable Protective Immune Response in Hamsters.

    Directory of Open Access Journals (Sweden)

    Jacqueline Araújo Fiuza

    2016-01-01

    Full Text Available Visceral leishmaniasis (VL is a neglected tropical disease and is fatal if untreated. There is no vaccine available against leishmaniasis. The majority of patients with cutaneous leishmaniasis (CL or VL develop a long-term protective immunity after cure from infection, which indicates that development of an effective vaccine against leishmaniasis is possible. Such protection may also be achieved by immunization with live attenuated parasites that do not cause disease. We have previously reported a protective response in mice, hamsters and dogs with Leishmania donovani centrin gene knock-out parasites (LdCen-/-, a live attenuated parasite with a cell division specific centrin1 gene deletion. In this study we have explored the effects of salivary protein LJM19 as an adjuvant and intradermal (ID route of immunization on the efficacy of LdCen-/- parasites as a vaccine against virulent L. donovani.To explore the potential of a combination of LdCen-/- parasites and salivary protein LJM19 as vaccine antigens, LdCen-/- ID immunization followed by ID challenge with virulent L. donovani were performed in hamsters in a 9-month follow up study. We determined parasite burden (serial dilution, antibody production (ELISA and cytokine expression (qPCR in these animals. Compared to controls, animals immunized with LdCen-/- + LJM19 induced a strong antibody response, a reduction in spleen and liver parasite burden and a higher expression of pro-inflammatory cytokines after immunization and one month post-challenge. Additionally, a low parasite load in lymph nodes, spleen and liver, and a non-inflamed spleen was observed in immunized animals 9 months after the challenge infection.Our results demonstrate that an ID vaccination using LdCen-/-parasites in combination with sand fly salivary protein LJM19 has the capability to confer long lasting protection against visceral leishmaniasis that is comparable to intravenous or intracardial immunization.

  16. Functional expression of parasite drug targets and their human orthologs in yeast.

    Directory of Open Access Journals (Sweden)

    Elizabeth Bilsland

    2011-10-01

    Full Text Available The exacting nutritional requirements and complicated life cycles of parasites mean that they are not always amenable to high-throughput drug screening using automated procedures. Therefore, we have engineered the yeast Saccharomyces cerevisiae to act as a surrogate for expressing anti-parasitic targets from a range of biomedically important pathogens, to facilitate the rapid identification of new therapeutic agents.Using pyrimethamine/dihydrofolate reductase (DHFR as a model parasite drug/drug target system, we explore the potential of engineered yeast strains (expressing DHFR enzymes from Plasmodium falciparum, P. vivax, Homo sapiens, Schistosoma mansoni, Leishmania major, Trypanosoma brucei and T. cruzi to exhibit appropriate differential sensitivity to pyrimethamine. Here, we demonstrate that yeast strains (lacking the major drug efflux pump, Pdr5p expressing yeast ((ScDFR1, human ((HsDHFR, Schistosoma ((SmDHFR, and Trypanosoma ((TbDHFR and (TcDHFR DHFRs are insensitive to pyrimethamine treatment, whereas yeast strains producing Plasmodium ((PfDHFR and (PvDHFR DHFRs are hypersensitive. Reassuringly, yeast strains expressing field-verified, drug-resistant mutants of P. falciparum DHFR ((Pfdhfr(51I,59R,108N are completely insensitive to pyrimethamine, further validating our approach to drug screening. We further show the versatility of the approach by replacing yeast essential genes with other potential drug targets, namely phosphoglycerate kinases (PGKs and N-myristoyl transferases (NMTs.We have generated a number of yeast strains that can be successfully harnessed for the rapid and selective identification of urgently needed anti-parasitic agents.

  17. Inhibition of early T cell cytokine production by arsenic trioxide occurs independently of Nrf2.

    Directory of Open Access Journals (Sweden)

    Kelly R VanDenBerg

    Full Text Available Nuclear factor erythroid 2-related factor 2 (Nrf2 is a stress-activated transcription factor that induces a variety of cytoprotective genes. Nrf2 also mediates immunosuppressive effects in multiple inflammatory models. Upon activation, Nrf2 dissociates from its repressor protein, Keap1, and translocates to the nucleus where it induces Nrf2 target genes. The Nrf2-Keap1 interaction is disrupted by the environmental toxicant and chemotherapeutic agent arsenic trioxide (ATO. The purpose of the present study was to determine the effects of ATO on early events of T cell activation and the role of Nrf2 in those effects. The Nrf2 target genes Hmox-1, Nqo-1, and Gclc were all upregulated by ATO (1-2 μM in splenocytes derived from wild-type, but not Nrf2-null, mice, suggesting that Nrf2 is activated by ATO in splenocytes. ATO also inhibited IFNγ, IL-2, and GM-CSF mRNA and protein production in wild-type splenocytes activated with the T cell activator, anti-CD3/anti-CD28. However, ATO also decreased production of these cytokines in activated splenocytes from Nrf2-null mice, suggesting the inhibition is independent of Nrf2. Interestingly, ATO inhibited TNFα protein secretion, but not mRNA expression, in activated splenocytes suggesting the inhibition is due to post-transcriptional modification. In addition, c-Fos DNA binding was significantly diminished by ATO in wild-type and Nrf2-null splenocytes activated with anti-CD3/anti-CD28, consistent with the observed inhibition of cytokine production by ATO. Collectively, this study suggests that although ATO activates Nrf2 in splenocytes, inhibition of early T cell cytokine production by ATO occurs independently of Nrf2 and may instead be due to impaired AP-1 DNA binding.

  18. Edible vaccines against veterinary parasitic diseases--current status and future prospects.

    Science.gov (United States)

    Jacob, Siju S; Cherian, Susan; Sumithra, T G; Raina, O K; Sankar, M

    2013-04-08

    Protection of domestic animals against parasitic infections remains a major challenge in most of the developing countries, especially in the surge of drug resistant strains. In this circumstance vaccination seems to be the sole practical strategy to combat parasites. Most of the presently available live or killed parasitic vaccines possess many disadvantages. Thus, expression of parasitic antigens has seen a continued interest over the past few decades. However, only a limited success was achieved using bacterial, yeast, insect and mammalian expression systems. This is witnessed by an increasing number of reports on transgenic plant expression of previously reported and new antigens. Oral delivery of plant-made vaccines is particularly attractive due to their exceptional advantages. Moreover, the regulatory burden for veterinary vaccines is less compared to human vaccines. This led to an incredible investment in the field of transgenic plant vaccines for veterinary purpose. Plant based vaccine trials have been conducted to combat various significant parasitic diseases such as fasciolosis, schistosomosis, poultry coccidiosis, porcine cycticercosis and ascariosis. Besides, passive immunization by oral delivery of antibodies expressed in transgenic plants against poultry coccidiosis is an innovative strategy. These trials may pave way to the development of promising edible veterinary vaccines in the near future. As the existing data regarding edible parasitic vaccines are scattered, an attempt has been made to assemble the available literature. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity.

    Directory of Open Access Journals (Sweden)

    Caline G Matar

    2015-05-01

    Full Text Available Immunity to non-cerebral severe malaria is estimated to occur within 1-2 infections in areas of endemic transmission for Plasmodium falciparum. Yet, nearly 20% of infected children die annually as a result of severe malaria. Multiple risk factors are postulated to exacerbate malarial disease, one being co-infections with other pathogens. Children living in Sub-Saharan Africa are seropositive for Epstein Barr Virus (EBV by the age of 6 months. This timing overlaps with the waning of protective maternal antibodies and susceptibility to primary Plasmodium infection. However, the impact of acute EBV infection on the generation of anti-malarial immunity is unknown. Using well established mouse models of infection, we show here that acute, but not latent murine gammaherpesvirus 68 (MHV68 infection suppresses the anti-malarial humoral response to a secondary malaria infection. Importantly, this resulted in the transformation of a non-lethal P. yoelii XNL infection into a lethal one; an outcome that is correlated with a defect in the maintenance of germinal center B cells and T follicular helper (Tfh cells in the spleen. Furthermore, we have identified the MHV68 M2 protein as an important virus encoded protein that can: (i suppress anti-MHV68 humoral responses during acute MHV68 infection; and (ii plays a critical role in the observed suppression of anti-malarial humoral responses in the setting of co-infection. Notably, co-infection with an M2-null mutant MHV68 eliminates lethality of P. yoelii XNL. Collectively, our data demonstrates that an acute gammaherpesvirus infection can negatively impact the development of an anti-malarial immune response. This suggests that acute infection with EBV should be investigated as a risk factor for non-cerebral severe malaria in young children living in areas endemic for Plasmodium transmission.

  20. Cytokines, hepatic cell profiling and cell interactions during bone marrow cell therapy for liver fibrosis in cholestatic mice.

    Directory of Open Access Journals (Sweden)

    Daphne Pinheiro

    Full Text Available Bone marrow cells (BMC migrate to the injured liver after transplantation, contributing to regeneration through multiple pathways, but mechanisms involved are unclear. This work aimed to study BMC migration, characterize cytokine profile, cell populations and proliferation in mice with liver fibrosis transplanted with GFP+ BMC. Confocal microscopy analysis showed GFP+ BMC near regions expressing HGF and SDF-1 in the fibrotic liver. Impaired liver cell proliferation in fibrotic groups was restored after BMC transplantation. Regarding total cell populations, there was a significant reduction in CD68+ cells and increased Ly6G+ cells in transplanted fibrotic group. BMC contributed to the total populations of CD144, CD11b and Ly6G cells in the fibrotic liver, related to an increment of anti-fibrotic cytokines (IL-10, IL-13, IFN-γ and HGF and reduction of pro-inflammatory cytokines (IL-17A and IL-6. Therefore, HGF and SDF-1 may represent important chemoattractants for transplanted BMC in the injured liver, where these cells can give rise to populations of extrahepatic macrophages, neutrophils and endothelial progenitor cells that can interact synergistically with other liver cells towards the modulation of an anti-fibrotic cytokine profile promoting the onset of liver regeneration.

  1. Drug target identification in protozoan parasites.

    Science.gov (United States)

    Müller, Joachim; Hemphill, Andrew

    2016-08-01

    Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high-throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses.

  2. Strain-dependent release of cytokines modulated by Lactobacillus salivarius human isolates in an in vitro model

    Science.gov (United States)

    2010-01-01

    Background Oral administration of probiotics is known to modulate cytokines profile not only locally, but also systemically. Four strains of Lactobacillus salivarius, LDR0723, BNL1059, RGS1746 and CRL1528, were evaluated for their ability to modulate release of pro- and anti-inflammatory cytokines. Findings Strains were assessed for effects on production of Interleukin-12 (IL-12), Interferon-γ (IFN-γ), Interleukin-4 (IL-4) and Interleukin-5 (IL-5) by incubating bacterial suspensions with THP-1 macrophage like cells. Cytokines were determined by means of specific quantitative enzyme-linked immunosorbent assays. LDR0723 and CRL1528 led to a sustained increment in production of IL-12 and IFN-γ and to a decrease in release of IL-4 and IL-5, while BNL1059 and RGS1746 favoured Th2 response, leading to a decrease in Th1/Th2 ratio with respect to unstimulated cells. Conclusions In conclusion, capability of L. salivarius to modulate immune response was strictly strain dependent and strains of the same species might have opposite effects. Therefore, a careful evaluation of anti-inflammatory properties of lactobacilli should be performed on single strain, before any consideration on potential probiotic use. PMID:20184725

  3. Functional Impairment of Myeloid Dendritic Cells during Advanced Stage of HIV-1 Infection: Role of Factors Regulating Cytokine Signaling.

    Directory of Open Access Journals (Sweden)

    Meenakshi Sachdeva

    Full Text Available Severely immunocompromised state during advanced stage of HIV-1 infection has been linked to functionally defective antigen presentation by dendritic cells (DCs. The molecular mechanisms behind DC impairment are still obscure. We investigated changes in DC function and association of key regulators of cytokine signaling during different stages of HIV-1 infection and following antiretroviral therapy (ART.Phenotypic and functional characteristics of circulating myeloid DCs (mDCs in 56 ART-naive patients (23 in early and 33 in advanced stage of disease, 36 on ART and 24 healthy controls were evaluated. Sixteen patients were studied longitudinally prior-to and 6 months after the start of ART. For functional studies, monocyte-derived DCs (Mo-DCs were evaluated for endocytosis, allo-stimulation and cytokine secretion. The expression of suppressor of cytokine signaling (SOCS-1 and other regulators of cytokine signaling was evaluated by real-time RT-PCR.The ability to respond to an antigenic stimulation was severely impaired in patients in advanced HIV-1 disease which showed partial recovery in the treated group. Mo-DCs from patients with advanced HIV-disease remained immature with low allo-stimulation and reduced cytokine secretion even after TLR-4 mediated stimulation ex-vivo. The cells had an increased expression of negative regulatory factors like SOCS-1, SOCS-3, SH2-containing phosphatase (SHP-1 and a reduced expression of positive regulators like Janus kinase (JAK2 and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB1. A functional recovery after siRNA mediated silencing of SOCS-1 in these mo-DCs confirms the role of negative regulatory factors in functional impairment of these cells.Functionally defective DCs in advanced stage of HIV-1 infection seems to be due to imbalanced state of negative and positive regulatory gene expression. Whether this is a cause or effect of increased viral replication at this stage of disease

  4. MicroRNA-Mediated Gene Silencing in Plant Defense and Viral Counter-Defense

    Directory of Open Access Journals (Sweden)

    Sheng-Rui Liu

    2017-09-01

    Full Text Available MicroRNAs (miRNAs are non-coding RNAs of approximately 20–24 nucleotides in length that serve as central regulators of eukaryotic gene expression by targeting mRNAs for cleavage or translational repression. In plants, miRNAs are associated with numerous regulatory pathways in growth and development processes, and defensive responses in plant–pathogen interactions. Recently, significant progress has been made in understanding miRNA-mediated gene silencing and how viruses counter this defense mechanism. Here, we summarize the current knowledge and recent advances in understanding the roles of miRNAs involved in the plant defense against viruses and viral counter-defense. We also document the application of miRNAs in plant antiviral defense. This review discusses the current understanding of the mechanisms of miRNA-mediated gene silencing and provides insights on the never-ending arms race between plants and viruses.

  5. Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD.

    Science.gov (United States)

    Hechinger, Anne-Kathrin; Smith, Benjamin A H; Flynn, Ryan; Hanke, Kathrin; McDonald-Hyman, Cameron; Taylor, Patricia A; Pfeifer, Dietmar; Hackanson, Björn; Leonhardt, Franziska; Prinz, Gabriele; Dierbach, Heide; Schmitt-Graeff, Annette; Kovarik, Jiri; Blazar, Bruce R; Zeiser, Robert

    2015-01-15

    The common γ chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-γ, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3(-/-) T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common γ-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation. © 2015 by The American Society of Hematology.

  6. Amino acid substitutions in the melanoma antigen recognized by T cell 1 peptide modulate cytokine responses in melanoma-specific T cells

    DEFF Research Database (Denmark)

    Nielsen, M B; Kirkin, A F; Loftus, D

    2000-01-01

    enhances the production of mRNA for interleukin (IL)-5, IL-10, IL-13, IL-15, and interferon-gamma and significantly enhances release of IL-13 and IL-10 from anti-MART-1 cytotoxic T cells. Another heteroclitic peptide, 1L, with an A to L substitution in MART-1(27-35), also enhances the tyrosine...... phosphorylation response in anti-MART-1 cytotoxic CD8+ T cells. Yet, 1L does not enhance the production of T helper cell type 2-like cytokines (IL-10 and IL-13). Together these data show that minor amino acid modifications of immunodominant melanoma peptides profoundly influence the cytokine response in melanoma...

  7. Countering money laundering and terrorism financing: can the resultant intrusion into the right of privacy by the law be justified?

    OpenAIRE

    Ruff, Adam Michael

    2017-01-01

    This thesis examines whether anti-money laundering and counter-terrorism financing (AML/CTF) law strikes the right balance between the need to counter money laundering and terrorism financing (ML/TF) and the need to preserve the right of privacy. To do this, the thesis examines both the effectiveness of AML/CTF law and the scope of the right of privacy. The thesis reviews the history of AML/CTF law, including attempts to estimate the size of the money laundering problem, and assesses the ...

  8. Space and power efficient hybrid counters array

    Science.gov (United States)

    Gara, Alan G [Mount Kisco, NY; Salapura, Valentina [Chappaqua, NY

    2009-05-12

    A hybrid counter array device for counting events. The hybrid counter array includes a first counter portion comprising N counter devices, each counter device for receiving signals representing occurrences of events from an event source and providing a first count value corresponding to a lower order bits of the hybrid counter array. The hybrid counter array includes a second counter portion comprising a memory array device having N addressable memory locations in correspondence with the N counter devices, each addressable memory location for storing a second count value representing higher order bits of the hybrid counter array. A control device monitors each of the N counter devices of the first counter portion and initiates updating a value of a corresponding second count value stored at the corresponding addressable memory location in the second counter portion. Thus, a combination of the first and second count values provide an instantaneous measure of number of events received.

  9. Effects of dietary resveratrol supplementation on hepatic and serum pro-/anti-inflammatory activity in juvenile GIFT tilapia, Oreochromis niloticus.

    Science.gov (United States)

    Zheng, Yao; Zhao, Zhixiang; Wu, Wei; Song, Chao; Meng, Shunlong; Fan, Limin; Bing, Xuwen; Chen, Jiazhang

    2017-08-01

    Dietary resveratrol (RES) supplementation may have some pharmacological effects including anti-inflammation. Previous studies have shown that Kupffer cell activation and apoptosis induction increases the transcription of pro- and anti-inflammatory cytokines. The main purpose of this study was to investigate the pro- and anti-inflammatory activities of 0.1 or 0.3 g/kg RES as a dietary supplement in juvenile freshwater tilapia (Oreochromis niloticus). The results showed that hepatic and serum immunoglobulin M (IgM) significantly decreased and increased while anti- and pro-inflammatory cytokines significantly increased and decreased, respectively, in the RES-treated groups. The expression of serum and hepatic IgM and anti-inflammatory cytokines [interleukin (IL)-10] and its inverse inhibitor interferon (IFN)-γ significantly increased while pro-inflammatory cytokine transcription significantly decreased. Hematoxylin-eosin staining and scanning electron microscopy revealed intestinal deformation, irregular goblet cells, and apoptotic cells in the 0.3 g/kg RES groups. RES (0.3 g/kg) also induced necrosis, apoptosis, reduction in Kupffer cell number, compressed sinusoids, and deformation of epidermal cells in the liver of the treated groups. In conclusion, the results of the present study show that high doses of RES were absorbed in the gut and then damaged the liver and intestinal tissue. Copyright © 2017. Published by Elsevier Ltd.

  10. Countering Center Gossip--Guidelines for Implementing an Anti-Gossip Policy.

    Science.gov (United States)

    Copeland, Margaret Leitch; Bruno, Holly Elissa

    2001-01-01

    Discusses gossip in early childhood settings as a threat to professionalism. Identifies reasons for staff gossip, provides guidance for developing an anti-gossip program policy, and presents an activity to distinguish gossip and shared information. Discusses how directors can influence parents' discussions with staff and get staff to confront each…

  11. TLR4 and NKT cell synergy in immunotherapy against visceral leishmaniasis.

    Directory of Open Access Journals (Sweden)

    Subir Karmakar

    Full Text Available NKT cells play an important role in autoimmune diseases, tumor surveillance, and infectious diseases, providing in most cases protection against infection. NKT cells are reactive to CD1d presented glycolipid antigens. They can modulate immune responses by promoting the secretion of type 1, type 2, or immune regulatory cytokines. Pathogen-derived signals to dendritic cells mediated via Toll like Receptors (TLR can be modulated by activated invariant Natural Killer T (iNKT cells. The terminal β-(1-4-galactose residues of glycans can modulate host responsiveness in a T helper type-1 direction via IFN-γ and TLRs. We have attempted to develop a defined immunotherapeutic, based on the cooperative action of a TLR ligand and iNKT cell using a mouse model of visceral leishmaniasis. We evaluated the anti-Leishmania immune responses and the protective efficacy of the β-(1-4-galactose terminal NKT cell ligand glycosphingophospholipid (GSPL antigen of L. donovani parasites. Our results suggest that TLR4 can function as an upstream sensor for GSPL and provoke intracellular inflammatory signaling necessary for parasite killing. Treatment with GSPL was able to induce a strong effective T cell response that contributed to effective control of acute parasite burden and led to undetectable parasite persistence in the infected animals. These studies for the first time demonstrate the interactions between a TLR ligand and iNKT cell activation in visceral leishmaniasis immunotherapeutic.

  12. Fisetin Inhibits Hyperglycemia-Induced Proinflammatory Cytokine Production by Epigenetic Mechanisms

    Directory of Open Access Journals (Sweden)

    Hye Joo Kim

    2012-01-01

    Full Text Available Diabetes is characterized by a proinflammatory state, and several inflammatory processes have been associated with both type 1 and type 2 diabetes and the resulting complications. High glucose levels induce the release of proinflammatory cytokines. Fisetin, a flavonoid dietary ingredient found in the smoke tree (Cotinus coggygria, and is also widely distributed in fruits and vegetables. Fisetin is known to exert anti-inflammatory effects via inhibition of the NF-κB signaling pathway. In this study, we analyzed the effects of fisetin on proinflammatory cytokine secretion and epigenetic regulation, in human monocytes cultured under hyperglycemic conditions. Human monocytic (THP-1 cells were cultured under control (14.5 mmol/L mannitol, normoglycemic (NG, 5.5 mmol/L glucose, or hyperglycemic (HG, 20 mmol/L glucose conditions, in the absence or presence of fisetin. Fisetin was added (3–10 μM for 48 h. While the HG condition significantly induced histone acetylation, NF-κB activation, and proinflammatory cytokine (IL-6 and TNF-α release from THP-1 cells, fisetin suppressed NF-κB activity and cytokine release. Fisetin treatment also significantly reduced CBP/p300 gene expression, as well as the levels of acetylation and HAT activity of the CBP/p300 protein, which is a known NF-κB coactivator. These results suggest that fisetin inhibits HG-induced cytokine production in monocytes, through epigenetic changes involving NF-κB. We therefore propose that fisetin supplementation be considered for diabetes prevention.

  13. Bovine leukemia virus reduces anti-viral cytokine activities and NK cytotoxicity by inducing TGF-β secretion from regulatory T cells.

    Science.gov (United States)

    Ohira, Kosuke; Nakahara, Ayako; Konnai, Satoru; Okagawa, Tomohiro; Nishimori, Asami; Maekawa, Naoya; Ikebuchi, Ryoyo; Kohara, Junko; Murata, Shiro; Ohashi, Kazuhiko

    2016-03-01

    CD4(+)CD25(high)Foxp3(+) T cells suppress excess immune responses that lead to autoimmune and/or inflammatory diseases, and maintain host immune homeostasis. However, CD4(+)CD25(high)Foxp3(+) T cells reportedly contribute to disease progression by over suppressing immune responses in some chronic infections. In this study, kinetic and functional analyses of CD4(+)CD25(high)Foxp3(+) T cells were performed in cattle with bovine leukemia virus (BLV) infections, which have reported immunosuppressive characteristics. In initial experiments, production of the Th1 cytokines IFN-γ and TNF-α was reduced in BLV-infected cattle compared with uninfected cattle, and numbers of IFN-γ or TNF-α producing CD4(+) T cells decreased with disease progression. In contrast, IFN-γ production by NK cells was inversely correlated with BLV proviral loads in infected cattle. Additionally, during persistent lymphocytosis disease stages, NK cytotoxicity was depressed as indicated by low expression of the cytolytic protein perforin. Concomitantly, total CD4(+)CD25(high)Foxp3(+) T cell numbers and percentages of TGF-β(+) cells were increased, suggesting that TGF-β plays a role in the functional declines of CD4(+) T cells and NK cells. In further experiments, recombinant bovine TGF-β suppressed IFN-γ and TNF-α production by CD4(+) T cells and NK cytotoxicity in cultured cells. These data suggest that TGF-β from CD4(+)CD25(high)Foxp3(+) T cells is immunosuppressive and contributes to disease progression and the development of opportunistic infections during BLV infection.

  14. Modelling parasite transmission in a grazing system: the importance of host behaviour and immunity.

    Directory of Open Access Journals (Sweden)

    Naomi J Fox

    Full Text Available Parasitic helminths present one of the most pervasive challenges to grazing herbivores. Many macro-parasite transmission models focus on host physiological defence strategies, omitting more complex interactions between hosts and their environments. This work represents the first model that integrates both the behavioural and physiological elements of gastro-intestinal nematode transmission dynamics in a managed grazing system. A spatially explicit, individual-based, stochastic model is developed, that incorporates both the hosts' immunological responses to parasitism, and key grazing behaviours including faecal avoidance. The results demonstrate that grazing behaviour affects both the timing and intensity of parasite outbreaks, through generating spatial heterogeneity in parasite risk and nutritional resources, and changing the timing of exposure to the parasites' free-living stages. The influence of grazing behaviour varies with the host-parasite combination, dependent on the development times of different parasite species and variations in host immune response. Our outputs include the counterintuitive finding that under certain conditions perceived parasite avoidance behaviours (faecal avoidance can increase parasite risk, for certain host-parasite combinations. Through incorporating the two-way interaction between infection dynamics and grazing behaviour, the potential benefits of parasite-induced anorexia are also demonstrated. Hosts with phenotypic plasticity in grazing behaviour, that make grazing decisions dependent on current parasite burden, can reduce infection with minimal loss of intake over the grazing season. This paper explores how both host behaviours and immunity influence macro-parasite transmission in a spatially and temporally heterogeneous environment. The magnitude and timing of parasite outbreaks is influenced by host immunity and behaviour, and the interactions between them; the incorporation of both regulatory processes

  15. Fisetin Inhibits Hyperglycemia-Induced Proinflammatory Cytokine Production by Epigenetic Mechanisms

    OpenAIRE

    Hye Joo Kim; Seong Hwan Kim; Jung-Mi Yun

    2012-01-01

    Diabetes is characterized by a proinflammatory state, and several inflammatory processes have been associated with both type 1 and type 2 diabetes and the resulting complications. High glucose levels induce the release of proinflammatory cytokines. Fisetin, a flavonoid dietary ingredient found in the smoke tree (Cotinus coggygria), and is also widely distributed in fruits and vegetables. Fisetin is known to exert anti-inflammatory effects via inhibition of the NF-?B signaling pathway. In this...

  16. Distinct Immunoregulatory Mechanisms in Mesenchymal Stem Cells: Role of the Cytokine Environment

    Czech Academy of Sciences Publication Activity Database

    Holáň, Vladimír; Heřmánková, Barbora; Boháčová, Pavla; Kössl, Jan; Chudíčková, Milada; Hájková, Michaela; Krulová, Magdaléna; Zajícová, Alena; Javorková, Eliška

    2016-01-01

    Roč. 12, č. 6 (2016), s. 654-663 ISSN 1550-8943 R&D Projects: GA ČR(CZ) GA14-12580S; GA MŠk(CZ) ED1.1.00/02.0109; GA MŠk(CZ) LO1508; GA MŠk(CZ) LO1309 Institutional support: RVO:68378041 Keywords : mesenchymal stem cells * regulatory B cells * cytokine environment Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.967, year: 2016

  17. Monocyte-Derived Signals Activate Human Natural Killer Cells in Response to Leishmania Parasites

    Science.gov (United States)

    Messlinger, Helena; Sebald, Heidi; Heger, Lukas; Dudziak, Diana; Bogdan, Christian; Schleicher, Ulrike

    2018-01-01

    Activated natural killer (NK) cells release interferon (IFN)-γ, which is crucial for the control of intracellular pathogens such as Leishmania. In contrast to experimental murine leishmaniasis, the human NK cell response to Leishmania is still poorly characterized. Here, we investigated the interaction of human blood NK cells with promastigotes of different Leishmania species (Leishmania major, Leishmania mexicana, Leishmania infantum, and Leishmania donovani). When peripheral blood mononuclear cells or purified NK cells and monocytes (all derived from healthy blood donors from Germany without a history of leishmaniasis) were exposed to promastigotes, NK cells showed increased surface expression of the activation marker CD69. The extent of this effect varied depending on the Leishmania species; differences between dermotropic and viscerotropic L. infantum strains were not observed. Upregulation of CD69 required direct contact between monocytes and Leishmania and was partly inhibitable by anti-interleukin (IL)-18. Unexpectedly, IL-18 was undetectable in most of the supernatants (SNs) of monocyte/parasite cocultures. Confocal fluorescence microscopy of non-permeabilized cells revealed that Leishmania-infected monocytes trans-presented IL-18 to NK cells. Native, but not heat-treated SNs of monocyte/Leishmania cocultures also induced CD69 on NK cells, indicating the involvement of a soluble heat-labile factor other than IL-18. A role for the NK cell-activating cytokines IL-1β, IL-2, IL-12, IL-15, IL-21, and IFN-α/β was excluded. The increase of CD69 was not paralleled by NK cell IFN-γ production or enhanced cytotoxicity. However, prior exposure of NK cells to Leishmania parasites synergistically increased their IFN-γ release in response to IL-12, which was dependent on endogenous IL-18. CD1c+ dendritic cells were identified as possible source of Leishmania-induced IL-12. Finally, we observed that direct contact between Leishmania and NK cells reduced the

  18. Monocyte-Derived Signals Activate Human Natural Killer Cells in Response to Leishmania Parasites

    Directory of Open Access Journals (Sweden)

    Helena Messlinger

    2018-01-01

    Full Text Available Activated natural killer (NK cells release interferon (IFN-γ, which is crucial for the control of intracellular pathogens such as Leishmania. In contrast to experimental murine leishmaniasis, the human NK cell response to Leishmania is still poorly characterized. Here, we investigated the interaction of human blood NK cells with promastigotes of different Leishmania species (Leishmania major, Leishmania mexicana, Leishmania infantum, and Leishmania donovani. When peripheral blood mononuclear cells or purified NK cells and monocytes (all derived from healthy blood donors from Germany without a history of leishmaniasis were exposed to promastigotes, NK cells showed increased surface expression of the activation marker CD69. The extent of this effect varied depending on the Leishmania species; differences between dermotropic and viscerotropic L. infantum strains were not observed. Upregulation of CD69 required direct contact between monocytes and Leishmania and was partly inhibitable by anti-interleukin (IL-18. Unexpectedly, IL-18 was undetectable in most of the supernatants (SNs of monocyte/parasite cocultures. Confocal fluorescence microscopy of non-permeabilized cells revealed that Leishmania-infected monocytes trans-presented IL-18 to NK cells. Native, but not heat-treated SNs of monocyte/Leishmania cocultures also induced CD69 on NK cells, indicating the involvement of a soluble heat-labile factor other than IL-18. A role for the NK cell-activating cytokines IL-1β, IL-2, IL-12, IL-15, IL-21, and IFN-α/β was excluded. The increase of CD69 was not paralleled by NK cell IFN-γ production or enhanced cytotoxicity. However, prior exposure of NK cells to Leishmania parasites synergistically increased their IFN-γ release in response to IL-12, which was dependent on endogenous IL-18. CD1c+ dendritic cells were identified as possible source of Leishmania-induced IL-12. Finally, we observed that direct contact between Leishmania and NK cells

  19. Cytokine production of stimulated whole blood cultures in rheumatoid arthritis patients receiving short-term infliximab therapy.

    NARCIS (Netherlands)

    Popa, C.; Netea, M.G.; Barrera Rico, P.; Radstake, T.R.D.J.; Riel, P.L.C.M. van; Kullberg, B.J.; Meer, J.W.M. van der

    2005-01-01

    Patients with rheumatoid arthritis (RA) treated with anti-tumor necrosis factor (TNF) strategies have an increased susceptibility to infections, especially those caused by intracellular pathogens. In this study we assessed the cytokine production capacity in patients with RA and we further

  20. Intestinal parasitic infections in HIV/AIDS patients: epidemiological, nutritional and immunological aspects

    Directory of Open Access Journals (Sweden)

    FAM Amâncio

    2012-01-01

    Full Text Available This study applied a socioeconomic questionnaire designed to evaluate the frequency of intestinal parasites and characterize epidemiological, nutritional, and immunological variables in 105 HIV/AIDS patients - with and without parasitic infections, attending the Day Hospital in Botucatu, UNESP, from 2007 to 2008. Body mass index was calculated and the following tests performed: parasitological stool examinations; eosinophil, IgE, CD4+ T and CD8+ T lymphocyte cell counts; albumin test; viral load measure; and TNF-α, IFN-γ, IL-2, IL-5 and IL-10 cytokine levels. Results were positive for parasitic intestinal infections in 12.4% of individuals. Most patients had good socioeconomic conditions with basic sanitation, urban dwellings, treated water supply and sewage, good nutritional and immunological status and were undergoing HAART. Parasites were found at the following frequencies: Entamoeba - five patients (38.5%, Giardia lamblia - four (30.7%, Blastocystis hominis - three (23.0%, Endolimax nana - two (15.4%, and Ascaris lumbricoides - one (7.7%. There were no significant differences between the two groups for eosinophils, albumin, IgE, CD4+ T and CD8+ T lymphocytes, INF-γ, IL-2, or IL-10. Most patients also showed undetectable viral load levels. Significant differences were found for TNF-α and IL-5. These results show the importance of new studies on immunodeficient individuals to increase understanding of such variables.

  1. Novel methods of cytokine detection: Real-time PCR, ELISPOT, and intracellular cytokine staining

    Directory of Open Access Journals (Sweden)

    Eliza Turlej

    2009-05-01

    Full Text Available Cytokines are small hormone-like proteins that play important roles in immune system control. Cytokines regulate the proliferation and differentiation of cells and hematopoiesis and act as mediators in the inflammatory reaction. Changes in cytokine levels are found in many diseases, such as sepsis, bowel inflammatory disease, autoimmune diseases, as well as graft-versus-host disease. Cytokines levels can be detected using in vivo, in vitro, and ex vivo techniques. The level of cytokine produced can be measured by immunoenzymatic test (ELISA in supernatant after cell culture with the addition of stimulant and in plasma by techniques that measure the level of cytokine secretion in cells (e.g. immunohistochemical staining, ELISPOT, and intracellular cytokine staining, and by molecular biological methods (RPA, real-time PCR, in situ hybridization, and Northern blot. Detection of cytokine mRNA in tissues is useful in the direct determination of heterogenic populations of cytokine-producing cells. Nowadays the most frequently used methods for measuring cytokine level are ELISPOT, intracellular cytokine staining with flow cytometry detection, and real-time PCR. These methods have an important clinical role in vaccine efficacy, in viral, bacterial, and verminous diagnostics, and in determining the efficacy of cancer treatment.

  2. Impact of Antidepressants on Cytokine Production of Depressed Patients in Vitro

    Directory of Open Access Journals (Sweden)

    Alexander Munzer

    2013-11-01

    Full Text Available The interplay between immune and nervous systems plays a pivotal role in the pathophysiology of depression. In depressive episodes, patients show increased production of pro-inflammatory cytokines such as interleukin (IL-1β and tumor necrosis factor (TNF-α. There is limited information on the effect of antidepressant drugs on cytokines, most studies report on a limited sample of cytokines and none have reported effects on IL-22. We systematically investigated the effect of three antidepressant drugs, citalopram, escitalopram and mirtazapine, on secretion of cytokines IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in a whole blood assay in vitro, using murine anti-human CD3 monoclonal antibody OKT3, and 5C3 monoclonal antibody against CD40, to stimulate T and B cells respectively. Citalopram increased production of IL-1β, IL-6, TNF-α and IL-22. Mirtazapine increased IL-1β, TNF-α and IL-22. Escitalopram decreased IL-17 levels. The influence of antidepressants on IL-2 and IL-4 levels was not significant for all three drugs. Compared to escitalopram, citalopram led to higher levels of IL-1β, IL-6, IL-17 and IL-22; and mirtazapine to higher levels of IL-1β, IL-17, IL-22 and TNF-α. Mirtazapine and citalopram increased IL-22 production. The differing profile of cytokine production may relate to differences in therapeutic effects, risk of relapse and side effects.

  3. Alpha-mangostin inhibits both dengue virus production and cytokine/chemokine expression.

    Science.gov (United States)

    Tarasuk, Mayuri; Songprakhon, Pucharee; Chimma, Pattamawan; Sratongno, Panudda; Na-Bangchang, Kesara; Yenchitsomanus, Pa-Thai

    2017-08-15

    Since severe dengue virus (DENV) infection in humans associates with both high viral load and massive cytokine production - referred to as "cytokine storm", an ideal drug for treatment of DENV infection should efficiently inhibit both virus production and cytokine expression. In searching for such an ideal drug, we discovered that α-mangostin (α-MG), a major bioactive compound purified from the pericarp of the mangosteen fruit (Garcinia mangostana Linn), which has been used in traditional medicine for several conditions including trauma, diarrhea, wound infection, pain, fever, and convulsion, inhibits both DENV production in cultured hepatocellular carcinoma HepG2 and Huh-7 cells, and cytokine/chemokine expression in HepG2 cells. α-MG could also efficiently inhibit all four serotypes of DENV. Treatment of DENV-infected cells with α-MG (20μM) significantly reduced the infection rates of four DENV serotypes by 47-55%. α-MG completely inhibited production of DENV-1 and DENV-3, and markedly reduced production of DENV-2 and DENV-4 by 100 folds. Furthermore, it could markedly reduce cytokine (IL-6 and TNF-α) and chemokine (RANTES, MIP-1β, and IP-10) transcription. These actions of α-MG are more potent than those of antiviral agent (ribavirin) and anti-inflammatory drug (dexamethasone). Thus, α-MG is potential to be further developed as therapeutic agent for DENV infection. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Nectar chemistry mediates the behavior of parasitized bees: consequences for plant fitness.

    Science.gov (United States)

    Richardson, Leif L; Bowers, M Deane; Irwin, Rebecca E

    2016-02-01

    Plants produce an array of secondary metabolites that play important ecological roles as anti-herbivore and anti-pathogen defenses. Many herbivores experience physiological costs when they consume secondary metabolites, yet some also benefit, for example when these chemicals confer resistance to parasites and predators. Secondary metabolites are often present in nectar and pollen, which is paradoxical given that floral rewards are important in the attraction of mutualists rather than deterrence of antagonists. Motivated by studies of interactions among plants, herbivores, and parasites, as well as research showing that secondary metabolites can reduce bee disease, we characterized the occurrence of two iridoid glycosides, aucubin and catalpol, in floral rewards and other tissues of the bee pollinated plant, Chelone glabra. We then experimentally investigated effects of nectar iridoid glycoside concentrations on the foraging behavior of bumble bee pollinators naturally afflicted by a parasitoid fly and a protozoan intestinal parasite, and subsequent effects on an estimate of plant reproduction. We found that floral nectar had lower iridoid glycoside concentrations than leaves, pollen, and corollas, and that, compared to those plant parts, the relative ratio of the two primary iridoid glycosides, aucubin and catalpol, was reversed in nectar. Whether bees carried parasitoid fly larvae did not affect their response to nectar chemistry; however, there was a significant interaction between protozoan parasite infection and nectar treatment, with infected bees foraging longer at flowers with high compared to low nectar iridoid glycoside concentrations. Parasitized bees were also more likely to return to inflorescences with high iridoid glycoside nectar. Consequently, flowers in the high iridoid glycoside nectar treatment donated significantly more pollen to conspecific stigmas than did flowers in the low iridoid glycoside treatment, suggesting an increase in male plant

  5. Analysis of SF and plasma cytokines provides insights into the mechanisms of inflammatory arthritis and may predict response to therapy.

    Science.gov (United States)

    Wright, Helen L; Bucknall, Roger C; Moots, Robert J; Edwards, Steven W

    2012-03-01

    Biologic drugs have revolutionized the care of RA, but are expensive and not universally effective. To further understand the inflammatory mechanisms underlying RA and identify potential biomarkers predicting response to therapy, we measured multiple cytokine concentrations in SF of patients with inflammatory arthritides (IAs) and, in a subset of patients with RA, correlated this with response to TNF-α inhibition. SF from 42 RA patients and 19 non-RA IA patients were analysed for 12 cytokines using a multiplex cytokine assay. Cytokines were also measured in the plasma of 16 RA patients before and following treatment with anti-TNF-α. Data were analysed using Mann-Whitney U-test, Spearman's rank correlation and cluster analysis with the Kruskal-Wallis test with Dunn's post-test analysis. RA SF contained significantly elevated levels of IL-1β, IL-1ra, IL-2, IL-4, IL-8, IL-10, IL-17, IFN-γ, G-CSF, GM-CSF and TNF-α compared with other IA SF. RA patients who did not respond to anti-TNF therapy had elevated IL-6 in their SF pre-therapy (P < 0.05), whereas responders had elevated IL-2 and G-CSF (P < 0.05). Plasma cytokine concentrations were not significantly modulated by TNF inhibitors, with the exception of IL-6, which decreased after 12 weeks (P < 0.05). Cytokine profiles in RA SF vary with treatment and response to therapy. Cytokine concentrations are significantly lower in plasma than in SF and relatively unchanged by TNF inhibitor therapy. Concentrations of IL-6, IL-2 and G-CSF in SF may predict response to TNF inhibitors.

  6. Comparison of Effect of Two-Hour Exposure to Forest and Urban Environments on Cytokine, Anti-Oxidant, and Stress Levels in Young Adults

    Directory of Open Access Journals (Sweden)

    Su Geun Im

    2016-06-01

    Full Text Available The purpose of this study was to investigate the effect of two-hour exposure to a forest environment on cytokine, anti-oxidant and stress levels among university students and to compare the results to those measured in urban environments. Forty-one subjects were recruited. For our crossover design, subjects were divided into two groups based on similar demographic characteristics. Group A remained in the urban environment and was asked to perform regular breathing for 2 h. Blood samples were collected and the serum levels of cytokines including interleukin-6 (IL-6, IL-8, tumor necrosis factor-α (TNF-α, and glutathione peroxidase (GPx were examined. Subjects were moved to a small town in a rural area for an equal amount of time to exclude carryover effects, and then remained for another 2 h in a forest environment. The second set of blood samples was collected to assess the effect of exposure to the forest environment. Using the same method, Group B was first exposed to the forest environment, followed by exposure to the urban environment. Blood samples collected after the subjects were exposed to the forest environment showed significantly lower levels of IL-8 and TNF-α compared to those in samples collected after urban environment exposure (10.76 vs. 9.21, t = 4.559, p < 0.001, and 0.97 vs. 0.87, t = 4.130, p < 0.001. The GPx concentration increased significantly after exposure to the forest environment (LnGPx = 5.09 vs. LnGPx = 5.21, t = −2.039, p < 0.05.

  7. Towards identifying novel anti-Eimeria agents: trace elements, vitamins, and plant-based natural products.

    Science.gov (United States)

    Wunderlich, Frank; Al-Quraishy, Saleh; Steinbrenner, Holger; Sies, Helmut; Dkhil, Mohamed A

    2014-10-01

    Eimeriosis, a widespread infectious disease of livestock, is caused by coccidian protozoans of the genus Eimeria. These obligate intracellular parasites strike the digestive tract of their hosts and give rise to enormous economic losses, particularly in poultry, ruminants including cattle, and rabbit farming. Vaccination, though a rational prophylactic measure, has not yet been as successful as initially thought. Numerous broad-spectrum anti-coccidial drugs are currently in use for treatment and prophylactic control of eimeriosis. However, increasing concerns about parasite resistance, consumer health, and environmental safety of the commercial drugs warrant efforts to search for novel agents with anti-Eimeria activity. This review summarizes current approaches to prevent and treat eimeriosis such as vaccination and commercial drugs, as well as recent attempts to use dietary antioxidants as novel anti-Eimeria agents. In particular, the trace elements selenium and zinc, the vitamins A and E, and natural products extracted from garlic, barberry, pomegranate, sweet wormwood, and other plants are discussed. Several of these novel anti-Eimeria agents exhibit a protective role against oxidative stress that occurs not only in the intestine of Eimeria-infected animals, but also in their non-parasitized tissues, in particular, in the first-pass organ liver. Currently, it appears to be promising to identify safe combinations of low-cost natural products with high anti-Eimeria efficacy for a potential use as feed supplementation in animal farming.

  8. Paternity-parasitism trade-offs: a model and test of host-parasite cooperation in an avian conspecific brood parasite.

    Science.gov (United States)

    Lyon, Bruce E; Hochachka, Wesley M; Eadie, John M

    2002-06-01

    Efforts to evaluate the evolutionary and ecological dynamics of conspecific brood parasitism in birds and other animals have focused on the fitness costs of parasitism to hosts and fitness benefits to parasites. However, it has been speculated recently that, in species with biparental care, host males might cooperate with parasitic females by allowing access to the host nest in exchange for copulations. We develop a cost-benefit model to explore the conditions under which such host-parasite cooperation might occur. When the brood parasite does not have a nest of her own, the only benefit to the host male is siring some of the parasitic eggs (quasi-parasitism). Cooperation with the parasite is favored when the ratio of host male paternity of his own eggs relative to his paternity of parasitic eggs exceeds the cost of parasitism. When the brood parasite has a nest of her own, a host male can gain additional, potentially more important benefits by siring the high-value, low-cost eggs laid by the parasite in her own nest. Under these conditions, host males should be even more likely to accept parasitic eggs in return for copulations with the parasitic female. We tested these predictions for American coots (Fulica americana), a species with a high frequency of conspecific brood parasitism. Multilocus DNA profiling indicated that host males did not sire any of the parasitic eggs laid in host nests, nor did they sire eggs laid by the parasite in her own nest. We used field estimates of the model parameters from a four-year study of coots to predict the minimum levels of paternity required for the costs of parasitism to be offset by the benefits of mating with brood parasites. Observed levels of paternity were significantly lower than those predicted under a variety of assumptions, and we reject the hypothesis that host males cooperated with parasitic females. Our model clarifies the specific costs and benefits that influence host-parasite cooperation and, more generally

  9. Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development

    Directory of Open Access Journals (Sweden)

    Zaloumis Sophie

    2012-08-01

    Full Text Available Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50, derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle. The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i

  10. Cucurbita ficifolia (Cucurbitaceae) modulates inflammatory cytokines and IFN-γ in obese mice.

    Science.gov (United States)

    Fortis-Barrera, Á; García-Macedo, R; Almanza-Perez, J C; Blancas-Flores, G; Zamilpa-Alvarez, A; Flores-Sáenz, J L; Cruz, M; Román-Ramos, R; Alarcón-Aguilar, F J

    2017-02-01

    This study investigated the effect of aqueous extract of Cucurbita ficifolia Bouché on systemic chronic inflammation in an obesity model induced by monosodium glutamate (MSG) via modulating the expression of adipokines (TNF-α, IL-6, resistin, and adiponectin) and immune-regulatory cytokines (IFN-γ and IL-10). Cucurbita ficifolia extract was administered daily by gavage to lean and MSG-obese mice for 30 days. At the end of treatment, cytokine mRNA expression in adipose tissue was determined by real-time polymerase chain reaction (PCR), and the protein levels of these cytokines were also quantified by enzyme-linked immunosorbent assay (ELISA). Cucurbita ficifolia extract decreased body mass and inflammation in MSG-obese mice by reducing the expression of TNF-α and IL-6; these decreases were parallel to significant reductions in protein levels. The extract also increased protein levels of IL-10 in lean mice and IFN-γ in both lean and MSG-obese mice. In conclusion, C. ficifolia extract modulates systemic chronic inflammation in MSG-obese mice and could have a beneficial effect on the adaptive immune system in obesity.

  11. Immunotoxicity of aflatoxin B1: Impairment of the cell-mediated response to vaccine antigen and modulation of cytokine expression

    International Nuclear Information System (INIS)

    Meissonnier, Guylaine M.; Pinton, Philippe; Laffitte, Joelle; Cossalter, Anne-Marie; Gong, Yun Yun; Wild, Christopher P.; Bertin, Gerard; Galtier, Pierre; Oswald, Isabelle P.

    2008-01-01

    Aflatoxin B1 (AFB1), a mycotoxin produced by Aspergillus flavus or A. parasiticus, is a frequent contaminant of food and feed. This toxin is hepatotoxic and immunotoxic. The present study analyzed in pigs the influence of AFB1 on humoral and cellular responses, and investigated whether the immunomodulation observed is produced through interference with cytokine expression. For 28 days, pigs were fed a control diet or a diet contaminated with 385, 867 or 1807 μg pure AFB1/kg feed. At days 4 and 15, pigs were vaccinated with ovalbumin. AFB1 exposure, confirmed by an observed dose-response in blood aflatoxin-albumin adduct, had no major effect on humoral immunity as measured by plasma concentrations of total IgA, IgG and IgM and of anti-ovalbumin IgG. Toxin exposure did not impair the mitogenic response of lymphocytes but delayed and decreased their specific proliferation in response to the vaccine antigen, suggesting impaired lymphocyte activation in pigs exposed to AFB1. The expression level of pro-inflammatory (TNF-α, IL-1β, IL-6, IFN-γ) and regulatory (IL-10) cytokines was assessed by real-time PCR in spleen. A significant up-regulation of all 5 cytokines was observed in spleen from pigs exposed to the highest dose of AFB1. In pigs exposed to the medium dose, IL-6 expression was increased and a trend towards increased IFN-γ and IL-10 was observed. In addition we demonstrate that IL-6 impaired in vitro the antigenic- but not the mitogenic-induced proliferation of lymphocytes from control pigs vaccinated with ovalbumin. These results indicate that AFB1 dietary exposure decreases cell-mediated immunity while inducing an inflammatory response. These impairments in the immune response could participate in failure of vaccination protocols and increased susceptibility to infections described in pigs exposed to AFB1

  12. IFN-γ-producing Th1-like regulatory T cells may limit acute cellular renal allograft rejection: Paradoxical post-transplantation effects of IFN-γ.

    Science.gov (United States)

    Xu, Xiaoguang; Huang, Haiyan; Wang, Qiang; Cai, Ming; Qian, Yeyong; Han, Yong; Wang, Xinying; Gao, Yu; Yuan, Ming; Xu, Liang; Yao, Chen; Xiao, Li; Shi, Bingyi

    2017-02-01

    IFN-γ is a protypical proinflammatory cytokine that plays a central role in inflammation and acute graft rejection. Accumulating evidence indicates that IFN-γ can exert previously unexpected immunoregulatory activities. However, little is known about the role of IFN-γ secreted by Th1-like regulatory T cells in human kidney transplantation. To determine the function of IFN-γ in acute T cell-mediated renal allograft rejection (ACR), we examined serum cytokine expression profiles in ACR patients by human cytokine multiplex immunoassay and analyzed the cellular origins of IFN-γ in peripheral blood and renal allograft biopsies from ACR cases and controls by flow cytometry and immunohistochemistry, respectively. The results showed significant reduction in serum concentrations of Th1-inducing cytokines IL-12p70 and IFN-γ as well as Th2-related cytokine IL-4 in ACR patients compared with stable controls. However, levels of several Th1-, Th2- and Th17-related cytokines, such as IL-2, TNF-α, TNF-β, IL-12 (p40), IL-10, IL-15, IL-17, IL-21, and IL-23, as well as the frequencies of Th1 and Th17 cell, did not differ between ACR cases and stable controls. Moreover, we found the levels of IFN-γ were correlated with those of the anti-inflammatory factor, IL-1 receptor antagonist (IL-1Ra) in ACR. Notably, the Th1-like Treg cell-to-Foxp3 - Th1 cell ratio was significantly lower in ACR patients compared with that in stable controls. In graft biopsies from ACR patients, Treg cells and Th1-like Treg cells were less abundant than those without ACR. Our study indicates that IFN-γ secreted from Th1-like Treg cells negatively modulates ACR. Copyright © 2016 Elsevier GmbH. All rights reserved.

  13. Social Parasites

    Science.gov (United States)

    Lopez, Miguel A.; Nguyen, HoangKim T.; Oberholzer, Michael; Hill, Kent L.

    2011-01-01

    Summary of recent advances Protozoan parasites cause tremendous human suffering worldwide, but strategies for therapeutic intervention are limited. Recent studies illustrate that the paradigm of microbes as social organisms can be brought to bear on questions about parasite biology, transmission and pathogenesis. This review discusses recent work demonstrating adaptation of social behaviors by parasitic protozoa that cause African sleeping sickness and malaria. The recognition of social behavior and cell-cell communication as a ubiquitous property of bacteria has transformed our view of microbiology, but protozoan parasites have not generally been considered in this context. Works discussed illustrate the potential for concepts of sociomicrobiology to provide insight into parasite biology and should stimulate new approaches for thinking about parasites and parasite-host interactions. PMID:22020108

  14. A low-level needle counter

    International Nuclear Information System (INIS)

    Fujita, Y.; Taguchi, Y.; Imamura, M.; Inoue, T.; Tanaka, S.

    1977-01-01

    A small end-window type gas-flow counter which has a sharpened needle (anode) against the end-window plane (cathode) was developed for low-level counting of β particles to the amount of less than one count per hour in solid sources of relatively high specific activity. The advantage of the needle counter for low-level work is that being of a conical shape the active volume as against the window area is small. The background count rate of 0.0092+-0.0005 cpm was obtained for a 10 mm dia needle counter operating in GM mode and in anticoincidence with a well-type NaI(Tl) guard crystal with massive shields. The counter design and the counter characteristics are presented in detail. The needle counter is simple in design, low-cost and stable in long time operation. (author)

  15. Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells

    DEFF Research Database (Denmark)

    Ortis, Fernanda; Naamane, Najib; Flamez, Daisy

    2010-01-01

    by the cytokines interleukin (IL)-1beta + interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha + IFN-gamma in primary rat beta-cells. RESEARCH DESIGN AND METHODS: Fluorescence-activated cell sorter-purified rat beta-cells were exposed to IL-1beta + IFN-gamma or TNF-alpha + IFN-gamma for 6 or 24 h......-cells, with temporal differences in the number of genes modulated by IL-1beta + IFNgamma or TNF-alpha + IFN-gamma. These cytokine combinations induced differential expression of inflammatory response genes, which is related to differential induction of IFN regulatory factor-7. Both treatments decreased the expression...... of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-alpha, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine...

  16. Inflammatory Cytokines: Potential Biomarkers of Immunologic Dysfunction in Autism Spectrum Disorders

    Directory of Open Access Journals (Sweden)

    Ningan Xu

    2015-01-01

    Full Text Available Autism is a disorder of neurobiological origin characterized by problems in communication and social skills and repetitive behavior. After more than six decades of research, the etiology of autism remains unknown, and no biomarkers have been proven to be characteristic of autism. A number of studies have shown that the cytokine levels in the blood, brain, and cerebrospinal fluid (CSF of autistic subjects differ from that of healthy individuals; for example, a series of studies suggests that interleukin-6 (IL-6, tumor necrosis factor-α (TNF-α, and interferon-γ (IFN-γ are significantly elevated in different tissues in autistic subjects. However, the expression of some cytokines, such as IL-1, IL-2, transforming growth factor-β (TGF-β, and granulocyte-macrophage colony-stimulating factor (GM-CSF, is controversial, and different studies have found various results in different tissues. In this review, we focused on several types of proinflammatory and anti-inflammatory cytokines that might affect different cell signal pathways and play a role in the pathophysiological mechanism of autistic spectrum disorders.

  17. Changes in some pro-and anti-inflammatory cytokines produced by bovine peripheral blood mononuclear cells following foot and mouth disease vaccination

    Directory of Open Access Journals (Sweden)

    N. Delirezh

    2016-09-01

    Full Text Available Interleukin (IL-17 is exclusively produced by CD4 helper T-cells upon activation. It most often acts as a pro-inflammatory cytokine, which stimulates the release of pro-inflammatory cytokines IL-6, IL-8, TNF-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF. In this study, we studied the in-vitro IL-17 response to specific antigens and a variety of mitogens and compared the IL-17 response to IL-2, IL-4, IL-5, IL-6, IL-10, and IFN-γ responses. We used a foot and mouth disease (FMD vaccine as specific antigens and mitogens (phytohemagglutinin [PHA], pokeweed mitogen [PWM], and concanavalin A [Con A] to stimulate peripheral blood mononuclear cells (PBMCs of vaccinated calves. Cell culture supernatant was harvested and analyzed for cytokines, using commercially available bovine ELISA kits. The mitogens induced a significant increase in IL-17 production. IL-17 was produced at high levels in response to the T cell-stimulated mitogens, PHA, and Con A, and at low levels in response to PWM mitogens. In contrast, level of the produced IL-17 cytokines in response to the FMDV antigens was lower as compared to those produced by mitogens. The FMDV antigens and mitogens significantly increased IL-17 production. There was not a correlation between IL-17 production and type-1 cytokine, IFN-γ, and IL-2, while there was a correlation between type-2 cytokine, IL-4, and IL-5 at either cytokine level produced by PBMCs stimulated by FMDV antigens. Moreover, there was an interaction between IL-17 and IL-6, that is, as IL-6 cytokine level elevated or diminished, IL-17 cytokine level increased or decreased, as well.

  18. Co-ordinated stage-dependent enhancement of Plasmodium falciparum antioxidant enzymes and heat shock protein expression in parasites growing in oxidatively stressed or G6PD-deficient red blood cells

    Directory of Open Access Journals (Sweden)

    Müller Sylke

    2009-05-01

    Full Text Available Abstract Background Plasmodium falciparum-parasitized red blood cells (RBCs are equipped with protective antioxidant enzymes and heat shock proteins (HSPs. The latter are only considered to protect against thermal stress. Important issues are poorly explored: first, it is insufficiently known how both systems are expressed in relation to the parasite developmental stage; secondly, it is unknown whether P. falciparum HSPs are redox-responsive, in view of redox sensitivity of HSP in eukaryotic cells; thirdly, it is poorly known how the antioxidant defense machinery would respond to increased oxidative stress or inhibited antioxidant defense. Those issues are interesting as several antimalarials increase the oxidative stress or block antioxidant defense in the parasitized RBC. In addition, numerous inhibitors of HSPs are currently developed for cancer therapy and might be tested as anti-malarials. Thus, the joint disruption of the parasite antioxidant enzymes/HSP system would interfere with parasite growth and open new perspectives for anti-malaria therapy. Methods Stage-dependent mRNA expression of ten representative P. falciparum antioxidant enzymes and hsp60/70–2/70–3/75/90 was studied by quantitative real-time RT-PCR in parasites growing in normal RBCs, in RBCs oxidatively-stressed by moderate H2O2 generation and in G6PD-deficient RBCs. Protein expression of antioxidant enzymes was assayed by Western blotting. The pentosephosphate-pathway flux was measured in isolated parasites after Sendai-virus lysis of RBC membrane. Results In parasites growing in normal RBCs, mRNA expression of antioxidant enzymes and HSPs displayed co-ordinated stage-dependent modulation, being low at ring, highest at early trophozoite and again very low at schizont stage. Additional exogenous oxidative stress or growth in antioxidant blunted G6PD-deficient RBCs indicated remarkable flexibility of both systems, manifested by enhanced, co-ordinated mRNA expression of

  19. Co-ordinated stage-dependent enhancement of Plasmodium falciparum antioxidant enzymes and heat shock protein expression in parasites growing in oxidatively stressed or G6PD-deficient red blood cells.

    Science.gov (United States)

    Akide-Ndunge, Oscar Bate; Tambini, Elisa; Giribaldi, Giuliana; McMillan, Paul J; Müller, Sylke; Arese, Paolo; Turrini, Francesco

    2009-05-29

    Plasmodium falciparum-parasitized red blood cells (RBCs) are equipped with protective antioxidant enzymes and heat shock proteins (HSPs). The latter are only considered to protect against thermal stress. Important issues are poorly explored: first, it is insufficiently known how both systems are expressed in relation to the parasite developmental stage; secondly, it is unknown whether P. falciparum HSPs are redox-responsive, in view of redox sensitivity of HSP in eukaryotic cells; thirdly, it is poorly known how the antioxidant defense machinery would respond to increased oxidative stress or inhibited antioxidant defense. Those issues are interesting as several antimalarials increase the oxidative stress or block antioxidant defense in the parasitized RBC. In addition, numerous inhibitors of HSPs are currently developed for cancer therapy and might be tested as anti-malarials. Thus, the joint disruption of the parasite antioxidant enzymes/HSP system would interfere with parasite growth and open new perspectives for anti-malaria therapy. Stage-dependent mRNA expression of ten representative P. falciparum antioxidant enzymes and hsp60/70-2/70-3/75/90 was studied by quantitative real-time RT-PCR in parasites growing in normal RBCs, in RBCs oxidatively-stressed by moderate H2O2 generation and in G6PD-deficient RBCs. Protein expression of antioxidant enzymes was assayed by Western blotting. The pentosephosphate-pathway flux was measured in isolated parasites after Sendai-virus lysis of RBC membrane. In parasites growing in normal RBCs, mRNA expression of antioxidant enzymes and HSPs displayed co-ordinated stage-dependent modulation, being low at ring, highest at early trophozoite and again very low at schizont stage. Additional exogenous oxidative stress or growth in antioxidant blunted G6PD-deficient RBCs indicated remarkable flexibility of both systems, manifested by enhanced, co-ordinated mRNA expression of antioxidant enzymes and HSPs. Protein expression of

  20. Stat6 activity-related Th2 cytokine profile and tumor growth advantage of human colorectal cancer cells in vitro and in vivo.

    Science.gov (United States)

    Li, Ben Hui; Xu, Shuang Bing; Li, Feng; Zou, Xiao Guang; Saimaiti, Abudukeyoumu; Simayi, Dilixia; Wang, Ying Hong; Zhang, Yan; Yuan, Jia; Zhang, Wen Jie

    2012-03-01

    Signal transducer and activator of transcription 6 (Stat6) is critical in Th2 polarization of immune cells and active Stat6 activity has been suggested in anti-tumor immunity in animal models. The present study aims at investigating the impact of natural Stat6 activity on tumor microenvironment in human colorectal cancer cells in vitro and in vivo. Using colorectal cancer cell lines HT-29 and Caco-2 whose IL-4/Stat6 activities were known and nude mice as a model, we examined correlative relationships between Stat6 activities and gene expression profiles together with cellular behaviors in vitro and in vivo. HT-29 cells carrying active Stat6 signaling displayed spontaneous expression profiles favoring Th2 cytokines, cell cycle promotion, anti-apoptosis and pro-metastasis with increased mRNA levels of IL-4, IL-13, GATA-3, CDK4, CD44v6 and S100A4 using RT-PCR. In contrast, Caco-2 cells carrying defective Stat6 signaling exhibited spontaneous expression profiles favoring Th1 and Th17 cytokines, cell cycle inhibition, pro-apoptosis and anti-metastasis with elevated mRNA expression of IFNγ, TNFα, IL-12A, IL-17, IL-23, T-bet, CDKN1A, CDKNIB, CDKN2A and NM23-H1. Xenograft tumors of Stat6-active HT-29 cells showed a growth advantage over those of Stat6-defective Caco-2 cells. Furthermore, mice bearing HT-29 tumors expressed increased levels of Th2 cytokines IL-4 and IL-5 in the blood and pro-growth and/or pro-metastasis proteins CDK4 and CD44v6 in the tumor. To the contrary, mice bearing Caco-2 tumors expressed heightened levels of Th1 cytokines IFNγ and TNF in the blood and pro-apoptosis and anti-metastatic proteins p53 and p27(kip1) in the tumor. Colorectal cancer cells carrying active Stat6 signaling may create a microenvironment favoring Th2 cytokines and promoting expression of genes related to pro-growth, pro-metastasis and anti-apoptosis, which leads to a tumor growth advantage in vivo. These findings may imply why Stat6 pathway is constitutively activated in a

  1. Xanthine-Catechin Mixture Enhances Lithium-Induced Anti-Inflammatory Response in Activated Macrophages In Vitro

    Directory of Open Access Journals (Sweden)

    Fernanda Barbisan

    2017-01-01

    Full Text Available Lithium (Li is a chemical element used for treating and preventing bipolar disorder (BD and exerts positive effects such as anti-inflammatory effects as well as undesirable side effects. These effects of Li can be influenced by interaction with some nutritional elements. Therefore, we investigated the potential effects of xanthine (caffeine and theobromine and catechin molecules present in some food beverages broadly consumed worldwide, such as coffee and tea, on Li-induced anti-inflammatory effects. In the present study, we concomitantly exposed RAW 264.7 macrophages to Li, isolated xanthine and catechin molecules, and a xanthine-catechin mixture (XC mixture. We evaluated the effects of these treatments on cell proliferation, cell cycle progression, oxidative and antioxidant marker expression, cytokine levels, gene expression, and GSK-3β enzyme expression. Treatment with the XC mixture potentialized Li-induced anti-inflammatory effects by intensification of the following: GSK-3β inhibitory action, lowering effect on proinflammatory cytokines (IL-1β, IL-6, and TNFα, and increase in the levels of IL-10 that is an anti-inflammatory cytokine. Despite the controversial nature of caffeine consumption by BD patients, these results suggested that consumption of caffeine, in low concentrations, mixed with other bioactive molecules along with Li may be safe.

  2. Acetate formation in the energy metabolism of parasitic helminths and protists.

    Science.gov (United States)

    Tielens, Aloysius G M; van Grinsven, Koen W A; Henze, Katrin; van Hellemond, Jaap J; Martin, William

    2010-03-15

    Formation and excretion of acetate as a metabolic end product of energy metabolism occurs in many protist and helminth parasites, such as the parasitic helminths Fasciola hepatica, Haemonchus contortus and Ascaris suum, and the protist parasites, Giardia lamblia, Entamoeba histolytica, Trichomonas vaginalis as well as Trypanosoma and Leishmania spp. In all of these parasites acetate is a main end product of their energy metabolism, whereas acetate formation does not occur in their mammalian hosts. Acetate production might therefore harbour novel targets for the development of new anti-parasitic drugs. In parasites, acetate is produced from acetyl-CoA by two different reactions, both involving substrate level phosphorylation, that are catalysed by either a cytosolic acetyl-CoA synthetase (ACS) or an organellar acetate:succinate CoA-transferase (ASCT). The ACS reaction is directly coupled to ATP synthesis, whereas the ASCT reaction yields succinyl-CoA for ATP formation via succinyl-CoA synthetase (SCS). Based on recent work on the ASCTs of F. hepatica, T. vaginalis and Trypanosoma brucei we suggest the existence of three subfamilies of enzymes within the CoA-transferase family I. Enzymes of these three subfamilies catalyse the ASCT reaction in eukaryotes via the same mechanism, but the subfamilies share little sequence homology. The CoA-transferases of the three subfamilies are all present inside ATP-producing organelles of parasites, those of subfamily IA in the mitochondria of trypanosomatids, subfamily IB in the mitochondria of parasitic worms and subfamily IC in hydrogenosome-bearing parasites. Together with the recent characterisation among non-parasitic protists of yet a third route of acetate formation involving acetate kinase (ACK) and phosphotransacetylase (PTA) that was previously unknown among eukaryotes, these recent developments provide a good opportunity to have a closer look at eukaryotic acetate formation. (c) 2010 Australian Society for Parasitology

  3. Interleukin-27 Early Impacts Leishmania infantum Infection in Mice and Correlates with Active Visceral Disease in Humans

    Directory of Open Access Journals (Sweden)

    Begoña Pérez-Cabezas

    2016-11-01

    Full Text Available The complexity of Leishmania-host interactions, one of the main leishmaniasis issues, is yet to be fully understood. We detected elevated IL-27 plasma levels in European patients with active visceral disease caused by Leishmania infantum, which returned to basal levels after successful treatment, suggesting this cytokine as a probable infection mediator. We further addressed this hypothesis recurring to two classical susceptible visceral leishmaniasis mouse models. BALB/c, but not C57BL/6 mice, showed increased IL-27 systemic levels after infection, which was associated with an upregulation of IL-27p28 expression by dendritic cells and higher parasite burdens. Neutralization of IL-27 in acutely infected BALB/c led to decreased parasite burdens and a transient increase in IFN-γ+ splenic T cells, while administration of IL-27 to C57BL/6 promoted a local anti-inflammatory cytokine response at the site of infection and increased parasite loads. Overall we show that, as in humans, BALB/c IL-27 systemic levels are infection-dependently upregulated and may favor parasite installation by controlling inflammation.

  4. Modeling the intra- and extracellular cytokine signaling pathway under heat stroke in the liver.

    Directory of Open Access Journals (Sweden)

    Maria Rodriguez-Fernandez

    Full Text Available Heat stroke (HS is a life-threatening illness induced by prolonged exposure to a hot environment that causes central nervous system abnormalities and severe hyperthermia. Current data suggest that the pathophysiological responses to heat stroke may not only be due to the immediate effects of heat exposure per se but also the result of a systemic inflammatory response syndrome (SIRS. The observation that pro- (e.g., IL-1 and anti-inflammatory (e.g., IL-10 cytokines are elevated concomitantly during recovery suggests a complex network of interactions involved in the manifestation of heat-induced SIRS. In this study, we measured a set of circulating cytokine/soluble cytokine receptor proteins and liver cytokine and receptor mRNA accumulation in wild-type and tumor necrosis factor (TNF receptor knockout mice to assess the effect of neutralization of TNF signaling on the SIRS following HS. Using a systems approach, we developed a computational model describing dynamic changes (intra- and extracellular events in the cytokine signaling pathways in response to HS that was fitted to novel genomic (liver mRNA accumulation and proteomic (circulating cytokines and receptors data using global optimization. The model allows integration of relevant biological knowledge and formulation of new hypotheses regarding the molecular mechanisms behind the complex etiology of HS that may serve as future therapeutic targets. Moreover, using our unique modeling framework, we explored cytokine signaling pathways with three in silico experiments (e.g. by simulating different heat insult scenarios and responses in cytokine knockout strains in silico.

  5. Cytokines as cellular communicators

    Directory of Open Access Journals (Sweden)

    R. Debets

    1996-01-01

    Full Text Available Cytokines and their receptors are involved in the pathophysiology of many diseases. Here we present a detailed review on cytokines, receptors and signalling routes, and show that one important lesson from cytokine biology is the complex and diverse regulation of cytokine activity. The activity of cytokines is controlled at the level of transcription, translation, storage, processing, posttranslational modification, trapping, binding by soluble proteins, and receptor number and/or function. Translation of this diverse regulation in strategies aimed at the control of cytokine activity will result in the development of more specific and selective drugs to treat diseases.

  6. Excessive Pro-Inflammatory Serum Cytokine Concentrations in Virulent Canine Babesiosis

    DEFF Research Database (Denmark)

    Goddard, Amelia; Leisewitz, Andrew L; Kjelgaard-Hansen, Mads

    2016-01-01

    compared between the different groups using the Mann-Whitney U test. IL-10 and MCP-1 concentrations were significantly elevated for the Babesia-infected dogs compared to the healthy controls. In contrast, the IL-8 concentration was significantly decreased in the Babesia-infected dogs compared......Babesia rossi infection causes a severe inflammatory response in the dog, which is the result of the balance between pro- and anti-inflammatory cytokine secretion. The aim of this study was to determine whether changes in cytokine concentrations were present in dogs with babesiosis and whether...... it was associated with disease outcome. Ninety-seven dogs naturally infected with B. rossi were studied and fifteen healthy dogs were included as controls. Diagnosis of babesiosis was confirmed by polymerase chain reaction and reverse line blot. Blood samples were collected from the jugular vein at admission, prior...

  7. Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages.

    Science.gov (United States)

    Garbati, Michael R; Hays, Laura E; Rathbun, R Keaney; Jillette, Nathaniel; Chin, Kathy; Al-Dhalimy, Muhsen; Agarwal, Anupriya; Newell, Amy E Hanlon; Olson, Susan B; Bagby, Grover C

    2016-03-01

    The Fanconi anemia proteins participate in a canonical pathway that repairs cross-linking agent-induced DNA damage. Cells with inactivated Fanconi anemia genes are universally hypersensitive to such agents. Fanconi anemia-deficient hematopoietic stem cells are also hypersensitive to inflammatory cytokines, and, as importantly, Fanconi anemia macrophages overproduce such cytokines in response to TLR4 and TLR7/8 agonists. We questioned whether TLR-induced DNA damage is the primary cause of aberrantly regulated cytokine production in Fanconi anemia macrophages by quantifying TLR agonist-induced TNF-α production, DNA strand breaks, crosslinker-induced chromosomal breakage, and Fanconi anemia core complex function in Fanconi anemia complementation group C-deficient human and murine macrophages. Although both M1 and M2 polarized Fanconi anemia cells were predictably hypersensitive to mitomycin C, only M1 macrophages overproduced TNF-α in response to TLR-activating signals. DNA damaging agents alone did not induce TNF-α production in the absence of TLR agonists in wild-type or Fanconi anemia macrophages, and mitomycin C did not enhance TLR responses in either normal or Fanconi anemia cells. TLR4 and TLR7/8 activation induced cytokine overproduction in Fanconi anemia macrophages. Also, although TLR4 activation was associated with induced double strand breaks, TLR7/8 activation was not. That DNA strand breaks and chromosome breaks are neither necessary nor sufficient to account for the overproduction of inflammatory cytokines by Fanconi anemia cells suggests that noncanonical anti-inflammatory functions of Fanconi anemia complementation group C contribute to the aberrant macrophage phenotype and suggests that suppression of macrophage/TLR hyperreactivity might prevent cytokine-induced stem cell attrition in Fanconi anemia. © Society for Leukocyte Biology.

  8. [Regulatory B cells activated by CpG-ODN combined with anti-CD40 monoclonal antibody inhibit CD4(+)T cell proliferation].

    Science.gov (United States)

    Wang, Keng; Tao, Lei; Su, Jianbing; Zhang, Yueyang; Zou, Binhua; Wang, Yiyuan; Li, Xiaojuan

    2016-09-01

    Objective To observe the immunosuppressive function of regulatory B cells (Bregs) in vitro after activated by CpG oligodeoxynucleotide (CpG-ODN) and anti-CD40 mAb. Methods Mice splenic CD5(+)CD1d(high)B cells and CD5(-)CD1d(low)B cells were sorted by flow cytometry. These B cells were first stimulated with CpG-ODN combined with anti-CD40 mAb for 24 hours, and then co-cultured with purified CD4(+)T cells. The interleukin 10 (IL-10) expression in the activated Bregs and other B cell subset, as well as the proliferation and interferon γ (IFN-γ) expression in the CD4(+) T cells activated by anti-CD3 mAb plus anti-CD28 mAb were determined by flow cytometry. Results CD5(+)CD1d(high) B cells activated by CpG-ODN plus anti-CD40 mAb blocked the up-regulated CD4(+)T proliferation and significantly reduced the IFN-γ level. At the same time, activated CD5(-)CD1d(low)B cells showed no inhibitory effect on CD4(+)T cells. Further study revealed that IL-10 expression in the CD5(+)CD1d(high) B cells were much higher than that in the CD5(-)CD1d(low)B cells after stimulated with CpG-ODN combined with anti-CD40 mAb for 24 hours. Conclusion CD5(+)CD1d(high) B cells activated by CpG-ODN combined with anti-CD40 mAb have immune inhibitory effects on CD4(+)T cell activation in vitro , which possibly due to IL-10 secretion.

  9. Metformin as a new therapy for endometriosis, its effects on both clinical picture and cytokines profile

    Directory of Open Access Journals (Sweden)

    Ashraf Ahmed Foda

    2012-12-01

    Conclusion: Metformin therapy in patients with endometriosis resulted in a significant reduction in the symptomatic cases, increased chance of pregnancy, and a decrease in the levels of serum cytokines, suggesting that it may have a therapeutic potential as an anti-endometriotic drug.

  10. Proportional counter system for radiation measurement

    Energy Technology Data Exchange (ETDEWEB)

    Sugimoto, M; Okudera, S

    1970-11-21

    A gas such as Xe or Kr employed in counter tubes is charged into the counter tube of a gas-flow type proportional counter for radiation measurement and into a vessel having a volume larger than that of the counter tube. The vessel communicates with the counter tube to circulate the gas via a pump through both the vessel and tube during measurement. An organic film such as a polyester synthetic resin film is used for the window of the counter tube to measure X-rays in the long wavelength range. Accordingly, a wide range of X-rays can be measured including both long and short wavelengths ranges by utilizing only one counter tube, thus permitting the gases employed to be effectively used.

  11. Regulatory T-cells in autoimmune diseases: challenges, controversies and--yet--unanswered questions.

    Science.gov (United States)

    Grant, Charlotte R; Liberal, Rodrigo; Mieli-Vergani, Giorgina; Vergani, Diego; Longhi, Maria Serena

    2015-02-01

    Regulatory T cells (Tregs) are central to the maintenance of self-tolerance and tissue homeostasis. Markers commonly used to define human Tregs in the research setting include high expression of CD25, FOXP3 positivity and low expression/negativity for CD127. Many other markers have been proposed, but none unequivocally identifies bona fide Tregs. Tregs are equipped with an array of mechanisms of suppression, including the modulation of antigen presenting cell maturation and function, the killing of target cells, the disruption of metabolic pathways and the production of anti-inflammatory cytokines. Treg impairment has been reported in a number of human autoimmune conditions and includes Treg numerical and functional defects and conversion into effector cells in response to inflammation. In addition to intrinsic Treg impairment, resistance of effector T cells to Treg control has been described. Discrepancies in the literature are common, reflecting differences in the choice of study participants and the technical challenges associated with investigating this cell population. Studies differ in terms of the methodology used to define and isolate putative regulatory cells and to assess their suppressive function. In this review we outline studies describing Treg frequency and suppressive function in systemic and organ specific autoimmune diseases, with a specific focus on the challenges faced when investigating Tregs in these conditions. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Exploration of over the counter sales of antibiotics in community pharmacies of Addis Ababa, Ethiopia: pharmacy professionals’ perspective

    Directory of Open Access Journals (Sweden)

    Gebremedhin Beedemariam Gebretekle

    2016-01-01

    Full Text Available Abstract Background Over the counter sale of antibiotics is a global problem and it is increasingly recognized as a source of antibiotic misuse and is believed to increase treatment costs, adverse effects of treatment and emergence of resistance. The increasing trend of over the counter sale of antibiotics in Ethiopia calls for exploration of why such dispensing is practiced. This study aims to explore reasons for over the counter sale of antibiotics in the community pharmacies of Addis Ababa, Ethiopia. Methods A phenomenological qualitative study was conducted in five randomly selected community pharmacies of Addis Ababa. One pharmacy professional from each pharmacy were interviewed at the spot using semi-structured, open-ended interview checklist. Besides, observation of professionals’ dispensing practice was made for at least one hour in the same community pharmacies using an observation checklist. Findings were categorized into specific themes that were developed following the objectives. This was facilitated by use of OpenCode 3.6 software. Results All participants pointed out that antibiotics were frequently dispensed without prescription and contend that the trend of such dispensing has been increasing. The findings indicated that the nonprescription sales of antibiotics were common for Amoxicillin, Ciprofloxacin and Cotrimoxazole. The poor, less educated and younger groups of the population were reported to frequently request antibiotics without prescription. The main reasons for nonprescription sale of antibiotics by pharmacy professionals were found to be related to pharmacy owner’s influence to maximize revenue, customer’s pressure, weak regulatory mechanism and professional conflicts of interest. Conclusion The study shows that nonprescription sale of antibiotics was common practice at least in Addis Ababa. The main reasons for this malpractice were the need to maximize revenue and weak regulatory mechanism. Hence, strong

  13. Exploration of over the counter sales of antibiotics in community pharmacies of Addis Ababa, Ethiopia: pharmacy professionals' perspective.

    Science.gov (United States)

    Gebretekle, Gebremedhin Beedemariam; Serbessa, Mirgissa Kaba

    2016-01-01

    Over the counter sale of antibiotics is a global problem and it is increasingly recognized as a source of antibiotic misuse and is believed to increase treatment costs, adverse effects of treatment and emergence of resistance. The increasing trend of over the counter sale of antibiotics in Ethiopia calls for exploration of why such dispensing is practiced. This study aims to explore reasons for over the counter sale of antibiotics in the community pharmacies of Addis Ababa, Ethiopia. A phenomenological qualitative study was conducted in five randomly selected community pharmacies of Addis Ababa. One pharmacy professional from each pharmacy were interviewed at the spot using semi-structured, open-ended interview checklist. Besides, observation of professionals' dispensing practice was made for at least one hour in the same community pharmacies using an observation checklist. Findings were categorized into specific themes that were developed following the objectives. This was facilitated by use of OpenCode 3.6 software. All participants pointed out that antibiotics were frequently dispensed without prescription and contend that the trend of such dispensing has been increasing. The findings indicated that the nonprescription sales of antibiotics were common for Amoxicillin, Ciprofloxacin and Cotrimoxazole. The poor, less educated and younger groups of the population were reported to frequently request antibiotics without prescription. The main reasons for nonprescription sale of antibiotics by pharmacy professionals were found to be related to pharmacy owner's influence to maximize revenue, customer's pressure, weak regulatory mechanism and professional conflicts of interest. The study shows that nonprescription sale of antibiotics was common practice at least in Addis Ababa. The main reasons for this malpractice were the need to maximize revenue and weak regulatory mechanism. Hence, strong regulatory enforcement and community awareness campaign is called for to limit

  14. Blockade of Toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures

    LENUS (Irish Health Repository)

    Nic An Ultaigh, Sinead

    2011-02-23

    Abstract Introduction The aim of this study was to examine the effect of blocking Toll-like receptor 2 (TLR2) in rheumatoid arthritis (RA) synovial cells. Methods RA synovial tissue biopsies, obtained under direct visualization at arthroscopy, were established as synovial explant cultures ex vivo or snap frozen for immunohistology. Mononuclear cell cultures were isolated from peripheral blood and synovial fluid of RA patients. Cultures were incubated with the TLR1\\/2 ligand, Pam3CSK4 (200 ng, 1 and 10 μg\\/ml), an anti-TLR2 antibody (OPN301, 1 μg\\/ml) or an immunoglobulin G (IgG) (1 μg\\/ml) matched control. The comparative effect of OPN301 and adalimumab (anti-tumour necrosis factor alpha) on spontaneous release of proinflammatory cytokines from RA synovial explants was determined using quantitative cytokine MSD multiplex assays or ELISA. OPN301 penetration into RA synovial tissue explants cultures was assessed by immunohistology. Results Pam3CSK4 significantly upregulated interleukin (IL)-6 and IL-8 in RA peripheral blood mononuclear cells (PBMCs), RA synovial fluid mononuclear cells (SFMCs) and RA synovial explant cultures (P < 0.05). OPN301 significantly decreased Pam3CSK4-induced cytokine production of tumour necrosis factor alpha (TNF-α), IL-1β, IL-6, interferon (IFN)-γ and IL-8 compared to IgG control in RA PBMCs and SFMCs cultures (all P < 0.05). OPN301 penetration of RA synovial tissue cultures was detected in the lining layer and perivascular regions. OPN301 significantly decreased spontaneous cytokine production of TNF-α, IL-1β, IFN-γ and IL-8 from RA synovial tissue explant cultures (all P < 0.05). Importantly, the inhibitory effect of OPN on spontaneous cytokine secretion was comparable to inhibition by anti-TNFα monoclonal antibody adalimumab. Conclusions These findings further support targeting TLR2 as a potential therapeutic agent for the treatment of RA.

  15. The role of cytokine signaling in the pathogenesis of cutaneous T-cell lymphoma

    DEFF Research Database (Denmark)

    abraham, Robert; Zhang, Qiang; Ødum, Niels

    2011-01-01

    Cutaneous T-cell lymphoma (CTCL) displays immunosuppressive properties and phenotypic plasticity. The malignant T cells in CTCL can possess features of immunomodulating regulatory T cells (Treg) and IL-17-producing helper T cells (Th17) depending on the stimuli they receive from antigen presenting...... therapeutic agents may potentially exploit the phenotypic plasticity of CTCL such that the malignant T cells become vulnerable to antitumor immunity....... cells and other sources. IL-2-type cytokines activate STAT5 to promote expression of Treg-related FoxP3, while various cytokines can activate STAT3 to induce synthesis of IL-10 and IL-17. When the Treg phenotype is activated in the early stages of CTCL, “immune evasion” can occur, allowing the clonal T...

  16. In vitro leukocyte response of three-spined sticklebacks (Gasterosteus aculeatus) to helminth parasite antigens.

    Science.gov (United States)

    Franke, Frederik; Rahn, Anna K; Dittmar, Janine; Erin, Noémie; Rieger, Jennifer K; Haase, David; Samonte-Padilla, Irene E; Lange, Joseph; Jakobsen, Per J; Hermida, Miguel; Fernández, Carlos; Kurtz, Joachim; Bakker, Theo C M; Reusch, Thorsten B H; Kalbe, Martin; Scharsack, Jörn P

    2014-01-01

    Helminth parasites of teleost fish have evolved strategies to evade and manipulate the immune responses of their hosts. Responsiveness of fish host immunity to helminth antigens may therefore vary depending on the degree of host-parasite counter-adaptation. Generalist parasites, infective for a number of host species, might be unable to adapt optimally to the immune system of a certain host species, while specialist parasites might display high levels of adaptation to a particular host species. The degree of adaptations may further differ between sympatric and allopatric host-parasite combinations. Here, we test these hypotheses by in vitro exposure of head kidney leukocytes from three-spined sticklebacks (Gasterosteus aculeatus) to antigens from parasites with a broad fish host range (Diplostomum pseudospathaceum, Triaenophorus nodulosus), a specific fish parasite of cyprinids (Ligula intestinalis) and parasites highly specific only to a single fish species as second intermediate host (Schistocephalus pungitii, which does not infect G. aculeatus, and Schistocephalus solidus, infecting G. aculeatus). In vitro responses of stickleback leukocytes to S. solidus antigens from six European populations, with S. solidus prevalence from aculeatus to a G. aculeatus-infecting species. Generalist parasites seem to maintain their ability to infect different host species at the costs of relatively higher immunogenicity compared to specialist parasites. In a comparison of sympatric and allopatric combinations of stickleback leukocytes and antigens from S. solidus, magnitudes of in vitro responses were dependent on the prevalence of the parasite in the population of origin, rather than on sympatry. Antigens from Norwegian (prevalence 30-50%) and Spanish (40-66%) S. solidus induced generally higher in vitro responses compared to S. solidus from two German (<1%) populations. Likewise, leukocytes from stickleback populations with a high S. solidus prevalence showed

  17. Sequence mining and transcript profiling to explore cyst nematode parasitism

    Directory of Open Access Journals (Sweden)

    Recknor Justin

    2009-01-01

    currently known 6,860 H. glycines genes to a pool of 788 most promising candidate genes (including known parasitism genes and documented their expression profiles. Using our approach to pre-select genes likely involved in parasitism now allows detailed functional analyses in a manner not feasible for larger numbers of genes. The generation of the candidate pool described here is an important enabling advance because it will significantly facilitate the unraveling of fascinating plant-animal interactions and deliver knowledge that can be transferred to other pathogen-host systems. Ultimately, the exploration of true parasitism genes verified from the gene pool delineated here will identify weaknesses in the nematode life cycle that can be exploited by novel anti-nematode efforts.

  18. Deciphering the ubiquitin-mediated pathway in apicomplexan parasites: a potential strategy to interfere with parasite virulence.

    Science.gov (United States)

    Ponts, Nadia; Yang, Jianfeng; Chung, Duk-Won Doug; Prudhomme, Jacques; Girke, Thomas; Horrocks, Paul; Le Roch, Karine G

    2008-06-11

    Reversible modification of proteins through the attachment of ubiquitin or ubiquitin-like modifiers is an essential post-translational regulatory mechanism in eukaryotes. The conjugation of ubiquitin or ubiquitin-like proteins has been demonstrated to play roles in growth, adaptation and homeostasis in all eukaryotes, with perturbation of ubiquitin-mediated systems associated with the pathogenesis of many human diseases, including cancer and neurodegenerative disorders. Here we describe the use of an HMM search of functional Pfam domains found in the key components of the ubiquitin-mediated pathway necessary to activate and reversibly modify target proteins in eight apicomplexan parasitic protozoa for which complete or late-stage genome projects exist. In parallel, the same search was conducted on five model organisms, single-celled and metazoans, to generate data to validate both the search parameters employed and aid paralog classification in Apicomplexa. For each of the 13 species investigated, a set of proteins predicted to be involved in the ubiquitylation pathway has been identified and demonstrates increasing component members of the ubiquitylation pathway correlating with organism and genome complexity. Sequence homology and domain architecture analyses facilitated prediction of apicomplexan-specific protein function, particularly those involved in regulating cell division during these parasite's complex life cycles. This study provides a comprehensive analysis of proteins predicted to be involved in the apicomplexan ubiquitin-mediated pathway. Given the importance of such pathway in a wide variety of cellular processes, our data is a key step in elucidating the biological networks that, in part, direct the pathogenicity of these parasites resulting in a massive impact on global health. Moreover, apicomplexan-specific adaptations of the ubiquitylation pathway may represent new therapeutic targets for much needed drugs against apicomplexan parasites.

  19. Superior Cervical Ganglia Neurons Induce Foxp3+ Regulatory T Cells via Calcitonin Gene-Related Peptide.

    Science.gov (United States)

    Szklany, Kirsten; Ruiter, Evelyn; Mian, Firoz; Kunze, Wolfgang; Bienenstock, John; Forsythe, Paul; Karimi, Khalil

    2016-01-01

    The nervous and immune systems communicate bidirectionally, utilizing diverse molecular signals including cytokines and neurotransmitters to provide an integrated response to changes in the body's internal and external environment. Although, neuro-immune interactions are becoming better understood under inflammatory circumstances and it has been evidenced that interaction between neurons and T cells results in the conversion of encephalitogenic T cells to T regulatory cells, relatively little is known about the communication between neurons and naïve T cells. Here, we demonstrate that following co-culture of naïve CD4+ T cells with superior cervical ganglion neurons, the percentage of Foxp3 expressing CD4+CD25+ cells significantly increased. This was mediated in part by immune-regulatory cytokines TGF-β and IL-10, as well as the neuropeptide calcitonin gene-related peptide while vasoactive intestinal peptide was shown to play no role in generation of T regulatory cells. Additionally, T cells co-cultured with neurons showed a decrease in the levels of pro-inflammatory cytokine IFN-γ released upon in vitro stimulation. These findings suggest that the generation of Tregs may be promoted by naïve CD4+ T cell: neuron interaction through the release of neuropeptide CGRP.

  20. Modulation by Polypodium leucotomos extract of cytokine patterns in experimental trichomoniasis model

    Directory of Open Access Journals (Sweden)

    Nogal-Ruiz J.J.

    2003-03-01

    Full Text Available The immunomodulating effects of Anapsos®, an aqueous hydrosoluble extract obtained from the rhizomes of the fern Polypodium leucotomos, on both pathogenicity and cytokine levels in serum (IFN-γ/IL-4 were assayed in a Trichomonas vaginalis experimental model (BALB/c mice infected with 107 trichomonads and examined at day 15 after infection. Doses of 20 mg/kg/day administered for 10 days before the infection with the parasite induced a decrease of the experimental pathogenicity approximately 10-20 % compared to controls. Gross histopathologic changes at abdominal organs and mortality rate, as a consequence of pathogenicity of the protozoa and the immune response of the host, were evaluated. IFN-y and IL-4 cytokines were determined on days -5, 0, 5, 10, and 15 postinfection by indirect ELISA. Treatment with PAL before infection modulates and downregulates the IFN-γ concentration, while anticipates and upregulates the IL-4 level. The assays performed have showed the utility of the murine model of experimental trichomoniasis for the evaluation of immunomodulatory activity of synthetic or natural products.

  1. Cysteine Protease Inhibitors as Chemotherapy: Lessons from a Parasite Target

    Science.gov (United States)

    Selzer, Paul M.; Pingel, Sabine; Hsieh, Ivy; Ugele, Bernhard; Chan, Victor J.; Engel, Juan C.; Bogyo, Matthew; Russell, David G.; Sakanari, Judy A.; McKerrow, James H.

    1999-09-01

    Papain family cysteine proteases are key factors in the pathogenesis of cancer invasion, arthritis, osteoporosis, and microbial infections. Targeting this enzyme family is therefore one strategy in the development of new chemotherapy for a number of diseases. Little is known, however, about the efficacy, selectivity, and safety of cysteine protease inhibitors in cell culture or in vivo. We now report that specific cysteine protease inhibitors kill Leishmania parasites in vitro, at concentrations that do not overtly affect mammalian host cells. Inhibition of Leishmania cysteine protease activity was accompanied by defects in the parasite's lysosome/endosome compartment resembling those seen in lysosomal storage diseases. Colocalization of anti-protease antibodies with biotinylated surface proteins and accumulation of undigested debris and protease in the flagellar pocket of treated parasites were consistent with a pathway of protease trafficking from flagellar pocket to the lysosome/endosome compartment. The inhibitors were sufficiently absorbed and stable in vivo to ameliorate the pathology associated with a mouse model of Leishmania infection.

  2. Counter-discourse in Zimbabwean literature

    NARCIS (Netherlands)

    Mangena, Tendai

    2015-01-01

    Counter-Discourse in Zimbabwean Literature is a study of specific aspects of counter-discursive Zimbabwean narratives in English. In discussing the selected texts, my thesis is based on Terdiman’s (1989) the postcolonial concept of counter-discourse. In Zimbabwean literature challenges to a dominant

  3. Flavanol-Rich Cocoa Powder Interacts with Lactobacillus rhamnossus LGG to Alter the Antibody Response to Infection with the Parasitic Nematode Ascaris suum

    Directory of Open Access Journals (Sweden)

    Saebyeol Jang

    2017-10-01

    Full Text Available Consumption of the probiotic bacteria Lactobacillus rhamnosus LGG and flavanol-rich cocoa have purported immune modulating effects. This study compared the host response to infection with Ascaris suum in three-month-old pigs fed a standard growth diet supplemented with a vehicle control: LGG, cocoa powder (CP or LGG + CP. Pigs were inoculated with infective A. suum eggs during Week 5 of dietary treatment and euthanized 17 days later. Lactobacillus abundance was increased in pigs fed LGG or LGG + CP. Specific anti-A. suum IgG2 antibodies were decreased (p < 0.05 in LGG + CP-fed pigs compared to pigs fed CP alone. Pigs fed LGG had significantly reduced expression (p < 0.05 of Eosinophil peroxidase (EPX, Interleukin 13 (IL-13, Eotaxin 3 (CCL26, Toll-like receptor 2 (TLR2, TLR4, and TLR9 and Interleukin-1Beta (IL1B in the tracheal-bronchial lymph node (TBLN independent of CP treatment. These results suggested that feeding LGG significantly reduced the localized prototypical Th2-related markers of infection with A. suum in the TBLN. Although feeding CP does not appear to affect the A. suum-induced Th2-associated cytokine response, feeding LGG + CP reduced anti-A. suum antibodies and delayed intestinal expulsion of parasitic larvae from the intestine.

  4. Effect of Oxidized Dextran on Cytokine Production and Activation of IRF3 Transcription Factor in Macrophages from Mice of Opposite Strains with Different Sensitivity to Tuberculosis Infection.

    Science.gov (United States)

    Chechushkov, A V; Kozhin, P M; Zaitseva, N S; Gainutdinov, P I; Men'shchikova, E B; Troitskii, A V; Shkurupy, V A

    2018-04-16

    We studied differences in the production of pro- and anti-inflammatory cytokines and IRF3 transcription factor by peritoneal macrophages from mice of opposite strains CBA/J and C57Bl/6 and the effect of 60-kDa oxidized dextran on these parameters. Macrophages from C57Bl/6 mice were mainly characterized by the production of proinflammatory cytokines TNFα, IL-12, and MCP-1 (markers of M1 polarization). By contrast, CBA/J mice exhibited a relatively high level of anti-inflammatory cytokine IL-10 and lower expression of proinflammatory cytokines (M2 phenotype). IRF3 content in peritoneal macrophages of CBA/J mice was higher than in C57Bl/6 mice. Oxidized dextran decreased the expression of IRF3 upon stimulation of cells from CBA/J mice with LPS, but increased this process in C57Bl/6 mice. Despite a diversity of oxidized dextran-induced changes in cytokine production, the data confirm our hypothesis that this agent can stimulate the alternative activation of macrophages.

  5. Semaphorin 4C Protects against Allergic Inflammation: Requirement of Regulatory CD138+ Plasma Cells.

    Science.gov (United States)

    Xue, Di; Kaufman, Gabriel N; Dembele, Marieme; Beland, Marianne; Massoud, Amir H; Mindt, Barbara C; Fiter, Ryan; Fixman, Elizabeth D; Martin, James G; Friedel, Roland H; Divangahi, Maziar; Fritz, Jörg H; Mazer, Bruce D

    2017-01-01

    The regulatory properties of B cells have been studied in autoimmune diseases; however, their role in allergic diseases is poorly understood. We demonstrate that Semaphorin 4C (Sema4C), an axonal guidance molecule, plays a crucial role in B cell regulatory function. Mice deficient in Sema4C exhibited increased airway inflammation after allergen exposure, with massive eosinophilic lung infiltrates and increased Th2 cytokines. This phenotype was reproduced by mixed bone marrow chimeric mice with Sema4C deficient only in B cells, indicating that B lymphocytes were the key cells affected by the absence of Sema4C expression in allergic inflammation. We determined that Sema4C-deficient CD19 + CD138 + cells exhibited decreased IL-10 and increased IL-4 expression in vivo and in vitro. Adoptive transfer of Sema4c -/- CD19 + CD138 + cells induced marked pulmonary inflammation, eosinophilia, and increased bronchoalveolar lavage fluid IL-4 and IL-5, whereas adoptive transfer of wild-type CD19 + CD138 + IL-10 + cells dramatically decreased allergic airway inflammation in wild-type and Sema4c -/- mice. This study identifies a novel pathway by which Th2-mediated immune responses are regulated. It highlights the importance of plasma cells as regulatory cells in allergic inflammation and suggests that CD138 + B cells contribute to cytokine balance and are important for maintenance of immune homeostasis in allergic airways disease. Furthermore, we demonstrate that Sema4C is critical for optimal regulatory cytokine production in CD138 + B cells. Copyright © 2016 by The American Association of Immunologists, Inc.

  6. 76 FR 33413 - Proposed Renewal Without Change; Comment Request; Nine Bank Secrecy Act Recordkeeping Requirements

    Science.gov (United States)

    2011-06-08

    ... with a caption, in the body of the text, ``BSA Recordkeeping Requirements Comments.'' FOR FURTHER..., or regulatory investigations or proceedings, or in the conduct of intelligence or counter-intelligence activities, including analysis, to protect against international terrorism, and to implement anti...

  7. Anti-inflammatory activity of Agaricus blazei Murill extract in the ...

    African Journals Online (AJOL)

    admin

    potential therapy of atherosclerosis disease. Keywords: Anti-inflammatory agent, Agaricus blazei Murill, Proinflammatory cytokine, TNF-α, IL-10. This is an ..... belong to the β2 integrin family. .... Response through Intestinal Epithelial Cells and.

  8. Corticosteroid-Induced MKP-1 Represses Pro-Inflammatory Cytokine Secretion by Enhancing Activity of Tristetraprolin (TTP) in ASM Cells

    NARCIS (Netherlands)

    Prabhala, Pavan; Ammit, Alaina; Bunge, Kristin; Ge, Qi

    2016-01-01

    Exaggerated cytokine secretion drives pathogenesis of a number of chronic inflammatory diseases, including asthma. Anti-inflammatory pharmacotherapies, including corticosteroids, are front-line therapies and although they have proven clinical utility, the molecular mechanisms responsible for their

  9. Serum levels of pro- and anti-inflammatory cytokines in non-pregnant women, during pregnancy, labour and abortion

    Directory of Open Access Journals (Sweden)

    S. Vassiliadis

    1998-01-01

    Full Text Available Disturbance of the cytokine equilibrium has been accused for many pathological disorders. Microbial infections, autoimmune diseases, graft rejection have been correlated to over- or under-production of specific cytokines which are produced as responder molecules to the various immune stimuli. The sole naturally occurring immune reaction in the organism is developed during the gestational period where, despite the presence of a semi-allogeneic graft, maternal immunoreactivity is driven to support fetal growth. The successful embryo development has been attributed to the important intervention of cytokines where some have been characterized as indispensable and others deleterious to fetal growth. However, the physiological levels of many factors during the gestational process have not been determined. Thus, in the present study we have measured and established the values of IL-1α, IL-2, IL-3, IL-4, IL-6, IL-10, IL-12, GM-CSF, TNF- α and IFN-γ during all phases of human pregnancy (first, second and third trimester of pregnancy, labour, abortions of the first trimester as well as in the non-pregnant control state. This is an attempt to assess serum protein concentrations and present the physiological levels of these cytokines at certain time intervals providing thus a diagnostic advantage in pregnancy cases where the mother cannot immunologically support the fetus. Exploitation of this knowledge and further research may be useful for therapeutic interventions in the future.

  10. Noise Depression of Parasitic Capacitance for Frequency Detection of Micromechanical Bulk Disk Resonator

    DEFF Research Database (Denmark)

    Tang, Meng; Cagliani, Alberto; Escouflaire, Marie

    2010-01-01

    the frequency noise of the system. A capacitor cancellation circuit is used to subtract the parasitic capacitor. Measurements are conducted before and after the cancellation, and results show that after cancellation, the anti resonance is suppressed and the frequency noise is decreased, thus decreasing...

  11. Inhibitory effect of apicidin on in vitro and in vivo growth of Babesia parasites

    OpenAIRE

    Munkhjargal, T; Aboulaila, M.R.A; Sivakumar, T; Yokoyama, Naoaki; Igarashi, Ikuo

    2009-01-01

    Apicidin, a histone deacetylase inhibitor, has a broad spectrum of anti-protozoal activities against apicomplexan parasites. In the present study, we evaluated the inhibitory effect of apicidin on the asexual growth of bovine Babesia parasites (B. bovis and B. bigemina) in vitro, as well as on the in vivo growth of B. microti in mice. The growth of B. bovis and B. bigemina was significantly inhibited in the presence of 3 ng/ml apicidin. Complete inhibition of B. bovis and B. bigemina growth w...

  12. Energy loss to parasitic modes of accelerating cavities

    International Nuclear Information System (INIS)

    Sands, M.

    1974-01-01

    At the maximum stored current, each circulating beam in PEP will consist of three bunches, each about 10 cm long containing 1.5 /times/ 10 12 particles. The large electric charge carried by such a bunch (2.5 /times/ 10/sup /minus/7/ coulomb) will, because of its short length, give rise to a large transient excitation of hundreds of parasitic modes in the accelerating cavities. The energy loss of the stored beam to the cavities from this process may be comparable to the loss to synchrotron radiation, and may, therefore, require a significant increase in power from the accelerating rf system. In this note I considered three aspects of this effect. First, an attempt is made to estimate the magnitude of the energy loss of a bunch in a single passage through the accelerating cavities. Then, I consider the effects of the periodic passages of the bunches in a single stored beam. And finally, I look at the consequences of storing two counter-rotating beams. The general conclusions are that the magnitude energy loss to the parasitic modes is serious, though probably not disastrous; and that, in general, the separate stored bunches will act incoherently. 2 refs., 7 figs

  13. Analgesic activity of piracetam: effect on cytokine production and oxidative stress.

    Science.gov (United States)

    Navarro, Suelen A; Serafim, Karla G G; Mizokami, Sandra S; Hohmann, Miriam S N; Casagrande, Rubia; Verri, Waldiceu A

    2013-04-01

    Piracetam is a prototype of nootropic drugs used to improve cognitive impairment. However, recent studies suggest that piracetam can have analgesic and anti-inflammatory effects. Inflammatory pain is the result of a process that depends on neutrophil migration, cytokines and prostanoids release and oxidative stress. We analyze whether piracetam has anti-nociceptive effects and its mechanisms. Per oral pretreatment with piracetam reduced in a dose-dependent manner the overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone, formalin and complete Freund's adjuvant. Piracetam also diminished carrageenin-induced mechanical and thermal hyperalgesia, myeloperoxidase activity, and TNF-α-induced mechanical hyperalgesia. Piracetam presented analgesic effects as post-treatment and local paw treatment. The analgesic mechanisms of piracetam were related to inhibition of carrageenin- and TNF-α-induced production of IL-1β as well as prevention of carrageenin-induced decrease of reduced glutathione, ferric reducing ability and free radical scavenging ability in the paw. These results demonstrate that piracetam presents analgesic activity upon a variety of inflammatory stimuli by a mechanism dependent on inhibition of cytokine production and oxidative stress. Considering its safety and clinical use for cognitive function, it is possible that piracetam represents a novel perspective of analgesic. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Cytokines in chronically critically ill patients after activity and rest.

    Science.gov (United States)

    Winkelman, Chris; Higgins, Patricia A; Chen, Yea Jyh Kathy; Levine, Alan D

    2007-04-01

    Inflammation, a common problem for patients in the intensive care unit (ICU), frequently is associated with serious and prolonged critical illnesses. To date, no study has examined whether physical activity influences inflammatory factors in critically ill adults. The objectives of this study were to (a) examine the relationships between type and duration of physical activity and serum levels of interleukin 6 (IL-6), a proinflammatory cytokine; IL-10, an anti-inflammatory cytokine; and their ratio and (b) determine if there are associations between cytokines or their ratio and activity or outcomes. This descriptive feasibility study investigated the approaches to measuring levels of physical activity and its relationship to serum levels of IL-6 and IL-10 and the ratio between them in patients with prolonged mechanical ventilation during periods of activity and rest. Measurements included serum IL-6 and IL-10 levels, direct observation and actigraphy, and prospective chart review. Ten critically ill patients who were mechanically ventilated for an average of 10 days in a large, urban, teaching hospital were enrolled. The average ratio of IL-6 to IL-10 improved after an average of 14.7 min of passive physical activity, typically multiple in-bed turns associated with hygiene. IL-6, IL-10, and their ratio were not associated with patient outcomes of weaning success or length of stay. High levels of IL-6 were associated with mortality. Cytokine balance may be improved by low levels of activity among patients with prolonged critical illness. The pattern of cytokines produced after activity may improve patients' recovery from prolonged critical illness and mechanical ventilation.

  15. Characterization of main cytokine sources from the innate and adaptive immune responses following primary 17DD yellow fever vaccination in adults.

    Science.gov (United States)

    Silva, Maria Luiza; Martins, Marina Angela; Espírito-Santo, Luçandra Ramos; Campi-Azevedo, Ana Carolina; Silveira-Lemos, Denise; Ribeiro, José Geraldo Leite; Homma, Akira; Kroon, Erna Geessien; Teixeira-Carvalho, Andréa; Elói-Santos, Silvana Maria; Martins-Filho, Olindo Assis

    2011-01-10

    The mechanisms of immune response following yellow fever (YF-17DD) vaccination are still poorly understood. In this study, we have performed a longitudinal investigation (days 0, 7, 15 and 30) to characterize the cytokine profile of innate and adaptive immunity following YF-17DD first-time vaccination. Data from non-stimulated cultures demonstrated a prominent participation of the innate immunity with increased frequency of TNF-α(+) neutrophils and IFN-γ(+) NK-cells at day 7 besides TNF-α(+) monocytes at day 7, day 15 and day 30. Increased frequency of IL-10(+) monocytes was observed at day 15 and day 30, and decreased percentage of IL-4(+) NK-cells were detected at day 7, day 15 and day 30. Time-dependent and oscillating cytokine pattern was observed in CD4(+) T-cells, with low percentage of IL-12(+), IL-4(+) and IL-10(+) cells at day 7 and increased frequency of TNF-α(+) cells at day 15 besides IFN-γ(+) and IL-5(+) cells at day 15 and day 30. Later changes with increased percentage of IL-12(+) and IL-5(+)CD8(+) T-cells were observed at day 30. Increased frequency of IL-10(+) B-cells was observed at day 15, when seroconversion was detected in all vaccinees. The overall cytokine analysis of non-stimulated leukocytes showed a transient shift towards a pro-inflammatory profile at day 7, mainly due to changes in the innate immunity, which draws back toward a mixed/regulatory pattern at day 15 and day 30. The changes induced by the in vitro YF-17DD vaccine-stimulation were mainly observed at day 0 and day 7 (before seroconversion) with minor changes at day 15 and day 30 (after seroconversion). These data support the hypothesis that a complex network with mixed pro/anti-inflammatory cytokine profile is associated with the establishment of the protective immunity following YF-17DD primo-vaccination, free of adverse events. Copyright © 2010 Elsevier Ltd. All rights reserved.

  16. Strain-dependent release of cytokines modulated by Lactobacillus salivarius human isolates in an in vitro model

    Directory of Open Access Journals (Sweden)

    Nicola Lucia

    2010-02-01

    Full Text Available Abstract Background Oral administration of probiotics is known to modulate cytokines profile not only locally, but also systemically. Four strains of Lactobacillus salivarius, LDR0723, BNL1059, RGS1746 and CRL1528, were evaluated for their ability to modulate release of pro- and anti-inflammatory cytokines. Findings Strains were assessed for effects on production of Interleukin-12 (IL-12, Interferon-γ (IFN-γ, Interleukin-4 (IL-4 and Interleukin-5 (IL-5 by incubating bacterial suspensions with THP-1 macrophage like cells. Cytokines were determined by means of specific quantitative enzyme-linked immunosorbent assays. LDR0723 and CRL1528 led to a sustained increment in production of IL-12 and IFN-γ and to a decrease in release of IL-4 and IL-5, while BNL1059 and RGS1746 favoured Th2 response, leading to a decrease in Th1/Th2 ratio with respect to unstimulated cells. Conclusions In conclusion, capability of L. salivarius to modulate immune response was strictly strain dependent and strains of the same species might have opposite effects. Therefore, a careful evaluation of anti-inflammatory properties of lactobacilli should be performed on single strain, before any consideration on potential probiotic use.

  17. The association between pro- and anti-inflammatory cytokine polymorphisms and periventricular leukomalacia in newborns with hypoxic-ischemic encephalopathy

    Directory of Open Access Journals (Sweden)

    Gabriel ML

    2016-05-01

    Full Text Available Marta Lúcia Gabriel,1 Fernanda Braojos Braga,1 Mariana Rodero Cardoso,1 Ana Cláudia Lopes,2 Vânia Belintani Piatto,2 Antônio Soares Souza1 1Radiology Department, 2Morphology Department, São José do Rio Preto Medical School, FAMERP, São Paulo, BrazilBackground: Periventricular leukomalacia (PVL is a frequent consequence of hypoxic-ischemic injury. Functional cytokine gene variants that result in altered production of inflammatory (tumor necrosis factor-alpha [TNF-α] and interleukin-1beta [IL-1β] or anti-inflammatory (interleukin-10 [IL-10] cytokines may modify disease processes, including PVL.Objective: The aim of this study was to evaluate if there is a relationship between the two proinflammatory polymorphisms (TNF-σ-1031T/C and IL-1 β-511C/T and the anti-inflammatory polymorphism IL-10-1082G/A and PVL risk in Brazilian newborns with and without this injury.Materials and methods: A cross-sectional case-control study performed at the Neonatal Intensive Care Unit of the Children's Hospital and Maternity of the São José do Rio Preto Medical School (FAMERP. Fifty preterm and term newborns were examined as index cases and 50 term newborns as controls, of both sexes for both groups. DNA was extracted from peripheral blood leukocytes, and the sites that encompassed the three polymorphisms were amplified by polymerase chain reaction-restriction fragment length polymorphism.Results: Gestational age ranged from 25 to 39 weeks, in the case group, and in the control group it ranged from 38 to 42.5 weeks (P<0.0001. Statistically significant association was found between TNF-α-1031T/C high expression genotype TC (odds ratio [OR], 2.495; 95% confidence interval [CI], 1.10–5.63; P=0.043 as well as between genotypes (TC + CC (OR, 2.471; 95% CI, 1.10–5.55; P=0.044 and risk of PVL. Statistically significant association was found between IL-1β-511C/T high expression genotypes (CT + TT (OR, 23.120; 95% CI, 1.31–409.4; P=0.003 and risk of PVL

  18. Exposure of Human CD8+ T Cells to Type-2 Cytokines Impairs Division and Differentiation and Induces Limited Polarization

    Directory of Open Access Journals (Sweden)

    Annette Fox

    2018-05-01

    Full Text Available Effector CD8+ T cells generally produce type-1 cytokines and mediators of the perforin/granzyme cytolytic pathway, yet type-2-polarized CD8+ cells (Tc2 are detected in type-2 (T2 cytokine-driven diseases such as asthma. It is unclear whether T2 cytokine exposure during activation is sufficient to polarize human CD8+ T cells. To address this question, a protocol was developed for high-efficiency activation of human CD8+ T cells in which purified single cells or populations were stimulated with plate-bound anti-CD3 and anti-CD11a mAb for up to 8 days in T2 polarizing or neutral conditions, before functional analysis. Activation of CD8+ naïve T cells (TN in T2 compared with neutral conditions decreased the size of single-cell clones, although early division kinetics were equivalent, indicating an effect on overall division number. Activation of TN in T2 conditions followed by brief anti-CD3 mAb restimulation favored expression of T2 cytokines, GATA3 and Eomes, and lowered expression of type-1 cytokines, Prf1, Gzmb, T-BET, and Prdm1. However, IL-4 was only weakly expressed, and PMA and ionomycin restimulation favored IFN-γ over IL-4 expression. Activation of TN in T2 compared with neutral conditions prevented downregulation of costimulatory (CD27, CD28 and lymph-node homing receptors (CCR7 and CD95 acquisition, which typically occur during differentiation into effector phenotypes. CD3 was rapidly and substantially induced after activation in neutral, but not T2 conditions, potentially contributing to greater division and differentiation in neutral conditions. CD8+ central memory T cells (TCM were less able to enter division upon reactivation in T2 compared with neutral conditions, and were more refractory to modulating IFN-γ and IL-4 production than CD8+ TN. In summary, while activation of TN in T2 conditions can generate T2 cytokine-biased cells, IL-4 expression is weak, T2 bias is lost upon strong restimulation, differentiation, and division

  19. The Interleukin-20 Cytokine Family in Liver Disease

    Directory of Open Access Journals (Sweden)

    Esther Caparrós

    2018-05-01

    Full Text Available The three main causes of inflammation and chronic injury in the liver are viral hepatitis, alcohol consumption, and non-alcoholic steatohepatitis, all of which can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma, which in turn may prompt the need for liver transplant. The interleukin (IL-20 is a subfamily part of the IL-10 family of cytokines that helps the liver respond to damage and disease, they participate in the control of tissue homeostasis, and in the immunological responses developed in this organ. The best-studied member of the family in inflammatory balance of the liver is the IL-22 cytokine, which on the one hand may have a protective role in fibrosis progression but on the other may induce liver tissue susceptibility in hepatocellular carcinoma development. Other members of the family might also carry out this dual function, as some of them share IL receptor subunits and signal through common intracellular pathways. Investigators are starting to consider the potential for targeting IL-20 subfamily members in liver disease. The recently explored role of miRNA in the transcriptional regulation of IL-22 and IL-24 opens the door to promising new approaches for controlling the local immune response and limiting organ injury. The IL-20RA cytokine receptor has also been classified as being under miRNA control in non-alcoholic steatohepatitis. Moreover, researchers have proposed combining anti-inflammatory drugs with IL-22 as a hepatoprotective IL for alcoholic liver disease (ALD treatment, and clinical trials of ILs for managing severe alcoholic-derived liver degeneration are ongoing. In this review, we focus on exploring the role of the IL-20 subfamily of cytokines in viral hepatitis, ALD, non-alcoholic steatohepatitis, and hepatocellular carcinoma, as well as delineating the main strategies explored so far in terms of therapeutic possibilities of the IL-20 subfamily of cytokines in liver disease.

  20. What is Counter-Enlightenment?

    OpenAIRE

    Darrin M. McMahon

    2017-01-01

    This article counters recent suggestions that there was no such thing as a “Counter-Enlightenment” or “Counter-Enlightenments,” and that such terms ought thus to be abandoned.   While acknowledging inevitable difficulties with the terms, the article argues that there can be no doubting the reality.   European countries faced a variety of vehement and self-conscious movements that defined themselves precisely through their opposition to what they took to be the corrosive effects of the Enlight...

  1. Anti-fibrotic effects of a novel small compound on the regulation of cytokine production in a mouse model of colorectal fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Imai, Jin [Center for Matrix Biology and Medicine, Tokai University School of Medicine, Kanagawa (Japan); Department of Gastroenterology, Tokai University School of Medicine, Kanagawa (Japan); Hozumi, Katsuto, E-mail: hozumi@is.icc.u-tokai.ac.jp [Center for Matrix Biology and Medicine, Tokai University School of Medicine, Kanagawa (Japan); Department of Immunology, Tokai University School of Medicine, Kanagawa (Japan); Sumiyoshi, Hideaki [Center for Matrix Biology and Medicine, Tokai University School of Medicine, Kanagawa (Japan); Department of Regenerative Medicine, Tokai University School of Medicine, Kanagawa (Japan); Yazawa, Masaki; Hirano, Ken-ichi [Department of Immunology, Tokai University School of Medicine, Kanagawa (Japan); Abe, Jun; Higashi, Kiyoshi [Environmental Health Science Laboratory, Sumitomo Chemical Company Limited, Osaka (Japan); Inagaki, Yutaka [Center for Matrix Biology and Medicine, Tokai University School of Medicine, Kanagawa (Japan); Department of Regenerative Medicine, Tokai University School of Medicine, Kanagawa (Japan); Mine, Tetsuya [Department of Gastroenterology, Tokai University School of Medicine, Kanagawa (Japan)

    2015-12-25

    Intestinal fibrotic stricture is a major complication of inflammatory bowel disease. Despite its clinical importance, anti-fibrotic therapy has not been implemented. Transforming growth factor-β (TGF-β) is considered to be a major factor contributing to tissue fibrosis. We have previously shown that the administration of a small compound, HSc025, which promotes the nuclear translocation of YB-1 as a downstream effector of IFN-γ and antagonizes TGF-β/Smad signaling, improves fibrosis in several murine tissues. In this study, we evaluated the anti-fibrotic effect of HSc025 on colorectal fibrosis in TNBS-induced murine chronic colitis. Daily oral administration of HSc025 (3, 15 and 75 mg/kg) suppressed collagen production and decreased the severity of colorectal fibrosis in a dose-dependent manner. In addition, the local production of TGF-β was decreased after HSc025 treatment, whereas that of IL-13 and TNF-α was not affected. HSc025 administration maintained the level of IFN-γ production, even at a late stage when IFN-γ production was lost without the drug treatment. These results demonstrate that HSc025 could be a therapeutic candidate for intestinal fibrosis in inflammatory bowel disease that acts by altering the local production of cytokines, as well as by directly suppressing collagen production. - Highlights: • Colorectal fibrosis of TNBS-induced colitis was attenuated by HSc025 administration. • Local production of TGF-b was suppressed by the modulation of TGF-b/IFN-g signaling. • Derepression of IFN-g production was induced by the drug treatment.

  2. Anti-fibrotic effects of a novel small compound on the regulation of cytokine production in a mouse model of colorectal fibrosis

    International Nuclear Information System (INIS)

    Imai, Jin; Hozumi, Katsuto; Sumiyoshi, Hideaki; Yazawa, Masaki; Hirano, Ken-ichi; Abe, Jun; Higashi, Kiyoshi; Inagaki, Yutaka; Mine, Tetsuya

    2015-01-01

    Intestinal fibrotic stricture is a major complication of inflammatory bowel disease. Despite its clinical importance, anti-fibrotic therapy has not been implemented. Transforming growth factor-β (TGF-β) is considered to be a major factor contributing to tissue fibrosis. We have previously shown that the administration of a small compound, HSc025, which promotes the nuclear translocation of YB-1 as a downstream effector of IFN-γ and antagonizes TGF-β/Smad signaling, improves fibrosis in several murine tissues. In this study, we evaluated the anti-fibrotic effect of HSc025 on colorectal fibrosis in TNBS-induced murine chronic colitis. Daily oral administration of HSc025 (3, 15 and 75 mg/kg) suppressed collagen production and decreased the severity of colorectal fibrosis in a dose-dependent manner. In addition, the local production of TGF-β was decreased after HSc025 treatment, whereas that of IL-13 and TNF-α was not affected. HSc025 administration maintained the level of IFN-γ production, even at a late stage when IFN-γ production was lost without the drug treatment. These results demonstrate that HSc025 could be a therapeutic candidate for intestinal fibrosis in inflammatory bowel disease that acts by altering the local production of cytokines, as well as by directly suppressing collagen production. - Highlights: • Colorectal fibrosis of TNBS-induced colitis was attenuated by HSc025 administration. • Local production of TGF-b was suppressed by the modulation of TGF-b/IFN-g signaling. • Derepression of IFN-g production was induced by the drug treatment.

  3. CYTOKINE DISBALANCE AT HERPESVIRUS MYOCARDITIS

    Directory of Open Access Journals (Sweden)

    Peremot S. D

    2016-12-01

    , IL-10, INF-γ, TNF-α in blood serum was conducted by the method of solid-phase enzyme-linked immunosorbent assay, population structure of lymphocytes with different antigenic determinants (CD3+, CD4+, CD8+, CD16/56, CD19+, СD95+ was determined by monoclonal antibodies by cytofluorimetric assay. Obtained data processing was conducted with the use of parametric and non-parametric methods of biostatistics by programs EXEL-2003® and Biostatistics 4.03. Results and discussion. The data obtained indicates the disbalance in their system, which above all is characterized by a considerable level increase of pro-inflammatory IL-6 up to 134,09 ± 22,72 pg/ml (control level 11,83 ± 1,64 pg/ml and in relation to moderate growth of levels of IL-2 та TNF-α at subacute myocarditis. Such increase in level of IL-6 can take place due to the change of pro-inflammatory effect to anti-inflammatory in a remote period. In a complex with IL-10 IL-6 limits the secretion of TNF-α. For this reason, its level remains high at chronic herpesvirus myocarditis and exceeds the level of the control group by over 8 times. In addition, there is an increase of levels of anti-inflammatory IL-4, IL-10 cytokines at the chronic form of herpesvirus myocarditis course by 2,9 and 3,1 times respectively. At the same time, the level of IL-10 increased not only in comparison with the level of the control group but also almost 2 times exceeded the proper index at subacute myocarditis. Instead of the predicted INF-γ level rise, its decline was discovered, in patients with subacute course the index value was the lowest. This phenomenon can be the result of mast cells activity and in its turn influences the synthesis of collogen and processes of myocardium remodeling. Analysis of sub-population composition of lymphocytes discovered the increase in number of CD3+CD95+ lymphocytes of peripheral blood at myocarditis, especially in the group of patients with subacute herpesvirus myocarditis with its level

  4. A portable neutron coincidence counter

    Energy Technology Data Exchange (ETDEWEB)

    Peurrung, A.J.; Bowyer, S.M.; Craig, R.A.; Dudder, G.B.; Knopf, M.A.; Panisko, M.E.; Reeder, P.L.; Stromswold, D.C.; Sunberg, D.S.

    1996-11-01

    Pacific Northwest National Laboratory has designed and constructed a prototype portable neutron coincidence counter intended for use in a variety of applications, such as the verification and inspection of weapons components, safety measurements for novel and challenging situations, portable portal deployment to prevent the transportation of fissile materials, uranium enrichment measurements in hard-to-reach locations, waste assays for objects that cannot be measured by existing measurement systems, and decontamination and decommissioning. The counting system weighs less than 40 kg and is composed of parts each weighing no more than 5 kg. In addition, the counter`s design is sufficiently flexible to allow rapid, reliable assembly around containers of nearly arbitrary size and shape. The counter is able to discern the presence of 1 kg of weapons-grade plutonium within an ALR-8 (30-gal drum) in roughly 100 seconds and 10 g in roughly 1000 seconds. The counter`s electronics are also designed for maximum adaptability, allowing operation under a wide variety of circumstances, including exposure to gamma-ray fields of 1 R/h. This report provides a detailed review of the design and construction process. Finally, preliminary experimental measurements that confirm the performance capabilities of this counter are discussed. 6 refs., 18 figs., 3 tabs.

  5. Immune-relevant thrombocytes of common carp undergo parasite-induced nitric oxide-mediated apoptosis.

    Science.gov (United States)

    Fink, Inge R; Ribeiro, Carla M S; Forlenza, Maria; Taverne-Thiele, Anja; Rombout, Jan H W M; Savelkoul, Huub F J; Wiegertjes, Geert F

    2015-06-01

    Common carp thrombocytes account for 30-40% of peripheral blood leukocytes and are abundant in the healthy animals' spleen, the thrombopoietic organ. We show that, ex vivo, thrombocytes from healthy carp express a large number of immune-relevant genes, among which several cytokines and Toll-like receptors, clearly pointing at immune functions of carp thrombocytes. Few studies have described the role of fish thrombocytes during infection. Carp are natural host to two different but related protozoan parasites, Trypanoplasma borreli and Trypanosoma carassii, which reside in the blood and tissue fluids. We used the two parasites to undertake controlled studies on the role of fish thrombocytes during these infections. In vivo, but only during infection with T. borreli, thrombocytes were massively depleted from the blood and spleen leading to severe thrombocytopenia. Ex vivo, addition of nitric oxide induced a clear and rapid apoptosis of thrombocytes from healthy carp, supporting a role for nitric oxide-mediated control of immune-relevant thrombocytes during infection with T. borreli. The potential advantage for parasites to selectively deplete the host of thrombocytes via nitric oxide-induced apoptosis is discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. ANTI-MICROBIAL AND ANTI-AMOEBIC ACTIVITY SOME AZOMETHINES - POTENTIAL TEXTILE DYESTUFFS

    Directory of Open Access Journals (Sweden)

    DJORDJEVIC Dragan

    2016-05-01

    Full Text Available In this paper, new synthesized three azomethine derivatives applied in dyeing textiles checking the anti-microbial properties of active components, at the same time [1-3]. The emphasis is thrown on the verification of anti-microbial properties that are important for obtaining textile with significantly improved performance. All compounds were characterized and evaluated for their anti-microbial activity against 7 pathogenic bacteria, 1 parasitic protozoan and 1 fungus. It estimated anti-bacterial activity in vitro against the following microorganisms Staphylococcus aureus, Bacillus anthracis, Streptococcus faecalis, Enterobacter sp., Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, and Candida albicans. The anti-amoebic activity in vitro was evaluated against the HM1: IMSS strain of Entamoeba histolytica and the results were compared with the standard drug, metronidazole. The synthesized azomethines, showed very good substantivity for wool fibers, gave fine coloring, with good degree of exhaustion after dyeing. The combination of extended synthetic analogues of natural molecules leads to discovery of chemical entities which might be excellent anti-microbial and anti-amoebic compounds as depicted in our results. Being highly the effects this compound can be explored in future as an option for decreasing pathogenic potential of infecting from different sources. Azomethines containing hydrazone (dyestuff 1 and phenylhydrazone (dyestuff 2 as moiety show average yield and moderate inhibition activity while azomethines containing thiosemicarbazone (dyestuff 3 as moiety show higher yield and greater inhibition activity towards gram-negative and gram-positive bacteria as well as a fungus.

  7. Regulatory dendritic cell infusion prolongs kidney allograft survival in non-human primates

    OpenAIRE

    Ezzelarab, M.; Zahorchak, A.F.; Lu, L.; Morelli, A.E.; Chalasani, G.; Demetris, A.J.; Lakkis, F.G.; Wijkstrom, M.; Murase, N.; Humar, A.; Shapiro, R.; Cooper, D.K.C.; Thomson, A.W.

    2013-01-01

    We examined the influence of regulatory dendritic cells (DCreg), generated from cytokine-mobilized donor blood monocytes in vitamin D3 and IL-10, on renal allograft survival in a clinically-relevant rhesus macaque model. DCreg expressed low MHC class II and costimulatory molecules, but comparatively high levels of programmed death ligand-1 (B7-H1), and were resistant to pro-inflammatory cytokine-induced maturation. They were infused intravenously (3.5–10×106/kg), together with the B7-CD28 cos...

  8. Chemokines cooperate with TNF to provide protective anti-viral immunity and to enhance inflammation.

    Science.gov (United States)

    Alejo, Alí; Ruiz-Argüello, M Begoña; Pontejo, Sergio M; Fernández de Marco, María Del Mar; Saraiva, Margarida; Hernáez, Bruno; Alcamí, Antonio

    2018-05-03

    The role of cytokines and chemokines in anti-viral defense has been demonstrated, but their relative contribution to protective anti-viral responses in vivo is not fully understood. Cytokine response modifier D (CrmD) is a secreted receptor for TNF and lymphotoxin containing the smallpox virus-encoded chemokine receptor (SECRET) domain and is expressed by ectromelia virus, the causative agent of the smallpox-like disease mousepox. Here we show that CrmD is an essential virulence factor that controls natural killer cell activation and allows progression of fatal mousepox, and demonstrate that both SECRET and TNF binding domains are required for full CrmD activity. Vaccination with recombinant CrmD protects animals from lethal mousepox. These results indicate that a specific set of chemokines enhance the inflammatory and protective anti-viral responses mediated by TNF and lymphotoxin, and illustrate how viruses optimize anti-TNF strategies with the addition of a chemokine binding domain as soluble decoy receptors.

  9. Short-term exercise training reduces anti-inflammatory action of interleukin-10 in adults with obesity.

    Science.gov (United States)

    Barry, Julianne C; Simtchouk, Svetlana; Durrer, Cody; Jung, Mary E; Mui, Alice L; Little, Jonathan P

    2018-06-06

    A key pathological component of obesity is chronic low-grade inflammation, which is propagated by infiltration of immune cells into tissues and overproduction of pro-inflammatory cytokines. Cytokines that possess anti-inflammatory properties, such as interleukin (IL)-10 and IL6, may also play an important role. This study was designed to determine the impact of short-term exercise on the anti-inflammatory action of IL10 and IL6. Thirty-three inactive obese adults were randomized to two weeks of high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT). Fasting blood samples were collected before and after training. Lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production was measured in whole blood cultures in the presence or absence of IL10 or IL6. IL10 and IL6 receptor expression were measured on circulating monocytes, neutrophils, and T cells. HIIT and MICT reduced the ability of IL10 to inhibit LPS-induced TNFα production, with a greater effect with HIIT (Group × Time and IL10 × Time interactions, p's  0.05). HIIT and MICT differentially affected IL6 function (Group × Time and IL6 × Time interactions, p's < 0.05) with evidence of reductions in the anti-inflammatory ability of IL6 with HIIT. Neither HIIT nor MICT altered levels of circulating IL10, IL6, or TNFα. The impact of short-term HIIT and MICT resulted in differential effects on anti-inflammatory cytokine function. The clinical implications remain to be determined but these novel findings indicate that measuring anti-inflammatory cytokine action could reveal important immunomodulatory effects of exercise. Copyright © 2018. Published by Elsevier Ltd.

  10. A PKA survival pathway inhibited by DPT-PKI, a new specific cell permeable PKA inhibitor, is induced by T. annulata in parasitized B-lymphocytes.

    Science.gov (United States)

    Guergnon, Julien; Dessauge, Frederic; Traincard, François; Cayla, Xavier; Rebollo, Angelita; Bost, Pierre Etienne; Langsley, Gordon; Garcia, Alphonse

    2006-08-01

    T. annulata, an intracellular pathogenic parasite of the Aplicomplexa protozoan family infects bovine B-lymphocytes and macrophages. Parasitized cells that become transformed survive and proliferate independently of exogenous growth factors. In the present study, we used the isogenic non parasitized BL3 and parasitized TBL3 B cell lines, as a model to evaluate the contribution of two-major PI3-K- and PKA-dependent anti-apoptotic pathways in the survival of T. annulata parasitized B lymphocytes. We found that T. annulata increases PKA activity, induces over-expression of the catalytic subunit and down-regulates the pro-survival phosphorylation state of Akt/PKB. Consistent with a role of PKA activation in survival, two pharmacological inhibitors H89 and KT5720 ablate PKA-dependent survival of parasitized cells. To specifically inhibit PKA pro-survival pathways we linked the DPTsh1 peptide shuttle sequence to PKI(5-24) and we generated DPT-PKI, a cell permeable PKI. DPT-PKI specifically inhibited PKA activity in bovine cell extracts and, as expected, also inhibited the PKA-dependent survival of T. annulata parasitized TBL3 cells. Thus, parasite-dependent constitutive activation of PKA in TBL3 cells generates an anti-apoptotic pathway that can protect T. annulata-infected B cells from apoptosis. These results also indicate that DPT-PKI could be a powerful tool to inhibit PKA pathways in other cell types.

  11. Obesity Related Alterations in Plasma Cytokines and Metabolic Hormones in Chimpanzees

    Directory of Open Access Journals (Sweden)

    Pramod Nehete

    2014-01-01

    Full Text Available Obesity is characterized by chronic low-grade inflammation and serves as a major risk factor for hypertension, coronary artery disease, dyslipidemias, and type-2 diabetes. The purpose of this study was to examine changes in metabolic hormones, inflammatory cytokines, and immune function, in lean, overweight, and obese chimpanzees in a controlled environment. We observed increased plasma circulating levels of proinflammatory TH-1 cytokines, Interferon gamma, interleukin-6, interleukin-12p40, tumor necrosis factor, soluble CD40 ligand, and Interleukin-1β and anti-inflammatory TH-2 cytokines, Interleukin-4, Interleukin-RA, Interleukin-10, and Interleukin-13 in overweight and obese chimpanzees. We also observed increased levels of metabolic hormones glucagon-like-peptide-1, glucagon, connecting peptide, insulin, pancreatic peptide YY3–36, and leptin in the plasma of overweight and obese chimpanzees. Chemokine, eotaxin, fractalkine, and monocyte chemoattractant protein-1 were higher in lean compared to obese chimpanzees, while chemokine ligand 8 increased in plasma of obese chimpanzees. We also observed an obesity-related effect on immune function as demonstrated by lower mitogen induced proliferation, and natural killer activity and higher production of IFN-γ by PBMC in Elispot assay, These findings suggest that lean, overweight, and obese chimpanzees share circulating inflammatory cytokines and metabolic hormone levels with humans and that chimpanzees can serve as a useful animal model for human studies.

  12. Bovine lactoferricin, an antimicrobial peptide, is anti-inflammatory and anti-catabolic in human articular cartilage and synovium

    Science.gov (United States)

    Yan, Dongyao; Chen, Di; Shen, Jie; Xiao, Guozhi; van Wijnen, Andre J; Im, Hee-Jeong

    2012-01-01

    Bovine lactoferricin (LfcinB) is a multi-functional peptide derived from proteolytic cleavage of bovine lactoferrin. LfcinB was found to antagonize the biological effects mediated by angiogenic growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) in endothelial cells. However, the effect of LfcinB on human articular cartilage remained unknown. Here, our findings demonstrate that LfcinB restored the proteoglycan loss promoted by catabolic factors (interleukin-1 β) IL-1β and FGF-2 in vitro and ex vivo. Mechanistically, LfcinB attenuated the effects of IL-1β and FGF-2 on the expression of cartilage-degrading enzymes (MMP-1, MMP-3, and MMP-13), destructive cytokines (IL-1β and IL-6), and inflammatory mediators (iNOS and TLR2). LfcinB induced protective cytokine expression (IL-4 and IL-10), and downregulated aggrecanase basal expression. LfcinB specifically activated ERK MAPK and Akt signaling pathways, which may account for its anti-inflammatory activity. We also revealed that LfcinB exerted similar protective effects on human synovial fibroblasts challenged by IL-1β, with minimal cytotoxicity. Collectively, our results suggest that LfcinB possesses potent anti-catabolic and anti-inflammatory bioactivities in human articular tissues, and may be utilized for the prevention and/or treatment of OA in the future. PMID:22740381

  13. Over-expression of Stat5b confers protection against diabetes in the non-obese diabetic (NOD) mice via up-regulation of CD4+CD25+ regulatory T cells

    International Nuclear Information System (INIS)

    Jin, Yulan; Purohit, Sharad; Chen, Xueqin; Yi, Bing; She, Jin-Xiong

    2012-01-01

    Highlights: ► This is the first study to provide direct evidence of the role of Stat5b in NOD mice. ► Over-expression of wild type Stat5b transgene protects NOD mice against diabetes. ► This protection may be mediated by the up-regulation of CD4 + CD25 + Tregs. -- Abstract: The signal transducers and activators of transcription (STAT) family of proteins play a critical role in cytokine signaling required for fine tuning of immune regulation. Previous reports showed that a mutation (L327M) in the Stat5b protein leads to aberrant cytokine signaling in the NOD mice. To further elaborate the role of Stat5b in diabetes, we established a NOD transgenic mouse that over-expresses the wild type Stat5b gene. The incidences of spontaneous diabetes as well as cyclophosphamide-induced diabetes were significantly reduced and delayed in the Stat5b transgenic NOD mice compared to their littermate controls. The total cell numbers of CD4 + T cells and especially CD8 + T cells in the spleen and pancreatic lymph node were increased in the Stat5b transgenic NOD mice. Consistent with these findings, CD4 + and CD8 + T cells from the Stat5b transgenic NOD mice showed a higher proliferation capacity and up-regulation of multiple cytokines including IL-2, IFN-γ, TNF-α and IL-10 as well as anti-apoptotic gene Bcl-xl. Furthermore, the number and proportion of CD4 + CD25 + regulatory T cells were significantly increased in transgenic mice although in vitro suppression ability of the regulatory T-cells was not affected by the transgene. Our results suggest that Stat5b confers protection against diabetes in the NOD mice by regulating the numbers and function of multiple immune cell types, especially by up-regulating CD4 + CD25 + regulatory T cells.

  14. Angiogenic Factors and Cytokines in Diabetic Retinopathy

    Science.gov (United States)

    Abcouwer, Steven F.

    2013-01-01

    Diabetic retinopathy (DR) is a sight-threatening complication of both type-1 and type-2 diabetes. The recent success of treatments inhibiting the function of vascular endothelial growth factor (VEGF) demonstrates that specific targeting of a growth factor responsible for vascular permeability and growth is an effective means of treating DR-associated vascular dysfunction, edema and angiogenesis. This has stimulated research of alternative therapeutic targets involved in the control of retinal vascular function. However, additional treatment options and preventative measures are still needed and these require a greater understanding of the pathological mechanisms leading to the disturbance of retinal tissue homeostasis in DR. Although severe DR can be treated as a vascular disease, abundant data suggests that inflammation is also occurring in the diabetic retina.Thus, anti-inflammatory therapies may also be useful for treatment and prevention of DR. Herein, the evidence for altered expression of angiogenic factors and cytokines in DR is reviewed and possible mechanisms by which the expression of VEGF and cytokines may be increased in the diabetic retina are examined. In addition, the potential role for microglial activation in diabetic retinal neuroinflammation is explored. PMID:24319628

  15. Inflammation in Depression and the Potential for Anti-Inflammatory Treatment

    DEFF Research Database (Denmark)

    Köhler, Karl Ole; Krogh, Jesper; Mors, Ole

    2016-01-01

    , nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine-inhibitors have shown antidepressant treatment effects compared to placebo, but also statins, poly-unsaturated fatty acids, pioglitazone, minocycline, modafinil, and corticosteroids may yield antidepressant treatment effects. However, the complexity...

  16. Cytokines and Liver Diseases

    Directory of Open Access Journals (Sweden)

    Herbert Tilg

    2001-01-01

    Full Text Available Cytokines are pleiotropic peptides produced by virtually every nucleated cell in the body. In most tissues, including the liver, constitutive production of cytokines is absent or minimal. There is increasing evidence that several cytokines mediate hepatic inflammation, apoptosis and necrosis of liver cells, cholestasis and fibrosis. Interestingly, the same mediators also mediate the regeneration of liver tissue after injury. Among the various cytokines, the proinflammatory cytokine tumour necrosis factor-alpha (TNF-a has emerged as a key factor in various aspects of liver disease, such as cachexia and/or cholestasis. Thus, antagonism of TNF-a and other injury-related cytokines in liver diseases merits evaluation as a treatment of these diseases. However, because the same cytokines are also necessary for the regeneration of the tissue after the liver has been injured, inhibition of these mediators might impair hepatic recovery. The near future will bring the exiting clinical challenge of testing new anticytokine strategies in various liver diseases.

  17. Norisoboldine ameliorates collagen-induced arthritis through regulating the balance between Th17 and regulatory T cells in gut-associated lymphoid tissues

    International Nuclear Information System (INIS)

    Tong, Bei; Dou, Yannong; Wang, Ting; Yu, Juntao; Wu, Xin; Lu, Qian; Chou, Guixin; Wang, Zhengtao; Kong, Lingyi; Dai, Yue; Xia, Yufeng

    2015-01-01

    Norisoboldine (NOR), the main active ingredient of the dry root of Lindera aggregata, was previously proven to have substantial therapeutic effects on collagen-induced arthritis (CIA) in mice by oral administration. However, it exhibited a very poor bioavailability in normal rats. The pharmacokinetic–pharmacodynamics disconnection attracts us to explore its anti-arthritic mechanism in more detail. In this study, NOR, administered orally, markedly attenuated the pathological changes in CIA rats, which was accompanied by the down-regulation of pro-inflammatory cytokines and the up-regulation of anti-inflammatory cytokine IL-10. Pharmacokinetic studies demonstrated that the plasma concentration of NOR was moderately elevated in CIA rats compared with normal rats, but it was still far lower than the minimal effective concentration required for inhibiting the proliferation and activation of T lymphocytes in vitro. Interestingly, NOR was shown to regulate the balance between Th17 and regulatory T (Treg) cells in the intestinal lymph nodes more strikingly than in other tissues. It could increase the expression of Foxp3 mRNA in both gut and joints, and markedly up-regulate the number of integrin α4β7 (a marker of gut source)-positive Foxp3 + cells in the joints of CIA rats. These results suggest that the gut might be the primary action site of NOR, and NOR exerts anti-arthritis effect through regulating the balance between Th17 and Treg cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from the gut to joint. The findings of the present study also provide a plausible explanation for the anti-arthritic effects of poorly absorbed compounds like NOR. - Highlights: • Norisoboldine, administered orally, markedly attenuates the clinical signs of CIA. • Norisoboldine regulates the balance of Th17/Treg cells in the intestinal lymph node. • Norisoboldine induces the migration of Treg cells from the gut to joint

  18. Norisoboldine ameliorates collagen-induced arthritis through regulating the balance between Th17 and regulatory T cells in gut-associated lymphoid tissues

    Energy Technology Data Exchange (ETDEWEB)

    Tong, Bei; Dou, Yannong; Wang, Ting; Yu, Juntao; Wu, Xin; Lu, Qian [Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009 (China); Chou, Guixin; Wang, Zhengtao [Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Kong, Lingyi [Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009 (China); Dai, Yue, E-mail: yuedaicpu@hotmail.com [Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009 (China); Xia, Yufeng, E-mail: yfxiacpu@126.com [Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009 (China)

    2015-01-01

    Norisoboldine (NOR), the main active ingredient of the dry root of Lindera aggregata, was previously proven to have substantial therapeutic effects on collagen-induced arthritis (CIA) in mice by oral administration. However, it exhibited a very poor bioavailability in normal rats. The pharmacokinetic–pharmacodynamics disconnection attracts us to explore its anti-arthritic mechanism in more detail. In this study, NOR, administered orally, markedly attenuated the pathological changes in CIA rats, which was accompanied by the down-regulation of pro-inflammatory cytokines and the up-regulation of anti-inflammatory cytokine IL-10. Pharmacokinetic studies demonstrated that the plasma concentration of NOR was moderately elevated in CIA rats compared with normal rats, but it was still far lower than the minimal effective concentration required for inhibiting the proliferation and activation of T lymphocytes in vitro. Interestingly, NOR was shown to regulate the balance between Th17 and regulatory T (Treg) cells in the intestinal lymph nodes more strikingly than in other tissues. It could increase the expression of Foxp3 mRNA in both gut and joints, and markedly up-regulate the number of integrin α4β7 (a marker of gut source)-positive Foxp3{sup +} cells in the joints of CIA rats. These results suggest that the gut might be the primary action site of NOR, and NOR exerts anti-arthritis effect through regulating the balance between Th17 and Treg cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from the gut to joint. The findings of the present study also provide a plausible explanation for the anti-arthritic effects of poorly absorbed compounds like NOR. - Highlights: • Norisoboldine, administered orally, markedly attenuates the clinical signs of CIA. • Norisoboldine regulates the balance of Th17/Treg cells in the intestinal lymph node. • Norisoboldine induces the migration of Treg cells from the gut to joint.

  19. Anti-colitis and -adhesion effects of daikenchuto via endogenous adrenomedullin enhancement in Crohn's disease mouse model.

    Science.gov (United States)

    Kono, Toru; Kaneko, Atsushi; Hira, Yoshiki; Suzuki, Tatsuya; Chisato, Naoyuki; Ohtake, Nobuhiro; Miura, Naoko; Watanabe, Tsuyoshi

    2010-06-01

    Adrenomedullin (ADM) is a member of the calcitonin family of regulatory peptides, and is reported to have anti-inflammatory effects in animal models of Crohn's disease (CD). We investigated the therapeutic effects of daikenchuto (DKT), an extracted Japanese herbal medicine, on the regulation of endogenous ADM in the gastrointestinal tract in a CD mouse model. Colitis was induced in mice by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS); afterwards, DKT was given orally. Colonic damage was assessed on day 3 by macroscopic and microscopic observation, enzyme immunoassays of proinflammatory cytokines in the colonic mucosa, and serum amyloid A (SAA), a hepatic acute-phase protein. To determine the involvement of ADM, an ADM antagonist was instilled intrarectally before DKT administration. The effect of DKT on ADM production by intestinal epithelial cells was evaluated by enzyme immunoassay and real-time PCR. DKT significantly attenuated mucosal damage and colonic inflammatory adhesions, and inhibited elevations of SAA in plasma and the proinflammatory cytokines TNFα and IFNγ in the colon. Small and large intestinal epithelial cells produced higher levels of ADM after DKT stimulation. A DKT-treated IEC-6 cell line also showed enhanced ADM production at protein and mRNA levels. Abolition of this effect by pretreatment with an ADM antagonist shows that DKT appears to exert its anti-colitis effect via up-regulation of endogenous ADM in the intestinal tract. DKT exerts beneficial effects in a CD mouse model through endogenous release and production of ADM. Endogenous ADM may be a therapeutic target for CD. Copyright © 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

  20. CEDAR counter (internal part)

    CERN Multimedia

    CERN PhotoLab

    1976-01-01

    Here on the mounting bench. The counter is a differential Cerenkov, corrected for chromaticity, able to differentiate pions from kaons up to 350 GeV. Counters of this type were used in all SPS hadron beams.