WorldWideScience

Sample records for lacking distinct cytokine

  1. T cell clones from Schistosoma haematobium infected and exposed individuals lacking distinct cytokine profiles for Th1/Th2 polarisation

    Directory of Open Access Journals (Sweden)

    Mduluza T

    2001-01-01

    Full Text Available T cell clones were derived from peripheral blood mononuclear cells of Schistosoma haematobium infected and uninfected individuals living in an endemic area. The clones were stimulated with S. haematobium worm and egg antigens and purified protein derivative. Attempts were made to classify the T cell clones according to production of the cytokines IL-4, IL-5 and IFN-gamma. All the T cell clones derived were observed to produce cytokines used as markers for the classification of Th1/Th2 subsets. However, the 'signature' cytokines marking each subset were produced at different levels. The classification depended on the dominating cytokine type, which was having either Th0/1 or Th0/2 subsets. The results indicated that no distinct cytokine profiles for polarisation of Th1/Th2 subsets were detected in these S. haematobium infected humans. The balance in the profiles of cytokines marking each subset were related to infection and re-infection status after treatment with praziquantel. In the present study, as judged by the changes in infection status with time, the T cell responses appeared to be less stable and more dynamic, suggesting that small quantitative changes in the balance of the cytokines response could result in either susceptibility or resistant to S. haematobium infection.

  2. Distinct Cytokine and Chemokine Profiles in Autism Spectrum Disorders

    Science.gov (United States)

    Han, Yvonne M. Y.; Cheung, Winnie K. Y.; Wong, Chun Kwok; Sze, Sophia L.; Cheng, Timmy W. S.; Yeung, Michael K.; Chan, Agnes S.

    2017-01-01

    Previous studies have shown that immunological factors are involved in the pathogenesis of autism spectrum disorders (ASDs). However, this research has been conducted almost exclusively in Western contexts, and only a handful of studies on immune measures have been conducted in Asian populations, such as Chinese populations. The present study examined whether immunological abnormalities are associated with cognitive deficits and problem behaviors in Chinese children with ASD and whether these children show different immunological profiles. Thirteen typically developing (TD) children and 22 children with ASD, aged 6–17 years, participated voluntarily in the study. Executive functions and short-term memory were measured using neuropsychological tests, and behavioral measures were assessed using parent ratings. The children were also assessed on immunological measures, specifically, the levels of cytokines and chemokines in the blood serum. Children with ASD showed greater deficits in cognitive functions, as well as altered levels of immunological measures, including CCL2, CCL5, and CXCL9 levels, compared to TD children, and the cognitive functions and associated behavioral deficits of children with ASD were significantly associated with different immunological measures. The children were further sub-classified into ASD with only autistic features (ASD-only) or ASD comorbid with attention deficit hyperactivity disorder (ASD + ADHD). The comorbidity results showed that there were no differences between the two groups of ASD children in any of the cognitive or behavioral measures. However, the results pertaining to immunological measures showed that the children with ASD-only and ASD + ADHD exhibited distinct cytokine and chemokine profiles and that abnormal immunologic function was associated with cognitive functions and inattention/hyperactivity symptoms. These results support the notion that altered immune functions may play a role in the selective

  3. Distinct First Trimester Cytokine Profiles for Gestational Hypertension and Preeclampsia.

    Science.gov (United States)

    Tangerås, Line H; Austdal, Marie; Skråstad, Ragnhild B; Salvesen, Kjell Å; Austgulen, Rigmor; Bathen, Tone F; Iversen, Ann-Charlotte

    2015-11-01

    Gestational hypertension and preeclampsia involve dysregulated maternal inflammatory responses to pregnancy, but whether such responses differ between the disorders has not been determined. We aimed to investigate disease-specific early pregnancy serum cytokine profiles of women subsequently developing gestational hypertension or preeclampsia for new insight into the underlying pathogeneses and differences between the disorders. The study cohort consisted of 548 pregnant Norwegian women who were either multiparous with previous gestational hypertension or preeclampsia or were nulliparous. Maternal sera at gestational weeks 11(0)-13(6) were assayed for 27 cytokines, C-reactive protein, total cholesterol, high-density lipoprotein, triglyceride, creatinine, calcium, uric acid, and placental growth factor. Compared with normotensive women, women with both hypertensive conditions presented an atherogenic lipid profile at early gestation, but only those later developing gestational hypertension had significantly higher serum levels of interleukin (IL)-5 and IL-12. Comparing the 2 hypertensive pregnancy disorders, women subsequently developing gestational hypertension had higher serum levels of IL-1β, IL-5, IL-7, IL-8, IL-13, basic fibroblast growth factor, and vascular endothelial growth factor than the women subsequently developing preeclampsia. This study identifies early pregnancy differences in serum cytokine profiles for gestational hypertension and preeclampsia. © 2015 American Heart Association, Inc.

  4. Distinct profiles of effector cytokines mark the different phases of Crohn's disease.

    Directory of Open Access Journals (Sweden)

    Francesca Zorzi

    Full Text Available OBJECTIVE: Crohn's Disease (CD-associated inflammation is supposed to be driven by T helper (Th1/Th17 cell-derived cytokines, even though there is evidence that the mucosal profile of cytokine may vary with the evolution of the disease. We aimed at comparing the pattern of effector cytokines in early and established lesions of CD. DESIGN: Mucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with (early lesions or without post-operative recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (established lesions. Inflammatory cell infiltrate was examined by immunofluorescence and cytokine expression was analysed by real-time PCR, flow-cytometry and ELISA. RESULTS: Before the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of T cells and macrophages, elevated levels of Th1-related cytokines and TNF-α and slightly increased IL-17A expression. Transition from this stage to endoscopic recurrence was marked by abundance of Th1 cytokines, marked increase in IL-17A, and induction of IL-6 and IL-23, two cytokines involved in the control of Th17 cell responses. In samples with established lesions, there was a mixed Th1/Th17 response with no TNF-α induction. Expression of IL-4 and IL-5 was up-regulated in both early and established lesions even though the fraction of IL-4-producing cells was lower than that of cells producing either interferon-γ or IL-17A. CONCLUSIONS: Distinct mucosal profiles of cytokines are produced during the different phases of CD. A better understanding of the cytokines temporally regulated in CD tissue could help optimize therapeutic interventions in CD.

  5. Aspergillus flavus induces granulomatous cerebral aspergillosis in mice with display of distinct cytokine profile.

    Science.gov (United States)

    Anand, R; Shankar, J; Tiwary, B N; Singh, A P

    2015-04-01

    Aspergillus flavus is one of the leading Aspergillus spp. resulting in invasive aspergillosis of central nervous system (CNS) in human beings. Immunological status in aspergillosis of central nervous system remains elusive in case of both immunocompetent and immunocompromised patients. Since cytokines are the major mediators of host response, evaluation of disease pathology along with cytokine profile in brain may provide snapshots of neuro-immunological response. An intravenous model of A. flavus infection was utilized to determine the pathogenicity of infection and cytokine profile in the brain of male BALB/c mice. Enumeration of colony forming units and histopathological analyses were performed on the brain tissue at distinct time periods. The kinetics of cytokines (TNF-α, IFN-γ, IL-12/IL-23p40, IL-6, IL-23, IL-17A and IL-4) was evaluated at 6, 12, 24, 48, 72 and 96h post infection (hPI) in brain homogenates using murine cytokine specific enzyme linked immunosorbent assay. Histological analysis exhibited the hyphae with leukocyte infiltrations leading to formation of granulomata along with ischemia and pyknosis of neurons in the brain of infected mice. Diseased mice displayed increased secretion of IFN-γ, IL-12p40 and IL-6 with a concomitant reduction in the secretion of Th2 cytokine IL-4, and Th17 promoting cytokine, IL-23 during the late phase of infection. A.flavus induced inflammatory granulomatous cerebral aspergillosis in mice, characterized by a marked increase in the Th1 cytokines and neurons undergoing necrosis. A marked increase in necrosis of neurons with concurrent inflammatory responses might have led to the host mortality during late phase of infection.

  6. Cytokines in chronic rheumatic diseases: is everything lack of homeostatic balance?

    Science.gov (United States)

    2009-01-01

    Biological systems have powerful inbuilt mechanisms of control intended to maintain homeostasis. Cytokines are no exception to this rule, and imbalance in cytokine activities may lead to inflammation with subsequent tissue and organ damage, altered function, and death. Balance is achieved through multiple, not mutually exclusive, mechanisms including the simultaneous production of agonist and antagonistic cytokines, expression of soluble receptors or membrane-bound nonsignaling receptors, priming and/or reprogramming of signaling, and uncoupling of ligand/receptor pairing from signal transduction. Insight into cytokine balance is leading to novel therapeutic approaches particularly in autoimmune conditions, which are intimately linked to a dysregulated cytokine production. PMID:19849823

  7. [An autopsy case of dementia lacking distinctive histology showing semantic dementia].

    Science.gov (United States)

    Ota, Satoru; Tsuchiya, Kuniaki; Anno, Midori; Akiyama, Haruhiko

    2005-03-01

    We report an autopsy case of dementia lacking distinctive histology (DLDH) showing semantic dementia. At age 47, a Japanese man developed aspontaneity, followed by semantic dementia a few months after the onset. Thereafter he developed disinhibition and the language disturbance, which progressed transcortical sensory aphasia and terminally mixed transcortical aphasia. At age 48, about 10 months after the disease onset, neurological examination revealed frontal signs and hyperreflexia in the four extremities and 4 months later, the patient presented with mild rigidity in the right upper and lower extremities. At age 49, 1 year and 8 months after the onset of the disease, he could not walk by himself. At age 50, 2 years and 8 months after the onset, he died of pneumonia. The brain weighed 1350 g. Macroscopically, atrophy of the frontal lobes and temporal lobes, predominant in the left, was evident. The caudate nucleus was severely atrophic, in addition to the depigmentation of the substantia nigra. Neuronal loss and astrocytosis was obvious in the cerebral cortex, prominently in the frontotemporal lobes, amygdala, caudate nucleus, putamen, pallidum, thalamus, and substantia nigra. In the caudate nucleus, prominent neuronal loss with fibrillary gliosis was obvious. Senile plaques, neurofibrillary tangles, Pick bodies, astrocytic plaques, and tufted astrocytes were not found by Gallyas and tau staining. Ubiquitin-immunoreactive intracytoplasmic inclusions were not encountered in the hippocampal dentate gyrus and superficial layers in the frontotemporal cortex. On the basis of meticulous perusal of the literature, we believe that our case is the first autopsy case of DLDH reported in Japan.

  8. Mastitis Pathogens with High Virulence in a Mouse Model Produce a Distinct Cytokine Profile In Vivo

    Science.gov (United States)

    Johnzon, Carl-Fredrik; Artursson, Karin; Söderlund, Robert; Guss, Bengt; Rönnberg, Elin; Pejler, Gunnar

    2016-01-01

    Mastitis is a serious medical condition of dairy cattle. Here, we evaluated whether the degree of virulence of mastitis pathogens in a mouse model can be linked to the inflammatory response that they provoke. Clinical isolates of Staphylococcus aureus (S. aureus) (strain 556 and 392) and Escherichia coli (E. coli) (676 and 127), and laboratory control strains [8325-4 (S. aureus) and MG1655 (E. coli)], were injected i.p. into mice, followed by the assessment of clinical scores and inflammatory parameters. As judged by clinical scoring, E. coli 127 exhibited the largest degree of virulence among the strains. All bacterial strains induced neutrophil recruitment. However, whereas E. coli 127 induced high peritoneal levels of CXCL1, G-CSF, and CCL2, strikingly lower levels of these were induced by the less virulent bacterial strains. High concentrations of these compounds were also seen in blood samples taken from animals infected with E. coli 127, suggesting systemic inflammation. Moreover, the levels of CXCL1 and G-CSF, both in the peritoneal fluid and in plasma, correlated with clinical score. Together, these findings suggest that highly virulent clinical mastitis isolates produce a distinct cytokine profile that shows a close correlation with the severity of the bacterial infection. PMID:27713743

  9. Distinct cytokine/chemokine network in semen and blood characterize different stages of HIV infection.

    Science.gov (United States)

    Vanpouille, Christophe; Introini, Andrea; Morris, Sheldon R; Margolis, Leonid; Daar, Eric S; Dube, Michael P; Little, Susan J; Smith, David M; Lisco, Andrea; Gianella, Sara

    2016-01-01

    The cytokine/chemokine network is used by the innate and adaptive immune system to orchestrate effective immune responses. Here, we describe the cross-sectional association between cytokine levels and stage of HIV infection to gain novel insights into HIV-1 immunopathogenesis and identify novel therapeutic targets. Concentrations of 31 cytokine/chemokines were retrospectively measured in blood and seminal plasma collected from 252 individuals enrolled in four well characterized cohorts: HIV-uninfected, untreated HIV-infected in early phase of infection, untreated HIV-infected in late phase of infection, and HIV-infected on antiretroviral therapy with undetectable HIV RNA levels in blood (<50 copies/ml). Cytokine/chemokine levels were measured by multiplex-bead array. Comparisons between groups were performed by Mann-Whitney U-test and P values were adjusted for multiple comparisons using the Benjamini-Hochberg method. Presence of HIV-infection skewed the cytokine/chemokine network towards a pro-inflammatory response in both blood and semen compared to HIV-uninfected controls. Such changes emerged within the first weeks of infection and were maintained thereafter: Among untreated HIV-infected individuals, none of the 31 measured cytokines were significantly different between early and later stages of infection. Suppression of plasma HIV RNA with ART did not result in normalization of the levels of pro-inflammatory cytokines in blood. In semen, several pro-inflammatory cytokines were even further upregulated in ART-treated compared with HIV-uninfected and HIV-untreated individuals. A profound disruption in the cytokine/chemokine network is evident in blood and semen from the earliest stage of HIV infection shortly after the first detection of systemic viremia. These changes are maintained throughout the chronic phase of the infection and do not normalize despite ART and suppression of plasma HIV RNA.

  10. Distinct chemokine receptor and cytokine expression profile in secondary progressive MS

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Sellebjerg, F

    2001-01-01

    Chemokines, small chemotactic cytokines, have been implicated in active relapsing-remitting MS (RRMS). However, the role of chemokines and chemokine receptors has not been specifically studied in secondary progressive MS (SPMS)....

  11. Distinct effects of calorie restriction on adipose tissue cytokine and angiogenesis profiles in obese and lean mice

    Directory of Open Access Journals (Sweden)

    Kurki Eveliina

    2012-06-01

    Full Text Available Abstract Background Obesity associates with low-grade inflammation and adipose tissue remodeling. Using sensitive high-throughput protein arrays we here investigated adipose tissue cytokine and angiogenesis-related protein profiles from obese and lean mice, and in particular, the influence of calorie restriction (CR. Methods Tissue samples from visceral fat were harvested from obese mice fed with a high-fat diet (60% of energy, lean controls receiving low-fat control diet as well as from obese and lean mice kept under CR (energy intake 70% of ad libitum intake for 50 days. Protein profiles were analyzed using mouse cytokine and angiogenesis protein array kits. Results In obese and lean mice, CR was associated with 11.3% and 15.6% reductions in body weight, as well as with 4.0% and 4.6% reductions in body fat percentage, respectively. Obesity induced adipose tissue cytokine expressions, the most highly upregulated cytokines being IL-1ra, IL-2, IL-16, MCP-1, MIG, RANTES, C5a, sICAM-1 and TIMP-1. CR increased sICAM-1 and TIMP-1 expression both in obese and lean mice. Overall, CR showed distinct effects on cytokine expressions; in obese mice CR largely decreased but in lean mice increased adipose tissue cytokine expressions. Obesity was also associated with increased expressions of angiogenesis-related proteins, in particular, angiogenin, endoglin, endostatin, endothelin-1, IGFBP-3, leptin, MMP-3, PAI-1, TIMP-4, CXCL16, platelet factor 4, DPPIV and coagulation factor III. CR increased endoglin, endostatin and platelet factor 4 expressions, and decreased IGFBP-3, NOV, MMP-9, CXCL16 and osteopontin expressions both in obese and lean mice. Interestingly, in obese mice, CR decreased leptin and TIMP-4 expressions, whereas in lean mice their expressions were increased. CR decreased MMP-3 and PAI-1 only in obese mice, whereas CR decreased FGF acidic, FGF basic and coagulation factor III, and increased angiogenin and DPPIV expression only in lean mice

  12. Distinct immunoregulatory cytokine pattern in Egyptian patients with occult Hepatitis C infection and unexplained persistently elevated liver transaminases

    Directory of Open Access Journals (Sweden)

    Yahia Z Gad

    2012-01-01

    Full Text Available Background/Aim: The immunopathogenesis of occult Hepatitis C virus (HCV infection is a matter of great controversy and has been suggested to involve a complex balance between cytokines with pro- and anti-inflammatory activity. This work aimed at studying the serum Th1 and Th2 cytokine production in patients with occult HCV infection. Materials and Methods: Serum levels of cytokines of Th1 (interleukin [IL]-2, INF-γ and Th2 (IL-4 were measured in 27 patients with occult HCV infection and 28 patients with chronic hepatitis C infection. Results: The levels of IL-2 and interferon-γ were highly significantly increased in patients with chronic HCV infection (P<0.001. IL-4 was highly significantly increased in occult HCV infection (P<0.001. Significant increases were noted in chronic HCV infection regarding bilirubin (P<0.001, ALT (P = 0.009, AST (P = 0.013, AFP (P<0.001, while serum albumin was significantly higher in occult HCV infection (P<0.001. Necroinflammation (P<0.001, fibrosis (P<0.001, and cirrhosis (P = 0.03 were significantly increased in chronic HCV infection. Conclusion: Our data revealed a high prevalence of occult HCV infection (25% in patients with unexplained persistently abnormal liver function test results. Those patients exhibited a distinct immunoregulatory cytokine pattern, favoring viral persistence and explaining the less aggressive course of this disease entity than chronic HCV infection.

  13. Soluble immune complexes shift the TLR-induced cytokine production of distinct polarized human macrophage subsets towards IL-10.

    Directory of Open Access Journals (Sweden)

    Carmen A Ambarus

    Full Text Available BACKGROUND: Costimulation of murine macrophages with immune complexes (ICs and TLR ligands leads to alternative activation. Studies on human myeloid cells, however, indicate that ICs induce an increased pro-inflammatory cytokine production. This study aimed to clarify the effect of ICs on the pro- versus anti-inflammatory profile of human polarized macrophages. MATERIALS AND METHODS: Monocytes isolated from peripheral blood of healthy donors were polarized for four days with IFN-γ, IL-4, IL-10, GM-CSF, M-CSF, or LPS, in the presence or absence of heat aggregated gamma-globulins (HAGGs. Phenotypic polarization markers were measured by flow cytometry. Polarized macrophages were stimulated with HAGGs or immobilized IgG alone or in combination with TLR ligands. TNF, IL-6, IL-10, IL-12, and IL-23 were measured by Luminex and/or RT-qPCR. RESULTS: HAGGs did not modulate the phenotypic polarization and the cytokine production of macrophages. However, HAGGs significantly altered the TLR-induced cytokine production of all polarized macrophage subsets, with the exception of MΦ(IL-4. In particular, HAGGs consistently enhanced the TLR-induced IL-10 production in both classically and alternatively polarized macrophages (M1 and M2. The effect of HAGGs on TNF and IL-6 production was less pronounced and depended on the polarization status, while IL-23p19 and IL-12p35 expression was not affected. In contrast with HAGGs, immobilized IgG induced a strong upregulation of not only IL-10, but also TNF and IL-6. CONCLUSION: HAGGs alone do not alter the phenotype and cytokine production of in vitro polarized human macrophages. In combination with TLR-ligands, however, HAGGs but not immobilized IgG shift the cytokine production of distinct macrophage subsets toward IL-10.

  14. Macrophages polarization is mediated by the combination of PRR ligands and distinct inflammatory cytokines.

    Science.gov (United States)

    Zhou, Lili; Cao, Xixi; Fang, Jie; Li, Yuhong; Fan, Mingwen

    2015-01-01

    Macrophages recognize microbes through Pattern Recognition Receptors (PRRs), and then release pro-inflammatory and anti-inflammatory cytokines. Recent studies have highlighted that collaboration between different PRRs. However, these studies have neglected the crosstalk between various PRRs on macrophages. In the present study, we investigated the interplay of nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) (NOD1, NOD2) and TLRs (TLR1, 2, 3, 4, 5, 6, 7, 8) in terms of macrophage activation, the expression and production of cytokines. The macrophages were stimulated with a single PRR ligand or a combination of TLR and NOD ligands. After 8 h of incubation, the mRNA expression of interleukin-1β (IL-1β), IL-4, IL-6, IL-10, IL-12p35, IL-12p40, IL-13, and interferon-γ (IFN-γ) was evaluated. The production of these cytokines was also measured. NOD2 synergized with TLR3 agonists on enhancement of IL-10 release. However, the combination of NOD1 with TLR3 ligands showed little effect on IL-10 production. Moreover, NOD2 inhibited the percentages of CD11b + F4/80 + cells activated by TLR3 agonist.

  15. Pancreatic β-cell death in response to pro-inflammatory cytokines is distinct from genuine apoptosis.

    Directory of Open Access Journals (Sweden)

    J Jason Collier

    Full Text Available A reduction in functional β-cell mass leads to both major forms of diabetes; pro-inflammatory cytokines, such as interleukin-1beta (IL-1β and gamma-interferon (γ-IFN, activate signaling pathways that direct pancreatic β-cell death and dysfunction. However, the molecular mechanism of β-cell death in this context is not well understood. In this report, we tested the hypothesis that individual cellular death pathways display characteristic phenotypes that allow them to be distinguished by the precise biochemical and metabolic responses that occur during stimulus-specific initiation. Using 832/13 and INS-1E rat insulinoma cells and isolated rat islets, we provide evidence that apoptosis is unlikely to be the primary pathway underlying β-cell death in response to IL-1β+γ-IFN. This conclusion was reached via the experimental results of several different interdisciplinary strategies, which included: 1 tandem mass spectrometry to delineate the metabolic differences between IL-1β+γ-IFN exposure versus apoptotic induction by camptothecin and 2 pharmacological and molecular interference with either NF-κB activity or apoptosome formation. These approaches provided clear distinctions in cell death pathways initiated by pro-inflammatory cytokines and bona fide inducers of apoptosis. Collectively, the results reported herein demonstrate that pancreatic β-cells undergo apoptosis in response to camptothecin or staurosporine, but not pro-inflammatory cytokines.

  16. Human decidual macrophages and NK cells differentially express Toll-like receptors and display distinct cytokine profiles upon TLR stimulation.

    Directory of Open Access Journals (Sweden)

    Marion eDuriez

    2014-07-01

    Full Text Available Maternofetal pathogen transmission is partially controlled at the level of the maternal uterine mucosa at the fetal implantation site (the decidua basalis, where maternal and fetal cells are in close contact. Toll-like receptors (TLRs may play an important role in initiating rapid immune responses against pathogens in the decidua basalis, however the tolerant microenvironment should be preserved in order to allow fetal development. Here we investigated the expression and functionality of TLRs expressed by decidual macrophages (dMs and NK cells (dNKs, the major decidual immune cell populations.We report for the first time that both human dMs and dNK cells express mRNAs encoding TLRs 1-9, albeit with a higher expression level in dMs. TLR2, TLR3 and TLR4 protein expression checked by flow cytometry was positive for both dMs and dNK cells. In vitro treatment of primary dMs and dNK cells with specific TLR2, TLR3, TLR4, TLR7/8 and TLR9 agonists enhanced their secretion of pro- and anti-inflammatory cytokines, as well as cytokines and chemokines involved in immune cell crosstalk. Only dNK cells released IFN-γ, whereas only dMs released IL-1β, IL-10 and IL-12. TLR9 activation of dMs resulted in a distinct pattern of cytokine expression compared to the other TLRs. The cytokine profiles expressed by dMs and dNK cells upon TLR activation are compatible with maintenance of the fetotolerant immune environment during initiation of immune responses to pathogens at the maternofetal interface.

  17. Melatonin and zinc treatment: distinctive modulation of cytokine production in chronic experimental Trypanosoma cruzi infection.

    Science.gov (United States)

    Brazão, Vânia; Del Vecchio Filipin, Marina; Santello, Fabricia Helena; Caetano, Leony Cristina; Abrahão, Ana Amélia Carraro; Toldo, Míriam Paula Alonso; do Prado, José Clóvis

    2011-12-01

    Melatonin by exhibiting antioxidant, anti-aging, and immunomodulatory properties favorably modulate the immune function, protecting the hosts from several infectious diseases. Zinc is an essential trace element important for the efficiency of the immune system in reason of its widespread role in the activity of enzymes, transcription factors and cytokines. The etiology of Chagas' disease, caused by a protozoan parasite Trypanosoma cruzi, has been the focus of considerable discussion, although chronic phase still remains not fully understood. This study showed that zinc and melatonin treatment did not affect the percentage of both CD4+ and CD8+ T lymphocytes subsets in chronically infected animals. Increased levels of IL-2 and IL-10, as well as, enhanced thymocyte proliferation in T. cruzi infected groups under zinc and melatonin therapy was observed as compared to untreated group. Conversely, during the chronic phase of infection, macrophages counts were reduced in melatonin and zinc-melatonin treated animals. The combined actions of zinc and melatonin have beneficial effects in counteracting parasite-induced immune dysregulation, protecting animals against the harmful actions of chronic T. cruzi infection. Furthermore, our results provide an experimental basis for further studies on the role of immunomodulatory therapies.

  18. Human leukocyte antigen-G expression in differentiated human airway epithelial cells: lack of modulation by Th2-associated cytokines

    Directory of Open Access Journals (Sweden)

    White Steven R

    2013-01-01

    Full Text Available Abstract Background Human leukocyte antigen (HLA-G is a nonclassical class I antigen with immunomodulatory roles including up-regulation of suppressor T regulatory lymphocytes. HLA-G was recently identified as an asthma susceptibility gene, and expression of a soluble isoform, HLA-G5, has been demonstrated in human airway epithelium. Increased presence of HLA-G5 has been demonstrated in bronchoalveolar lavage fluid recovered from patients with mild asthma; this suggests a role for this isoform in modulating airway inflammation though the mechanisms by which this occurs is unclear. Airway inflammation associated with Th2 cytokines such as IL-4 and IL-13 is a principal feature of asthma, but whether these cytokines elicit expression of HLA-G is not known. Methods We examined gene and protein expression of both soluble (G5 and membrane-bound (G1 HLA-G isoforms in primary differentiated human airway epithelial cells collected from normal lungs and grown in air-liquid interface culture. Cells were treated with up to 10 ng/ml of either IL-4, IL-5, or IL-13, or 100 ng/ml of the immunomodulatory cytokine IL-10, or 10,000 U/ml of the Th1-associated cytokine interferon-beta, for 24 hr, after which RNA was isolated for evaluation by quantitative PCR and protein was collected for Western blot analysis. Results HLA-G5 but not G1 was present in dAEC as demonstrated by quantitative PCR, western blot and confocal microscopy. Neither G5 nor G1 expression was increased by the Th2-associated cytokines IL-4, IL-5 or IL-13 over 24 hr, nor after treatment with IL-10, but was increased 4.5 ± 1.4 fold after treatment with 10,000 U/ml interferon-beta. Conclusions These data demonstrate the constitutive expression of a T lymphocyte regulatory molecule in differentiated human airway epithelial cells that is not modulated by Th2-associated cytokines.

  19. Altered Th17/Treg Ratio in Nasal Polyps With Distinct Cytokine Profile: Association With Patterns of Inflammation and Mucosal Remodeling.

    Science.gov (United States)

    Wu, Dawei; Wang, Jianting; Zhang, Min

    2016-03-01

    Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease that can be classified as eosinophilic or noneosinophilic. Nasal polyps can exhibit different types of mucosal inflammation and responses to treatment. Imbalanced ratios of T-helper 17(Th17) and regulatory T (Treg) cells may contribute to the pathogenesis of nasal polyps.This study assessed the frequency of Th17 and Treg cells and related cytokines in patients with nasal polyps and tested for associations with mucosal remodeling.Surgical samples from 12 controls and 33 CRSwNP patients were analyzed histopathologically. The frequency of Th17 and Treg cells in peripheral blood mononuclear cells (PBMCs) and tissues were determined using flow cytometry. Th17 and Treg cells-related cytokines in plasma were measured by Cytometric Bead Array (CBA) multiplex assays and enzyme-linked immunosorbent assays (ELISAs).Eosinophilic CRSwNP (ECRSwNP) patients exhibited robust eosinophilia, whereas non-ECRSwNP patients were characterized by neutrophilia. Compared with non-ECRSwNP, an increased Th17/Treg ratio in ECRSwNP was associated with a less increased frequency of Th17 cells and a more striking reduction of Treg cells. An altered Th17/Treg cell ratio was positively correlated with eosinophilic and neutrophilic infiltration, submucosal basement membrane thickness, and the degree of subepithelial collagen deposition. Compared with non-ECRSwNP, ECRSwNP had higher levels of IL-17A and IL-4, and lower levels of IL-10 and TGF-β1, whereas non-ECRSwNP showed higher levels of IFN-γ and IL-6.Th17/Treg cell imbalance in nasal polyps (both in tissues and PBMCs) with distinct cytokine profile may contribute to different inflammatory patterns (eosinophilic versus neutrophilic inflammation) and corresponding features of mucosal remodeling. Effective strategies can be designed to target a Th17/Treg imbalance to restore immune homeostasis in nasal polyps.

  20. The cytokines interleukin 27 and interferon-γ promote distinct Treg cell populations required to limit infection-induced pathology.

    Science.gov (United States)

    Hall, Aisling O'Hara; Beiting, Daniel P; Tato, Cristina; John, Beena; Oldenhove, Guillaume; Lombana, Claudia Gonzalez; Pritchard, Gretchen Harms; Silver, Jonathan S; Bouladoux, Nicolas; Stumhofer, Jason S; Harris, Tajie H; Grainger, John; Wojno, Elia D Tait; Wagage, Sagie; Roos, David S; Scott, Philip; Turka, Laurence A; Cherry, Sara; Reiner, Steven L; Cua, Daniel; Belkaid, Yasmine; Elloso, M Merle; Hunter, Christopher A

    2012-09-21

    Interferon-γ (IFN-γ) promotes a population of T-bet(+) CXCR3(+) regulatory T (Treg) cells that limit T helper 1 (Th1) cell-mediated pathology. Our studies demonstrate that interleukin-27 (IL-27) also promoted expression of T-bet and CXCR3 in Treg cells. During infection with Toxoplasma gondii, a similar population emerged that limited T cell responses and was dependent on IFN-γ in the periphery but on IL-27 at mucosal sites. Transfer of Treg cells ameliorated the infection-induced pathology observed in Il27(-/-) mice, and this was dependent on their ability to produce IL-10. Microarray analysis revealed that Treg cells exposed to either IFN-γ or IL-27 have distinct transcriptional profiles. Thus, IFN-γ and IL-27 have different roles in Treg cell biology and IL-27 is a key cytokine that promotes the development of Treg cells specialized to control Th1 cell-mediated immunity at local sites of inflammation.

  1. Inflammatory cytokines IL-1β and TNF-α regulate p75NTR expression in CNS neurons and astrocytes by distinct cell-type-specific signalling mechanisms

    Directory of Open Access Journals (Sweden)

    Wilma J Friedman

    2009-05-01

    Full Text Available The p75NTR (where NTR is neurotrophin receptor can mediate many distinct cellular functions, including cell survival and apoptosis, axonal growth and cell proliferation, depending on the cellular context. This multifunctional receptor is widely expressed in the CNS (central nervous system during development, but its expression is restricted in the adult brain. However, p75NTR is induced by a variety of pathophysiological insults, including seizures, lesions and degenerative disease. We have demonstrated previously that p75NTR is induced by seizures in neurons, where it induces apoptosis, and in astrocytes, where it may regulate proliferation. In the present study, we have investigated whether the inflammatory cytokines IL (interleukin-1β and TNF-α (tumour necrosis factor-α, that are commonly elevated in these pathological conditions, mediate the regulation of p75NTR in neurons and astrocytes. We have further analysed the signal transduction pathways by which these cytokines induce p75NTR expression in the different cell types, specifically investigating the roles of the NF-κB (nuclear factor κB and p38 MAPK (mitogen-activated protein kinase pathways. We have demonstrated that both cytokines regulate p75NTR expression; however, the mechanisms governing this regulation are cytokine- and cell-type specific. The distinct mechanisms of cytokine-mediated p75NTR regulation that we demonstrate in the present study may facilitate therapeutic intervention in regulation of this receptor in a cell-selective manner.

  2. Distinct cytokine release profiles from human endothelial and THP-1 macrophage-like cells exposed to different amphotericin B formulations.

    Science.gov (United States)

    Turtinen, Lloyd W; Bremer, Lindsay A; Prall, David N; Schwartzhoff, Jenifer; Hartsel, Scott C

    2005-01-01

    Amphotericin B(AmB) formulations, Fungizone, and Amphotec caused substantially greater proinflammatory cytokine release than AmBisome (L-AMB) and Abelcet in TPA differentiated THP-1 macrophages as determined by antibody based protein arrays. Lipopolysaccharide but not AmB induced significant pro-inflammatory cytokines in human endothelial cells.

  3. Morphologically Distinct Escherichia coli Bacteriophages Differ in Their Efficacy and Ability to Stimulate Cytokine Release In Vitro.

    Science.gov (United States)

    Khan Mirzaei, Mohammadali; Haileselassie, Yeneneh; Navis, Marit; Cooper, Callum; Sverremark-Ekström, Eva; Nilsson, Anders S

    2016-01-01

    Due to a global increase in the range and number of infections caused by multi-resistant bacteria, phage therapy is currently experiencing a resurgence of interest. However, there are a number of well-known concerns over the use of phages to treat bacterial infections. In order to address concerns over safety and the poorly understood pharmacokinetics of phages and their associated cocktails, immunological characterization is required. In the current investigation, the immunogenicity of four distinct phages (taken from the main families that comprise the Caudovirales order) and their interaction with donor derived peripheral blood mononuclear cells and immortalized cell lines (HT-29 and Caco-2 intestinal epithelial cells) were investigated using standard immunological techniques. When exposed to high phage concentrations (10(9) PFU/well), cytokine driven inflammatory responses were induced from all cell types. Although phages appeared to inhibit the growth of intestinal epithelial cell lines, they also appear to be non-cytotoxic. Despite co-incubation with different cell types, phages maintained a high killing efficiency, reducing extended-spectrum beta-lactamase-producing Escherichia coli numbers by 1-4 log10 compared to untreated controls. When provided with a suitable bacterial host, phages were also able to actively reproduce in the presence of human cells resulting in an approximately 2 log10 increase in phage titer compared to the initial inoculum. Through an increased understanding of the complex pharmacokinetics of phages, it may be possible to address some of the safety concerns surrounding phage preparations prior to creating new therapeutic strategies.

  4. Distinct differences in the responses of the human pancreatic β-cell line EndoC-βH1 and human islets to proinflammatory cytokines.

    Science.gov (United States)

    Oleson, Bryndon J; McGraw, Jennifer A; Broniowska, Katarzyna A; Annamalai, Mani; Chen, Jing; Bushkofsky, Justin R; Davis, Dawn B; Corbett, John A; Mathews, Clayton E

    2015-09-01

    While insulinoma cells have been developed and proven to be extremely useful in studies focused on mechanisms controlling β-cell function and viability, translating findings to human β-cells has proven difficult because of the limited access to human islets and the absence of suitable insulinoma cell lines of human origin. Recently, a human β-cell line, EndoC-βH1, has been derived from human fetal pancreatic buds. The purpose of this study was to determine whether human EndoC-βH1 cells respond to cytokines in a fashion comparable to human islets. Unlike most rodent-derived insulinoma cell lines that respond to cytokines in a manner consistent with rodent islets, EndoC-βH1 cells fail to respond to a combination of cytokines (IL-1, IFN-γ, and TNF) in a manner consistent with human islets. Nitric oxide, produced following inducible nitric oxide synthase (iNOS) expression, is a major mediator of cytokine-induced human islet cell damage. We show that EndoC-βH1 cells fail to express iNOS or produce nitric oxide in response to this combination of cytokines. Inhibitors of iNOS prevent cytokine-induced loss of human islet cell viability; however, they do not prevent cytokine-induced EndoC-βH1 cell death. Stressed human islets or human islets expressing heat shock protein 70 (HSP70) are resistant to cytokines, and, much like stressed human islets, EndoC-βH1 cells express HSP70 under basal conditions. Elevated basal expression of HSP70 in EndoC-βH1 cells is consistent with the lack of iNOS expression in response to cytokine treatment. While expressing HSP70, EndoC-βH1 cells fail to respond to endoplasmic reticulum stress activators, such as thapsigargin. These findings indicate that EndoC-βH1 cells do not faithfully recapitulate the response of human islets to cytokines. Therefore, caution should be exercised when making conclusions regarding the actions of cytokines on human islets when using this human-derived insulinoma cell line.

  5. Lack of Proinflammatory Cytokine Interleukin-6 or Tumor Necrosis Factor Receptor-1 Results in a Failure of the Innate Immune Response after Bacterial Meningitis

    Directory of Open Access Journals (Sweden)

    Lea-Jessica Albrecht

    2016-01-01

    Full Text Available The most frequent pathogen that causes bacterial meningitis is the Gram-positive bacterium Streptococcus pneumoniae. By entering the brain, host cells will be activated and proinflammatory cytokines like interleukin-6 (IL-6 and tumor necrosis factor-α (TNF-α are released. The goal of the current study was to examine the interaction between IL-6 and TNFR1 as receptor for TNF-α and the innate immune response in vivo in a model of Streptococcus pneumoniae-induced meningitis. For the experiments IL-6−/−, TNFR1−/−, and TNFR1-IL-6−/− KO mice were used. Our results revealed higher mortality rates and bacterial burden after infection in TNFR1−/−, IL-6−/−, and TNFR1-IL-6−/− mice and a decreased immune response including lower neutrophil infiltration in the meninges of TNFR1−/− and TNFR1-IL-6−/− mice in contrast to IL-6−/− and wild type mice. Furthermore, the increased mortality of TNFR1−/− and TNFR1-IL-6−/− mice correlated with decreased glial cell activation compared to IL-6−/− or wild type mice after pneumococcal meningitis. Altogether, the results show the importance of TNFR1 and IL-6 in the regulation of the innate immune response. The lack of TNFR1 and IL-6 results in higher mortality by weakened immune defence, whereas the lack of TNFR1 results in more severe impairment of the innate immune response than the lack of IL-6 alone.

  6. Cytokine production but lack of proliferation in peripheral blood mononuclear cells from chronic Chagas' disease cardiomyopathy patients in response to T. cruzi ribosomal P proteins.

    Directory of Open Access Journals (Sweden)

    Silvia A Longhi

    2014-06-01

    Full Text Available BACKGROUND: Trypanosoma cruzi ribosomal P proteins, P2β and P0, induce high levels of antibodies in patients with chronic Chagas' disease Cardiomyopathy (CCC. It is well known that these antibodies alter the beating rate of cardiomyocytes and provoke apoptosis by their interaction with β1-adrenergic and M2-muscarinic cardiac receptors. Based on these findings, we decided to study the cellular immune response to these proteins in CCC patients compared to non-infected individuals. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated proliferation, presence of surface activation markers and cytokine production in peripheral blood mononuclear cells (PBMC stimulated with P2β, the C-terminal portion of P0 (CP0 proteins and T. cruzi lysate from CCC patients predominantly infected with TcVI lineage. PBMC from CCC patients cultured with P2β or CP0 proteins, failed to proliferate and express CD25 and HLA-DR on T cell populations. However, multiplex cytokine assays showed that these antigens triggered higher secretion of IL-10, TNF-α and GM-CSF by PBMC as well as both CD4+ and CD8+ T cells subsets of CCC subjects. Upon T. cruzi lysate stimulation, PBMC from CCC patients not only proliferated but also became activated within the context of Th1 response. Interestingly, T. cruzi lysate was also able to induce the secretion of GM-CSF by CD4+ or CD8+ T cells. CONCLUSIONS/SIGNIFICANCE: Our results showed that although the lack of PBMC proliferation in CCC patients in response to ribosomal P proteins, the detection of IL-10, TNF-α and GM-CSF suggests that specific T cells could have both immunoregulatory and pro-inflammatory potential, which might modulate the immune response in Chagas' disease. Furthermore, it was possible to demonstrate for the first time that GM-CSF was produced by PBMC of CCC patients in response not only to recombinant ribosomal P proteins but also to parasite lysate, suggesting the value of this cytokine to evaluate T cells responses in T

  7. First in-depth analysis of the novel Th2-type cytokines in salmonid fish reveals distinct patterns of expression and modulation but overlapping bioactivities

    Science.gov (United States)

    Wang, Tiehui; Johansson, Petronella; Abós, Beatriz; Holt, Amy; Tafalla, Carolina; Jiang, Youshen; Wang, Alex; Xu, Qiaoqing; Qi, Zhitao; Huang, Wenshu; Costa, Maria M.; Diaz-Rosales, Patricia; Holland, Jason W.; Secombes, Christopher J.

    2016-01-01

    IL-4 and IL-13 are closely related canonical type-2 cytokines in mammals and have overlapping bioactivities via shared receptors. They are frequently activated together as part of the same immune response and are the signature cytokines produced by T-helper (Th)2 cells and type-2 innate lymphoid cells (ILC2), mediating immunity against extracellular pathogens. Little is known about the origin of type-2 responses, and whether they were an essential component of the early adaptive immune system that gave a fitness advantage by limiting collateral damage caused by metazoan parasites. Two evolutionary related type-2 cytokines, IL-4/13A and IL-4/13B, have been identified recently in several teleost fish that likely arose by duplication of an ancestral IL-4/13 gene as a consequence of a whole genome duplication event that occurred at the base of this lineage. However, studies of their comparative expression levels are largely missing and bioactivity analysis has been limited to IL-4/13A in zebrafish. Through interrogation of the recently released salmonid genomes, species in which an additional whole genome duplication event has occurred, four genomic IL-4/13 loci have been identified leading to the cloning of three active genes, IL-4/13A, IL-4/13B1 and IL-4/13B2, in both rainbow trout and Atlantic salmon. Comparative expression analysis by real-time PCR in rainbow trout revealed that the IL-4/13A expression is broad and high constitutively but less responsive to pathogen-associated molecular patterns (PAMPs) and pathogen challenge. In contrast, the expression of IL-4/13B1 and IL-4/13B2 is low constitutively but is highly induced by viral haemorrhagic septicaemia virus (VHSH) infection and during proliferative kidney disease (PKD) in vivo, and by formalin-killed bacteria, PAMPs, the T cell mitogen PHA, and the T-cell cytokines IL-2 and IL-21 in vitro. Moreover, bioactive recombinant cytokines of both IL-4/13A and B were produced and found to have shared but also distinct

  8. Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis.

    NARCIS (Netherlands)

    Bon, L. van; Popa, C.; Huibens, R.J.F.; Vonk, M.C.; York, M.; Simms, R.; Hesselstrand, R.; Wuttge, D.M.; Lafyatis, R.; Radstake, T.R.D.J.

    2010-01-01

    BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease and accumulating evidence suggests a role for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). OBJECTIVE: To map TLR-mediated cytokine responses of DCs from patients with SSc. METHODS: 45 patients with SSc were inclu

  9. Suppressor of Cytokine Signaling (SOCS 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1.

    Directory of Open Access Journals (Sweden)

    Edmond M Linossi

    Full Text Available Suppressor of Cytokine Signaling (SOCS5 is thought to act as a tumour suppressor through negative regulation of JAK/STAT and epidermal growth factor (EGF signaling. However, the mechanism/s by which SOCS5 acts on these two distinct pathways is unclear. We show for the first time that SOCS5 can interact directly with JAK via a unique, conserved region in its N-terminus, which we have termed the JAK interaction region (JIR. Co-expression of SOCS5 was able to specifically reduce JAK1 and JAK2 (but not JAK3 or TYK2 autophosphorylation and this function required both the conserved JIR and additional sequences within the long SOCS5 N-terminal region. We further demonstrate that SOCS5 can directly inhibit JAK1 kinase activity, although its mechanism of action appears distinct from that of SOCS1 and SOCS3. In addition, we identify phosphoTyr317 in Shc-1 as a high-affinity substrate for the SOCS5-SH2 domain and suggest that SOCS5 may negatively regulate EGF and growth factor-driven Shc-1 signaling by binding to this site. These findings suggest that different domains in SOCS5 contribute to two distinct mechanisms for regulation of cytokine and growth factor signaling.

  10. Chronic hepatitis C and persistent occult hepatitis C virus infection are characterized by distinct immune cell cytokine expression profiles.

    Science.gov (United States)

    Pham, T N Q; Mercer, S E; Michalak, T I

    2009-08-01

    Hepatitis C virus (HCV) replicates in immune cells in both chronic hepatitis C (CHC) and occult HCV infection, but the extent of virus replication in this compartment in these opposing infection forms varies greatly. It was unknown whether this could be linked to HCV genotype or to differences in host gene expression shaping the immune response, and whether HCV replication in immune cells is sensitive to endogenous antiviral cytokines. In this study, we uncovered that significantly greater HCV load in peripheral blood mononuclear cells (PBMC), but not in plasma, coincided with HCV genotypes 2 and 3 in CHC, but with genotype 1 in residual occult infection after clinical resolution of hepatitis C. Moreover, PBMC from individuals with occult infection transcribed significantly greater levels of IFN-alpha, IFN-gamma and TNF-alpha, but less interleukin (IL)-10 than those from CHC. In CHC, PBMC with low HCV load expressed significantly more IFN-gamma but less IL-12 than did cells with high virus content. In occult infection, HCV RNA detection in PBMC was associated with much lower IFN-alpha and IL-12 expression. Further, HCV replication in T lymphocytes could be completely eliminated by activation of endogenous IFN-gamma in CHC, but of IFN-alpha in occult infection. In conclusion, CHC and persistent occult HCV infection are characterized by clearly different profiles of antiviral cytokine response in circulating immune cells which are also different from those of healthy individuals. Higher expression of IL-10, combined with lower transcription of IFN-alpha, IFN-gamma and TNF-alpha, is associated with a more robust HCV replication in immune cells.

  11. Neonatal Plasma Polarizes TLR4-Mediated Cytokine Responses towards Low IL-12p70 and High IL-10 Production via Distinct Factors

    Science.gov (United States)

    Belderbos, Mirjam E.; Levy, Ofer; Stalpers, Femke; Kimpen, Jan L.; Meyaard, Linde; Bont, Louis

    2012-01-01

    Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR) responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs) produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4-mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88-independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP) or soluble CD14 (sCD14). The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4-mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection. PMID:22442690

  12. Neonatal plasma polarizes TLR4-mediated cytokine responses towards low IL-12p70 and high IL-10 production via distinct factors.

    Directory of Open Access Journals (Sweden)

    Mirjam E Belderbos

    Full Text Available Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4-mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88-independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP or soluble CD14 (sCD14. The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4-mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection.

  13. Unique cytokine secretion profile in children with both type I diabetes and asthma distinct from that of solely diabetic or asthmatic children.

    Science.gov (United States)

    Kainonen, Essi; Rautava, Samuli; Korkeamäki, Mika; Isolauri, Erika

    2006-05-01

    Asthma and type I diabetes are major causes of chronic illness in childhood which, according to the current paradigm, have mutually antagonistic immunopathologies. Nonetheless, the disorders appear to preferably coexist both on population and individual levels. To assess whether children with asthma and type I diabetes might have a common immunoregulatory defect. The spontaneous and anti-CD3+ anti-CD28-stimulated cytokine production patterns by peripheral blood mononuclear cells of 13 children with both asthma and diabetes, nine children with diabetes, 11 children with asthma and nine healthy children were assessed using cytometric bead assay. The spontaneous production of IFN-gamma, TNF-alpha and IL-10 by mononuclear cells in children with both asthma and diabetes was elevated compared to the other study groups (p=0.02, p=0.001 and p=0.04, respectively). Stimulation in vitro increased IL-10 secretion in solely diabetic (p=0.008), asthmatic (p=0.008) and healthy children (p=0.01), but not in children with both diseases (p=0.22). Children suffering from both diabetes and asthma display a unique cytokine secretion pattern, distinct from those of solely diabetic, asthmatic and healthy children. In particular, these children appear to have a defect in regulation of IL-10 secretion.

  14. Mx1 GTPase accumulates in distinct nuclear domains and inhibits influenza A virus in cells that lack promyelocytic leukaemia protein nuclear bodies.

    Science.gov (United States)

    Engelhardt, Othmar G; Sirma, Hüseyin; Pandolfi, Pier-Paolo; Haller, Otto

    2004-08-01

    The interferon-induced murine Mx1 GTPase is a nuclear protein. It specifically inhibits influenza A viruses at the step of primary transcription, a process known to occur in the nucleus of infected cells. However, the exact mechanism of inhibition is still poorly understood. The Mx1 GTPase has previously been shown to accumulate in distinct nuclear dots that are spatially associated with promyelocytic leukaemia protein (PML) nuclear bodies (NBs), but the significance of this association is not known. Here it is reported that, in cells lacking PML and, as a consequence, PML NBs, Mx1 still formed nuclear dots. These dots were indistinguishable from the dots observed in wild-type cells, indicating that intact PML NBs are not required for Mx1 dot formation. Furthermore, Mx1 retained its antiviral activity against influenza A virus in these PML-deficient cells, which were fully permissive for influenza A virus. Nuclear Mx proteins from other species showed a similar subnuclear distribution. This was also the case for the human MxA GTPase when this otherwise cytoplasmic protein was translocated into the nucleus by virtue of a foreign nuclear localization signal. Human MxA and mouse Mx1 do not interact or form heterooligomers. Yet, they co-localized to a large degree when co-expressed in the nucleus. Taken together, these findings suggest that Mx1 dots represent distinct nuclear domains ('Mx nuclear domains') that are frequently associated with, but functionally independent of, PML NBs.

  15. Multilocus sequence typing reveals a lack of diversity among Escherichia coli O157:H7 isolates that are distinct by pulsed-field gel electrophoresis.

    Science.gov (United States)

    Noller, Anna C; McEllistrem, M Catherine; Stine, O Colin; Morris, J Glenn; Boxrud, David J; Dixon, Bruce; Harrison, Lee H

    2003-02-01

    Escherichia coli O157:H7 is a major cause of foodborne illness in the United States. Pulsed-field gel electrophoresis (PFGE) is the molecular epidemiologic method mostly commonly used to identify food-borne outbreaks. Although PFGE is a powerful epidemiologic tool, it has disadvantages that make a DNA sequence-based approach potentially attractive. Multilocus sequence typing (MLST) analyzes the internal fragments of housekeeping genes to establish genetic relatedness between isolates. We sequenced selected portions of seven housekeeping genes and two membrane protein genes (ompA and espA) of 77 isolates that were diverse by PFGE to determine whether there was sufficient sequence variation to be useful as an epidemiologic tool. There was no DNA sequence diversity in the sequenced portions of the seven housekeeping genes and espA. For ompA, all but five isolates had sequence identical to that of the reference strains. E. coli O157:H7 has a striking lack of genetic diversity in the genes we explored, even among isolates that are clearly distinct by PFGE. Other approaches to identify improved molecular subtyping methods for E. coli 0157:H7 are needed.

  16. Insights into cytokine-receptor interactions from cytokine engineering.

    Science.gov (United States)

    Spangler, Jamie B; Moraga, Ignacio; Mendoza, Juan L; Garcia, K Christopher

    2015-01-01

    Cytokines exert a vast array of immunoregulatory actions critical to human biology and disease. However, the desired immunotherapeutic effects of native cytokines are often mitigated by toxicity or lack of efficacy, either of which results from cytokine receptor pleiotropy and/or undesired activation of off-target cells. As our understanding of the structural principles of cytokine-receptor interactions has advanced, mechanism-based manipulation of cytokine signaling through protein engineering has become an increasingly feasible and powerful approach. Modified cytokines, both agonists and antagonists, have been engineered with narrowed target cell specificities, and they have also yielded important mechanistic insights into cytokine biology and signaling. Here we review the theory and practice of cytokine engineering and rationalize the mechanisms of several engineered cytokines in the context of structure. We discuss specific examples of how structure-based cytokine engineering has opened new opportunities for cytokines as drugs, with a focus on the immunotherapeutic cytokines interferon, interleukin-2, and interleukin-4.

  17. ZnT8-Specific CD4+ T cells display distinct cytokine expression profiles between type 1 diabetes patients and healthy adults.

    Directory of Open Access Journals (Sweden)

    Daisuke Chujo

    Full Text Available Determination of antigen-specific T cell repertoires in human blood has been a challenge. Here, we show a novel integrated approach that permits determination of multiple parameters of antigen-specific T cell repertoires. The approach consists of two assays: the Direct assay and the Cytokine-driven assay. Briefly, human PBMCs are first stimulated with overlapping peptides encoding a given antigen for 48 hours to measure cytokine secretion (Direct assay. Peptide-reactive T cells are further expanded by IL-2 for 5 days; and after overnight starvation, expanded cells are stimulated with the same peptides from the initial culture to analyze cytokine secretion (Cytokine-driven assay. We first applied this integrated approach to determine the type of islet-antigen-specific T cells in healthy adults. Out of ten donors, the Direct assay identified GAD65-specific CD4(+ T cells in three adults and zinc transporter 8 (ZnT8-specific CD4(+ T cells in five adults. The intracytoplasmic cytokine staining assay showed that these islet-antigen-specific CD4(+ T cells belonged to the CD45RO(+ memory compartment. The Cytokine-driven assay further revealed that islet-antigen-specific CD4(+ T cells in healthy adults were capable of secreting various types of cytokines including type 1 and type 2 cytokines as well as IL-10. We next applied our integrated assay to determine whether the type of ZnT8-specific CD4(+ T cells is different between Type 1 diabetes patients and age/gender/HLA-matched healthy adults. We found that ZnT8-specific CD4(+ T cells were skewed towards Th1 cells in T1D patients, while Th2 and IL-10-producing cells were prevalent in healthy adults. In conclusion, the Direct assay and the Cytokine-driven assay complement each other, and the combination of the two assays provides information of antigen-specific T cell repertoires on the breadth, type, and avidity. This strategy is applicable to determine the differences in the quality of antigen-specific T

  18. In Vitro Endothelial Cell Proliferation Assay Reveals Distinct Levels of Proangiogenic Cytokines Characterizing Sera of Healthy Subjects and of Patients with Heart Failure

    Directory of Open Access Journals (Sweden)

    Rebecca Voltan

    2014-01-01

    Full Text Available Although myocardial angiogenesis is thought to play an important role in heart failure (HF, the involvement of circulating proinflammatory and proangiogenic cytokines in the pathogenesis and/or prognosis of HF has not been deeply investigated. By using a highly standardized proliferation assay with human endothelial cells, we first demonstrated that sera from older (mean age 52±7.6 years; n=46 healthy donors promoted endothelial cell proliferation to a significantly higher extent compared to sera obtained from younger healthy donors (mean age 29±8.6 years; n=20. The promotion of endothelial cell proliferation was accompanied by high serum levels of several proangiogenic cytokines. When we assessed endothelial cell proliferation in response to HF patients’ sera, we observed that a subset of sera (n=11 promoted cell proliferation to a significantly lesser extent compared to the majority of sera (n=18. Also, in this case, the difference between the patient groups in the ability to induce endothelial cell proliferation correlated to significant (P<0.05 differences in serum proangiogenic cytokine levels. Unexpectedly, HF patients associated to the highest endothelial proliferation index showed the worst prognosis as evaluated in terms of subsequent cardiovascular events in the follow-up, suggesting that high levels of circulating proangiogenic cytokines might be related to a worse prognosis.

  19. MICA Gene Deletion in 3411 DNA Samples from Five Distinct Populations in Mainland China and Lack of Association with Nasopharyngeal Carcinoma (NPC) in a Southern Chinese Han population.

    Science.gov (United States)

    Wang, WenYi; Tian, Wei; Zhu, FaMing; Li, LiXin; Cai, JinHong; Wang, Fan; Liu, KangLong; Jin, HeKun; Wang, JunLong

    2016-11-01

    Deletion of major histocompatibility complex class I chain-related genes A (MICA*Del) was investigated in 3,411 DNA samples from two southern Chinese Han populations (Hunan Han, HNH; Guangdong Han, GDH), two northern Chinese populations (Inner Mongolia Han, IMH; Inner Mongolia Mongol, IMM) and one southeastern Chinese Han population (Fujian Han, FJH) using an in-house polymerase chain reaction-sequence specific priming (PCR-SSP) assay, which enables direct discrimination between heterozygote and homozygote for MICA*Del. MICA*Del showed a frequency ranging from 0.8% in FJH to 5.7% in IMM (Pcorrected populations. In contrast to the association reported recently in a Taiwan Chinese population and a Malaysian Chinese cohort, MICA*Del distribution did not differ between 1,120 patients with nasopharyngeal carcinoma (NPC) and 1,483 normal controls in the HNH population (1.03% in NPC cases vs 1.18% in the controls, OR (95% CI) = 0.87 (0.51-1.47), p = 0.69). Further gender-stratified analysis also failed to disclose any male-specific association reported in a Taiwan Chinese population. Multi-locus typing of the 94 samples carrying MICA*Del revealed two new haplotypes, HLA-A*11:01-B*13:01-MICA*Del-MICB*009N-DRB1*04:06 and HLA-B*35:01-MICA*Del-MICB*009N-DRB1*15:01, in addition to HLA-B*48-MICA*Del. Unexpectedly, two samples with MICA*Del in the HNH population were each consistently found to have two distinct MICA alleles, indicating the existence of two MICA gene copies on certain HLA haplotypes. Based on the results from a sizeable case-control study, our data suggest that there is no association between MICA*Del and NPC in the southern Chinese Han population.

  20. T-cell-rich large B-cell lymphoma. A study of 30 cases, supporting its histologic heterogeneity and lack of clinical distinctiveness.

    Science.gov (United States)

    Krishnan, J; Wallberg, K; Frizzera, G

    1994-05-01

    To determine whether correlations existed between morphologic and immunophenotypic findings and clinical characteristics, 30 cases of T-cell-rich large B-cell lymphomas (TBL) were evaluated by histopathology, immunostaining, and polymerase chain reaction on paraffin-embedded material. All were characterized by a polymorphic cell composition, including a variable mixture of small and large lymphoid cells and reactive cell. Most cases (87%) fitted into one of three main histologic types of non-Hodgkin's lymphoma (diffuse, mixed cell; diffuse, large cell; follicular and diffuse, mixed cell), and one group of eight cases had the prototypic features described by Ramsay et al. (17). All cases showed a component of large CD20(L26)+ MB2+ B cells in a predominant back-ground of reactive T cells (> 50% of the total lymphoid forms). Clonality was demonstrated by light chain restriction in 67% of cases and by rearrangement of the immunoglobulin heavy chain gene and bcl-2 gene in 64% and 28% of cases, respectively. The patients were predominantly men (70%), ages 18-83 years (median of 62.5), and were initially seen predominantly with nodal disease (and extranodal involvement in 20%) at advanced stages (III-IV: 77%). Treatment was mostly aggressive chemotherapy, and the outcomes were favorable (84% alive and well). These features are not distinctive as compared with those of typical large-cell lymphoma, nor did subgroups within the series (prototypic cases versus others; cases with less [ 70%] T-cell infiltration) significantly differ in clinical presentation or outcome. Thus, this study confirms that TBL, while useful as a diagnostic variant to be distinguished from both peripheral T-cell lymphoma and Hodgkin's disease, is a heterogeneous assortment of diverse histopathologic categories rather than a clinicopathologic entity. The term "T-cell rich" might, however, be usefully retained as a morphologic specification to be added to recognized histologic categories of lymphoma.

  1. Coordinate cytokine regulatory sequences

    Science.gov (United States)

    Frazer, Kelly A.; Rubin, Edward M.; Loots, Gabriela G.

    2005-05-10

    The present invention provides CNS sequences that regulate the cytokine gene expression, expression cassettes and vectors comprising or lacking the CNS sequences, host cells and non-human transgenic animals comprising the CNS sequences or lacking the CNS sequences. The present invention also provides methods for identifying compounds that modulate the functions of CNS sequences as well as methods for diagnosing defects in the CNS sequences of patients.

  2. Cytokines and Blastocyst Hatching.

    Science.gov (United States)

    Seshagiri, Polani B; Vani, Venkatappa; Madhulika, Pathak

    2016-03-01

    Blastocyst implantation into the uterine endometrium establishes early pregnancy. This event is regulated by blastocyst- and/or endometrium-derived molecular factors which include hormones, growth factors, cell adhesion molecules, cytokines and proteases. Their coordinated expression and function are critical for a viable pregnancy. A rate-limiting event that immediately precedes implantation is the hatching of blastocyst. Ironically, blastocyst hatching is tacitly linked to peri-implantation events, although it is a distinct developmental phenomenon. The exact molecular network regulating hatching is still unclear. A number of implantation-associated molecular factors are expressed in the pre-implanting blastocyst. Among others, cytokines, expressed by peri-implantation blastocysts, are thought to be important for hatching, making blastocysts implantation competent. Pro-inflammatory (IL-6, LIF, GM-CSF) and anti-inflammatory (IL-11, CSF-1) cytokines improve hatching rates; they modulate proteases (MMPs, tPAs, cathepsins and ISP1). However, functional involvement of cytokines and their specific mediation of hatching-associated proteases are unclear. There is a need to understand mechanistic roles of cytokines and proteases in blastocyst hatching. This review will assess the available knowledge on blastocyst-derived pro-inflammatory and anti-inflammatory cytokines and their role in potentially regulating blastocyst hatching. They have implications in our understanding of early embryonic loss and infertility in mammals, including humans.

  3. Cytokine-Leukotriene Receptor Interactions

    Directory of Open Access Journals (Sweden)

    Marek Rola-Pleszczynski

    2007-01-01

    Full Text Available Biochemical and pharmacological studies have identified the structure of leukotrienes, the pathways that lead to their synthesis, and the signaling events they trigger when they interact with their cognate receptors. A privileged interaction exists between these lipid mediators and another group of molecules essential for inflammation and immune modulation, namely, cytokines. Whereas leukotrienes can trigger the synthesis and release of selected cytokines in distinct cell populations, many cytokines can affect cellular responsiveness to leukotrienes by modulating leukotriene receptor expression. As we progressively begin to unravel these complex interactions, new areas of cell-cell communication and eventual therapeutic interventions will emerge.

  4. The International Cytokine Conference (11th) Held in Dublin (Ireland) on September 20-24 2003 (European Cytokine Network, Volume 14, Number 3, September 2003)

    Science.gov (United States)

    2003-09-01

    a submucosal granu - Plasmacytoid dendritic cells constitute a distinct subset of dendritic locytic inflammation. By 3 months of age mucinous...role in eosinophil activation and migration into areas of inflammation in dis- The memory T-cell derived cytokine IL-17 is described to share its eases...classical eosinophils , IgG sub- I class switching and IgE), leading to the hypothesis that chickens lack, Recent evidence suggests that, in addition to

  5. Vasculogenic Cytokines in Wound Healing

    Directory of Open Access Journals (Sweden)

    Victor W. Wong

    2013-01-01

    Full Text Available Chronic wounds represent a growing healthcare burden that particularly afflicts aged, diabetic, vasculopathic, and obese patients. Studies have shown that nonhealing wounds are characterized by dysregulated cytokine networks that impair blood vessel formation. Two distinct forms of neovascularization have been described: vasculogenesis (driven by bone-marrow-derived circulating endothelial progenitor cells and angiogenesis (local endothelial cell sprouting from existing vasculature. Researchers have traditionally focused on angiogenesis but defects in vasculogenesis are increasingly recognized to impact diseases including wound healing. A more comprehensive understanding of vasculogenic cytokine networks may facilitate the development of novel strategies to treat recalcitrant wounds. Further, the clinical success of endothelial progenitor cell-based therapies will depend not only on the delivery of the cells themselves but also on the appropriate cytokine milieu to promote tissue regeneration. This paper will highlight major cytokines involved in vasculogenesis within the context of cutaneous wound healing.

  6. [Cytokines in bone diseases. What is cytokine?].

    Science.gov (United States)

    Murakami, Yousuke; Kohsaka, Hitoshi

    2010-10-01

    Cytokines have an essential role for cell-cell communication. They can regulate cell proliferation, differentiation, survival, and function. Interaction of cell surface receptor with cytokines is necessary for control of physiological responses. Activation of cytokine receptors transduces specific signal in the receptor-expressing cells, resulting that cytokines can regulate specific cell population. Thus, cytokines contribute directly or indirectly to morphogenesis, host defense and immune response, play critical roles for homeostasis and development.

  7. 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.

  8. Cytokines in Drosophila immunity.

    Science.gov (United States)

    Vanha-Aho, Leena-Maija; Valanne, Susanna; Rämet, Mika

    2016-02-01

    Cytokines are a large and diverse group of small proteins that can affect many biological processes, but most commonly cytokines are known as mediators of the immune response. In the event of an infection, cytokines are produced in response to an immune stimulus, and they function as key regulators of the immune response. Cytokines come in many shapes and sizes, and although they vary greatly in structure, their functions have been well conserved in evolution. The immune signaling pathways that respond to cytokines are remarkably conserved from fly to man. Therefore, Drosophila melanogaster, provides an excellent platform for studying the biology and function of cytokines. In this review, we will describe the cytokines and cytokine-like molecules found in the fly and discuss their roles in host immunity.

  9. Cytokines in bipolar disorder

    DEFF Research Database (Denmark)

    Munkholm, Klaus; Vinberg, Maj; Vedel Kessing, Lars

    2012-01-01

    and 767 healthy controls, evaluating 15 different cytokines-, cytokine receptors- or cytokine antagonists. The levels of tumor necrosis factor-α (TNF-α), the soluble tumor necrosis factor receptor type 1 (sTNF-R1) and the soluble inlerleukin-2 receptor (sIL-2R) were elevated in manic patients compared...

  10. Recursive Distinctioning

    CERN Document Server

    Isaacson, Joel

    2016-01-01

    Recursive distinctioning (RD) is a name coined by Joel Isaacson in his original patent document describing how fundamental patterns of process arise from the systematic application of operations of distinction and description upon themselves. Recursive distinctioning means just what it says. A pattern of distinctions is given in a space based on a graphical structure (such as a line of print or a planar lattice or given graph). Each node of the graph is occupied by a letter from some arbitrary alphabet. A specialized alphabet is given that can indicate distinctions about neighbors of a given node. The neighbors of a node are all nodes that are connected to the given node by edges in the graph. The letters in the specialized alphabet (call it SA) are used to describe the states of the letters in the given graph and at each stage in the recursion, letters in SA are written at all nodes in the graph, describing its previous state. The recursive structure that results from the iteration of descriptions is called ...

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

    Directory of Open Access Journals (Sweden)

    Anette Holck Draborg

    2016-01-01

    Full Text Available 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 EBV-directed T-cell response. The concentrations of 14 cytokines (IL2, IL4, IL5, IL6, IL10, IL12, IL17, IL18, IL1β, IFNγ, TNFα, TNFβ, TGFβ, and GM-CSF were quantified upon stimulation of whole blood with latent state antigen EBNA1, lytic cycle antigen EBV-EA/D, and the superantigen SEB. To avoid results affected by lack of lymphocytes, we focused on SLE patients with normal levels. Decreased induction of IL12, IFNγ, IL17, and IL6 upon EBNA1 stimulation and that of IFNγ, IL6, TNFβ, IL1β, and GM-CSF upon EBV-EA/D stimulation were detected in SLE patients compared to HCs. IFNγ responses, especially, were shown to be reduced. Induction of several cytokines was furthermore impaired in SLE patients upon SEB stimulation, but no difference was observed in basic levels. Results substantiate the previously proposed impaired regulation of the immune response against latent and lytic cycle EBV infection in SLE patients without lymphopenia. Furthermore, results indicate general dysfunction of leukocytes and their cytokine regulations in SLE patients.

  12. Eosinophil secretion of granule-derived cytokines

    Directory of Open Access Journals (Sweden)

    Lisa A Spencer

    2014-10-01

    Full Text Available Eosinophils are tissue-dwelling leukocytes, present in the thymus, and gastrointestinal and genitourinary tracts of healthy individuals at baseline, and recruited, often in large numbers, to allergic inflammatory foci and sites of active tissue repair. The biological significance of eosinophils is vast and varied. In health, eosinophils support uterine and mammary gland development, and maintain bone marrow plasma cells and adipose tissue alternatively activated macrophages, while in response to tissue insult eosinophils function as inflammatory effector cells, and, in the wake of an inflammatory response, promote tissue regeneration and wound healing. One common mechanism driving many of the diverse eosinophil functions is the regulated and differential secretion of a vast array of eosinophil-derived cytokines. Eosinophils are distinguished from most other leukocytes in that many, if not all, of the over three dozen eosinophil-derived cytokines are pre-synthesized and stored within intracellular granules, poised for very rapid, stimulus-induced secretion. Eosinophils engaged in cytokine secretion in situ utilize distinct pathways of cytokine release that include: classical exocytosis, whereby granules themselves fuse with the plasma membrane and release their entire contents extracellularly; piecemeal degranulation, whereby granule-derived cytokines are selectively mobilized into vesicles that emerge from granules, traverse the cytoplasm and fuse with the plasma membrane to release discrete packets of cytokines; and eosinophil cytolysis, whereby intact granules are extruded from eosinophils, and deposited within tissues. In this latter scenario, extracellular granules can themselves function as stimulus-responsive secretory-competent organelles within the tissue. Here we review the distinctive processes of differential secretion of eosinophil granule-derived cytokines.

  13. 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.

  14. Recombinant Cytokines from Plants

    OpenAIRE

    Patrycja Redkiewicz; Anna Góra-Sochacka; Tomas Vaněk; Agnieszka Sirko

    2011-01-01

    Plant-based platforms have been successfully applied for the last two decades for the efficient production of pharmaceutical proteins. The number of commercialized products biomanufactured in plants is, however, rather discouraging. Cytokines are small glycosylated polypeptides used in the treatment of cancer, immune disorders and various other related diseases. Because the clinical use of cytokines is limited by high production costs they are good candidates for plant-made pharmaceuticals. S...

  15. Cytokine genes as potential biomarkers for muscle weakness in OPMD

    DEFF Research Database (Denmark)

    Riaz, Muhammad; Raz, Yotam; van der Slujis, Barbara

    2016-01-01

    Molecular biomarkers emerge as an accurate diagnostic tool, but are scarce for myopathies. Lack of outcome measures sensitive to disease onset and symptom severity hamper evaluation of therapeutic developments. Cytokines are circulating immunogenic molecules, and their potential as biomarkers has...... been exploited in the last decade. Cytokines are released from many tissues, including skeletal muscles, but their application to monitor muscle pathology is sparse. We report that the cytokine functional group is altered in the transcriptome of oculopharyngeal muscular dystrophy (OPMD). OPMD...... of these cytokines were highly correlated in controls, but this correlation pattern was disrupted in OPMD. The levels of these 6 cytokines were not altered in expPABPN1 carriers at a pre-symptomatic stage, suggesting that this group of cytokines is a potential biomarker for muscle weakness in OPMD. Correlation...

  16. [Cytokines and asthma].

    Science.gov (United States)

    Gani, F; Senna, G; Piglia, P; Grosso, B; Mezzelani, P; Pozzi, E

    1998-10-01

    Asthma is a chronic inflammatory lung disease in which eosinophils are one of the most important involved cells. These cells accumulate in the lung because of cytokines, which are able to regulate cellular responses. The role of cytokines is well known in allergic asthma: IL4, IL5, IL3, GMCSF are the principally cytokine involved. IL4 regulate IgE synthesis while IL5, (and IL3) cause the activation and accumulation of eosinophils. In non allergic asthma, whilst only IL5 seemed to be important recent data, shows that also IL4 plays an important role. Therefore nowadays no relevant difference seems to exist between allergic and non allergic asthma; instead the primer is different: the allergen in allergic asthma and often an unknown factor in the non allergic asthma. Recently other cytokines have been proved to play a role in the pathogenesis of asthma. IL8 is chemotactic not only for neutrophils but also for eosinophils and might cause chronic inflammation in severe asthma. IL13 works like IL4, while RANTES seems to be a more important chemotactic agent than IL5. Finally IL10, which immunoregulates T lymphocyte responses, may reduce asthma inflammation. In conclusion cytokine made us to learn more about the pathogenesis of asthma even if we do not yet know when and how asthma inflammation develops.

  17. 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.

  18. Association of cytokine and matrix metalloproteinase profiles with disease activity and function in ankylosing spondylitis

    Science.gov (United States)

    2012-01-01

    Introduction The pathology of ankylosing spondylitis (AS) suggests that certain cytokines and matrix metalloproteinases (MMPs) might provide useful markers of disease activity. Serum levels of some cytokines and MMPs have been found to be elevated in active disease, but there is a general lack of information about biomarker profiles in AS and how these are related to disease activity and function. The purpose of this study was to investigate whether clinical measures of disease activity and function in AS are associated with particular profiles of circulating cytokines and MMPs. Methods Measurement of 30 cytokines, five MMPs and four tissue inhibitors of metalloproteinases was carried out using Luminex® technology on a well-characterised population of AS patients (n = 157). The relationship between biomarker levels and measures of disease activity (Bath ankylosing spondylitis disease activity index (BASDAI)), function (Bath ankylosing spondylitis functional index) and global health (Bath ankylosing spondylitis global health) was investigated. Principal component analysis was used to reduce the large number of biomarkers to a smaller set of independent components, which were investigated for their association with clinical measures. Further analyses were carried out using hierarchical clustering, multiple regression or multivariate logistic regression. Results Principal component analysis identified eight clusters consisting of various combinations of cytokines and MMPs. The strongest association with the BASDAI was found with a component consisting of MMP-8, MMP-9, hepatocyte growth factor and CXCL8, and was independent of C-reactive protein levels. This component was also associated with current smoking. Hierarchical clustering revealed two distinct patient clusters that could be separated on the basis of MMP levels. The high MMP cluster was associated with increased C-reactive protein, the BASDAI and the Bath ankylosing spondylitis functional index. Conclusions

  19. Cytokine Profiles during Invasive Nontyphoidal Salmonella Disease Predict Outcome in African Children

    Science.gov (United States)

    Gilchrist, James J.; Heath, Jennifer N.; Msefula, Chisomo L.; Gondwe, Esther N.; Naranbhai, Vivek; Mandala, Wilson; MacLennan, Jenny M.; Molyneux, Elizabeth M.; Graham, Stephen M.; Drayson, Mark T.; Molyneux, Malcolm E.

    2016-01-01

    Nontyphoidal Salmonella is a leading cause of sepsis in African children. Cytokine responses are central to the pathophysiology of sepsis and predict sepsis outcome in other settings. In this study, we investigated cytokine responses to invasive nontyphoidal Salmonella (iNTS) disease in Malawian children. We determined serum concentrations of 48 cytokines with multiplexed immunoassays in Malawian children during acute iNTS disease (n = 111) and in convalescence (n = 77). Principal component analysis and logistic regression were used to identify cytokine signatures of acute iNTS disease. We further investigated whether these responses are altered by HIV coinfection or severe malnutrition and whether cytokine responses predict inpatient mortality. Cytokine changes in acute iNTS disease were associated with two distinct cytokine signatures. The first is characterized by increased concentrations of mediators known to be associated with macrophage function, and the second is characterized by raised pro- and anti-inflammatory cytokines typical of responses reported in sepsis secondary to diverse pathogens. These cytokine responses were largely unaltered by either severe malnutrition or HIV coinfection. Children with fatal disease had a distinctive cytokine profile, characterized by raised mediators known to be associated with neutrophil function. In conclusion, cytokine responses to acute iNTS infection in Malawian children are reflective of both the cytokine storm typical of sepsis secondary to diverse pathogens and the intramacrophage replicative niche of NTS. The cytokine profile predictive of fatal disease supports a key role of neutrophils in the pathogenesis of NTS sepsis. PMID:27170644

  20. Cytokine Profiles during Invasive Nontyphoidal Salmonella Disease Predict Outcome in African Children.

    Science.gov (United States)

    Gilchrist, James J; Heath, Jennifer N; Msefula, Chisomo L; Gondwe, Esther N; Naranbhai, Vivek; Mandala, Wilson; MacLennan, Jenny M; Molyneux, Elizabeth M; Graham, Stephen M; Drayson, Mark T; Molyneux, Malcolm E; MacLennan, Calman A

    2016-07-01

    Nontyphoidal Salmonella is a leading cause of sepsis in African children. Cytokine responses are central to the pathophysiology of sepsis and predict sepsis outcome in other settings. In this study, we investigated cytokine responses to invasive nontyphoidal Salmonella (iNTS) disease in Malawian children. We determined serum concentrations of 48 cytokines with multiplexed immunoassays in Malawian children during acute iNTS disease (n = 111) and in convalescence (n = 77). Principal component analysis and logistic regression were used to identify cytokine signatures of acute iNTS disease. We further investigated whether these responses are altered by HIV coinfection or severe malnutrition and whether cytokine responses predict inpatient mortality. Cytokine changes in acute iNTS disease were associated with two distinct cytokine signatures. The first is characterized by increased concentrations of mediators known to be associated with macrophage function, and the second is characterized by raised pro- and anti-inflammatory cytokines typical of responses reported in sepsis secondary to diverse pathogens. These cytokine responses were largely unaltered by either severe malnutrition or HIV coinfection. Children with fatal disease had a distinctive cytokine profile, characterized by raised mediators known to be associated with neutrophil function. In conclusion, cytokine responses to acute iNTS infection in Malawian children are reflective of both the cytokine storm typical of sepsis secondary to diverse pathogens and the intramacrophage replicative niche of NTS. The cytokine profile predictive of fatal disease supports a key role of neutrophils in the pathogenesis of NTS sepsis.

  1. Cytokine Patterns and Endotypes in Acute and Chronic Rhinosinusitis.

    Science.gov (United States)

    Scheckenbach, Kathrin; Wagenmann, Martin

    2016-01-01

    Since rhinosinusitis is an inflammatory disease, cytokines as key regulators of inflammation play a central role in its pathophysiology. In acute rhinosinusitis, several proinflammatory cytokines of different types have been identified. Initial information about the involvement of the inflammasome in rhinosinusitis has been gained, but this area remains open for more detailed research. Although it has been accepted now that chronic rhinosinusitis (CRS) needs to be differentiated into CRS with and without nasal polyps, it has become clear that this distinction is insufficient to clearly define subgroups with uniform pathophysiology and cytokine patterns. While Th1-cytokines are mostly found in CRSsNP and Th2 cytokines in CRSwNP, there is a substantial overlap, and several other cytokines have also been detected. Attempts to identify CRS endotypes based on cytokines are ongoing but not yet generally accepted. Despite the central role of cytokines in rhinosinusitis, no specific cytokine-targeted therapies are currently available, and only very few studies have specifically addressed the effects of such biologicals in rhinosinusitis.

  2. Cytokiner og osteoporose

    DEFF Research Database (Denmark)

    Jørgensen, N R

    1997-01-01

    /testosterone, parathyroidhormone and 1,25(OH)2D3. Some of the cytokines primarily enhance osteoclastic bone resorption e.g. IL-1 (Interleukin-1), TNF (Tumor Necrosis Factor) and IL-6 (Interleukin-6), while others primarily stimulate bone formation e.g. TGF-beta (Transforming Growth Factor), IGF (Insulin-like Growth Factor......During the last few years, progress has been made towards the understanding of local regulation of bone remodelling especially in relation to osteoporosis. Cytokines have shown to be powerful regulators of bone resorption and formation, though under superior control from oestrogen...

  3. Cytokines in Sjogren's syndrome

    NARCIS (Netherlands)

    N. Roescher; P.P. Tak; G.G. Illei

    2009-01-01

    Cytokines play a central role in the regulation of immunity and are often found to be deregulated in autoimmune diseases. Sjogren's syndrome is a chronic autoimmune disease characterized by inflammation and loss of secretory function of the salivary and lachrymal glands. This review highlights the c

  4. Do women lack ambition?

    Science.gov (United States)

    Fels, Anna

    2004-04-01

    For men, ambition is considered a necessary and desirable part of life. Most women, however, associate ambition with egotism, self-aggrandizement, or manipulation. Getting to the bottom of why this is so required study of what ambition consists of--for both sexes. In childhood, the research uncovered, girls are clear about their ambitions. Their goals are grand, and they make no apologies for them. In nearly all childhood ambitions, two distinct factors are in place: the mastery of a special skill, and recognition for it. And what's true in childhood is no less true in later life: We all want our efforts and accomplishments acknowledged. Yet there are dramatic differences in how women and men create, reconfigure, and realize (or abandon) their goals. Most women are demure when praised for their achievements. One could chalk up this behavior to women's innate modesty or see it as a passive way of highlighting their accomplishments. But the fear of recognition that many women express suggests otherwise. Research has shown that such behavior varies according to social context: Women more openly seek and compete for affirmation when they are with other women, but they behave differently when competing with men. The underlying problem has to do with cultural ideals of femininity. Women face the reality that to appear feminine, they must provide or relinquish scarce resources to others--and recognition is indeed a scarce resource. Although women have more opportunities than ever before, they still come under social scrutiny that makes hard choices--such as when and whether to start a family or advance in the workplace--even harder. There are no easy solutions, but there are ways women can hold fast to their dreams. They must band together, learn to blow their own horns, and structure their lives in a way that promotes recognition.

  5. Unique Cytokine Signature in the Plasma of Patients with Fibromyalgia

    Directory of Open Access Journals (Sweden)

    Jamie Sturgill

    2014-01-01

    Full Text Available Fibromyalgia (FMS is a chronic pain syndrome with a complex but poorly understood pathogenesis affecting approximately 10 million adults in the United States. The lack of a clear etiology of FMS has limited the effective diagnosis and treatment of this debilitating condition. The objective of this secondary data analysis was to examine plasma cytokine levels in women with FMS using the Bio-Plex Human Cytokine 17-plex Assay. Post hoc analysis of plasma cytokine levels was performed to evaluate patterns that were not specified a priori. Upon examination, patients with FMS exhibited a marked reduction in TH2 cytokines such as IL-4, IL-5, and IL-13. The finding of this pattern of altered cytokine milieu not only supports the role of inflammation in FMS but also may lead to more definitive diagnostic tools for clinicians treating FMS. The TH2 suppression provides strong evidence of immune dysregulation in patients with FMS.

  6. Autophagy and cytokines.

    Science.gov (United States)

    Harris, James

    2011-11-01

    Autophagy is a highly conserved homoeostatic mechanism for the lysosomal degradation of cytosolic constituents, including long-lived macromolecules, organelles and intracellular pathogens. Autophagosomes are formed in response to a number of environmental stimuli, including amino acid deprivation, but also by both host- and pathogen-derived molecules, including toll-like receptor ligands and cytokines. In particular, IFN-γ, TNF-α, IL-1, IL-2, IL-6 and TGF-β have been shown to induce autophagy, while IL-4, IL-10 and IL-13 are inhibitory. Moreover, autophagy can itself regulate the production and secretion of cytokines, including IL-1, IL-18, TNF-α, and Type I IFN. This review discusses the potentially pivotal roles of autophagy in the regulation of inflammation and the coordination of innate and adaptive immune responses.

  7. Cytokines and anti-cytokines as therapeutics--an update.

    Science.gov (United States)

    Tayal, Vandana; Kalra, Bhupinder Singh

    2008-01-28

    Cytokines which comprise of a family of proteins--interleukins, lymphokines, monokines, interferons, and chemokines, are important components of the immune system. They act in concert with specific cytokine inhibitors and soluble cytokine receptors to regulate the human immune response. Their physiologic role in inflammation and pathologic role in systemic inflammatory states are now well recognized. An imbalance in cytokine production or cytokine receptor expression and/or dysregulation of a cytokine process contributes to various pathological disorders. Research is progressing rapidly in the area of cytokines and their therapeutic targets, the two major therapeutic modalities being the administration of purified recombinant cytokines and the use of their antagonists in various inflammatory disorders. However, given the large number of cytokines, it is disappointing that only relatively few can be used clinically. In the present article, we have made an attempt to review and present a glimpse of the history as well as up to date information that is pertinent to cytokines and anti-cytokine therapies in the treatment of cancer, autoimmune disorders and various other related diseases.

  8. Cytokine Therapies in Neurological Disease.

    Science.gov (United States)

    Azodi, Shila; Jacobson, Steven

    2016-07-01

    Cytokines are a heterogeneous group of glycoproteins that coordinate physiological functions. Cytokine deregulation is observed in many neurological diseases. This article reviews current research focused on human clinical trials of cytokine and anticytokine therapies in the treatment of several neurological disease including stroke, neuromuscular diseases, neuroinfectious diseases, demyelinating diseases, and neurobehavioral diseases. This research suggests that cytokine therapy applications may play an important role in offering new strategies for disease modulation and treatment. Further, this research provides insights into the causal link between cytokine deregulation and neurological diseases.

  9. Detection of autoantibodies to cytokines

    DEFF Research Database (Denmark)

    Bendtzen, K; Hansen, M B; Ross, C;

    2000-01-01

    Autoantibodies to various cytokines have been reported in normal individuals and in patients with various infectious and immunoinflammatory disorders, and similar antibodies (Ab) may be induced in patients receiving human recombinant cytokines. The clinical relevance of these Ab is often difficult...... to evaluate. Not only are in vitro neutralizing cytokine Ab not necessarily neutralizing in vivo, but assays for binding and neutralizing Ab to cytokines are often difficult to interpret. For example, denaturation of immobilized cytokines in immunoblotting techniques and immunometric assays may leave Ab...

  10. Salivary cytokine levels in early gingival inflammation

    DEFF Research Database (Denmark)

    Belstrøm, Daniel; Damgaard, Christian; Könönen, Eija

    2017-01-01

    chemoattractant protein (MCP)-1, IL-1β, and IL-1 receptor antagonist (IL-1Ra) in gingival inflammation. Twenty-eight systemically and orally healthy nonsmokers abstained from oral hygiene protocols for 10 days. After that, self-performed cleaning was resumed for 14 days. Plaque and gingival indexes were measured......Salivary protein levels have been studied in periodontitis. However, there is lack of information on salivary cytokine levels in early gingival inflammation. The aim of this study was to determine salivary levels of vascular endothelial growth factor (VEGF), interleukin (IL)-8, monocyte......, and saliva samples were collected at days 1, 4, 7, 10, and 24. Salivary cytokines were detected with Luminex®-xMAP™. Salivary IL-1β, IL-1Ra, and VEGF levels decreased after 10 days' development of experimental gingivitis and reached baseline levels at the end of the 2-week resolution period. Salivary IL-8...

  11. [Cytokines and hematopoiesis].

    Science.gov (United States)

    Mannoni, P

    1993-03-01

    The identification and purification of haemopoietic growth regulators have resulted in a better understanding of control mechanisms. Cloning and expression of the corresponding genes have shown that most of the activities observed correspond to specific glycoproteins produced by cells from numerous tissues, including those of bone marrow stroma and immune system. These cytokines activate the responsive cells through specific receptors expressed on their membranes. They exert an accurate control of haematopoiesis in a network of synergistic and antagonistic factors. The exact identification of their biological activities, together with the possibility of producing them in large amounts by genetic recombination, have already resulted in their therapeutic use with, in certain cases, a remarkable efficiency.

  12. [Cytokines in bone diseases. Cytokine and postmenopausal osteoporosis].

    Science.gov (United States)

    Inada, Masaki; Miyaura, Chisato

    2010-10-01

    Bone resorption is regulated by various cytokines. In postmenopausal osteoporosis, bone loss due to estrogen deficiency is closely related to the production of bone-resorbing cytokine. Especially, the increased production of IL-1, IL-6 and TNF-α could induce the expression of RANKL in bone tissues to enhance osteoclastogenesis. Relationship between estrogen deficiency and various cytokines is important to clarify the pathogenesis of postmenopausal osteoporosis.

  13. Class I Cytokine Receptors: Structure and function in the Membrane

    DEFF Research Database (Denmark)

    Bugge, Katrine Østergaard

    Class I cytokine receptors are involved in important biological functions of both physiological and pathological nature in mammals. However, the molecular details of the cross-membrane signal transduction through these receptors remain obscure. One of the major reasons for this is the lack...... of structural knowledge on their membrane-embedded transmembrane domains (TMDs), which connect the extracellular ligand binding domains to the intracellular signaling platforms. The overall aim of this thesis work was to improve our understanding of the class I cytokine receptor signaling across the membrane...... ample material of high quality for structural studies with NMR spectroscopy of several class I cytokine receptor TMDs. Furthermore, the structure of a class I cytokine receptor TMD in DHPC micelles was solved with solution-state NMR spectroscopy. Additionally, since structural studies of intact proteins...

  14. Differential control of Helios+/− Treg development by monocyte subsets through disparate inflammatory cytokines

    OpenAIRE

    Zhong, Hui; Yazdanbakhsh, Karina

    2013-01-01

    Control of Helios+/− Treg subset development is mediated through distinct cytokines and monocyte subpopulations.CD16+ monocytes inhibit Helios+ Treg proliferation through IL-12, whereas CD16− monocytes suppress Helios− Treg development through TNF-α.

  15. CYTOKINE REGULATION IN THE COURSE OF MULTIPLE MYELOMA PROGRESSION

    Directory of Open Access Journals (Sweden)

    O. V. Smirnova

    2015-01-01

    Full Text Available Cytokines are wide-range modifiers of biological reactions. Cytokine regulation provides proliferation, differentiation, cell function, cell-cell and inter-systemic interaction, direction and nature of immune response to invasion of infectious and non-infectious pathogens. There are several distinct groups of cytokines: pro-inflammatory, anti-inflammatory factors, regulators of cellular and humoral immunity etc. A distinct role of cytokines is not excluded for infectious complications accompanying multiple myeloma (MM. Cytokine regulatory effects on immune defense in the organism as a whole, and a balance between proand anti-inflammatory cytokines in blood of MM patients depend on the stage of multiple myeloma progression and possibility of infectious complications. Therefore, the aim of our study was to evaluate proand anti-inflammatory cytokines and cytokine regulation in patients with MM G-immunochemical option. Our study involved 101 patients with MM (IgG-variant, their age ranging between 40 and 76 years. The diagnosis was verified by clinical and laboratory examinations. The G-variant of MM was verified by immunofixation and electrophoresis. The definite diagnosis and disease staging was confirmed by a combination of diagnostic criteria. Heparinized blood samples were taken from the cubital vein in the morning (8 to 9 hours, in fasting state upon admission, prior to the starting a pathogenetic therapy. Dynamic monitoring of patients was carried out over the period of their staying in hospital. All patients were staged according to Durie and Salmon (1975 (stages II, III. At each stage, we discerned two sub-groups: A, without renal disease, B, with renal impairment. The control group consisted of 125 healthy volunteers matched for age and sex with the main group. IL-2, IL-4, IL-8, TNFα, and IFNγ levels in sera of the patients and healthy individuals were determined by enzyme immunoassay kits (JSC “Vector-Best”,Novosibirsk. In the

  16. Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes

    DEFF Research Database (Denmark)

    Haxholm, Gitte Wolfsberg; Nikolajsen, Louise Fletcher; Olsen, Johan Gotthardt;

    2015-01-01

    Class 1 cytokine receptors regulate essential biological processes through complex intracellular signaling networks. However, the structural platform for understanding their functions is currently incomplete as structure-function studies of the intracellular domains (ICDs) are critically lacking...

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

    Science.gov (United States)

    Wu, Yang; Tian, Zhigang; Wei, Haiming

    2017-01-01

    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. PMID:28824650

  18. Lacking power impairs executive functions

    NARCIS (Netherlands)

    Smith, P.K.; Jostmann, N.B.; Galinsky, A.D.; Dijk, W.W. van

    2008-01-01

    Four experiments explored whether lacking power impairs executive functioning, testing the hypothesis that the cognitive presses of powerlessness increase vulnerability to performance decrements during complex executive tasks. In the first three experiments, low power impaired performance on executi

  19. Cytokine receptors and hematopoietic differentiation.

    Science.gov (United States)

    Robb, L

    2007-10-15

    Colony-stimulating factors and other cytokines signal via their cognate receptors to regulate hematopoiesis. In many developmental systems, inductive signalling determines cell fate and, by analogy with this, it has been postulated that cytokines, signalling via their cognate receptors, may play an instructive role in lineage specification in hematopoiesis. An alternative to this instructive hypothesis is the stochastic or permissive hypothesis. The latter proposes that commitment to a particular hematopoietic lineage is an event that occurs independently of extrinsic signals. It predicts that the role of cytokines is to provide nonspecific survival and proliferation signals. In this review, we look at the role of cytokine receptor signalling in hematopoiesis and consider the evidence for both hypotheses. Data from experiments that genetically manipulate receptor gene expression in vitro or in vivo are reviewed. Experiments in which cytokine receptors were installed in multipotential cells showed that, in some cases, stimulation with the cognate ligand could lead to alterations in lineage output. The creation of genetically manipulated mouse strains demonstrated that cytokine receptors are required for expansion and survival of single lineages but did not reveal a role in lineage commitment. We conclude that hematopoietic differentiation involves mainly stochastic events, but that cytokine receptors also have some instructive role.

  20. Human astrocytes: secretome profiles of cytokines and chemokines.

    Directory of Open Access Journals (Sweden)

    Sung S Choi

    Full Text Available Astrocytes play a key role in maintenance of neuronal functions in the central nervous system by producing various cytokines, chemokines, and growth factors, which act as a molecular coordinator of neuron-glia communication. At the site of neuroinflammation, astrocyte-derived cytokines and chemokines play both neuroprotective and neurotoxic roles in brain lesions of human neurological diseases. At present, the comprehensive profile of human astrocyte-derived cytokines and chemokines during inflammation remains to be fully characterized. We investigated the cytokine secretome profile of highly purified human astrocytes by using a protein microarray. Non-stimulated human astrocytes in culture expressed eight cytokines, including G-CSF, GM-CSF, GROα (CXCL1, IL-6, IL-8 (CXCL8, MCP-1 (CCL2, MIF and Serpin E1. Following stimulation with IL-1β and TNF-α, activated astrocytes newly produced IL-1β, IL-1ra, TNF-α, IP-10 (CXCL10, MIP-1α (CCL3 and RANTES (CCL5, in addition to the induction of sICAM-1 and complement component 5. Database search indicated that most of cytokines and chemokines produced by non-stimulated and activated astrocytes are direct targets of the transcription factor NF-kB. These results indicated that cultured human astrocytes express a distinct set of NF-kB-target cytokines and chemokines in resting and activated conditions, suggesting that the NF-kB signaling pathway differentially regulates gene expression of cytokines and chemokines in human astrocytes under physiological and inflammatory conditions.

  1. Quantum Distinction: Quantum Distinctiones!

    OpenAIRE

    Zeps, Dainis

    2009-01-01

    10 pages; How many distinctions, in Latin, quantum distinctiones. We suggest approach of anthropic principle based on anthropic reference system which should be applied equally both in theoretical physics and in mathematics. We come to principle that within reference system of life subject of mathematics (that of thinking) should be equated with subject of physics (that of nature). For this reason we enter notions of series of distinctions, quantum distinction, and argue that quantum distinct...

  2. Cytokines and cytokine-specific therapy in asthma.

    Science.gov (United States)

    Desai, Dhananjay; Brightling, Christopher

    2012-01-01

    Asthma is increasing in prevalence worldwide. It is characterized by typical symptoms and variable airway obstruction punctuated with episodes of worsening symptoms known as exacerbations. Underlying this clinical expression of disease is airway inflammation and remodeling. Cytokines and their networks are implicated in the innate and adaptive immune responses driving airway inflammation in asthma and are modulated by host-environment interactions. Asthma is a complex heterogeneous disease, and the paradigm of Th2 cytokine-mediated eosinophilic inflammation as a consequence of allergic sensitization has been challenged and probably represents a subgroup of asthma. Indeed, as attention has switched to the importance of severe asthma, which represents the highest burden both to the patient and health care provider, there is an increasing recognition of inflammatory subphenotypes that are likely to be driven by different cytokine networks. Interestingly, these networks may be specific to aspects of clinical expression as well as inflammatory cell profiles and therefore present novel phenotype-specific therapeutic strategies. Here, we review the breadth of cytokines implicated in the pathogenesis of asthma and focus upon the outcomes of early clinical trials conducted using cytokines or cytokine-blocking therapies.

  3. Targeting the binding interface on a shared receptor subunit of a cytokine family enables the inhibition of multiple member cytokines with selectable target spectrum.

    Science.gov (United States)

    Nata, Toshie; Basheer, Asjad; Cocchi, Fiorenza; van Besien, Richard; Massoud, Raya; Jacobson, Steven; Azimi, Nazli; Tagaya, Yutaka

    2015-09-11

    The common γ molecule (γc) is a shared signaling receptor subunit used by six γc-cytokines. These cytokines play crucial roles in the differentiation of the mature immune system and are involved in many human diseases. Moreover, recent studies suggest that multiple γc-cytokines are pathogenically involved in a single disease, thus making the shared γc-molecule a logical target for therapeutic intervention. However, the current therapeutic strategies seem to lack options to treat such cases, partly because of the lack of appropriate neutralizing antibodies recognizing the γc and, more importantly, because of the inherent and practical limitations in the use of monoclonal antibodies. By targeting the binding interface of the γc and cytokines, we successfully designed peptides that not only inhibit multiple γc-cytokines but with a selectable target spectrum. Notably, the lead peptide inhibited three γc-cytokines without affecting the other three or non-γc-cytokines. Biological and mutational analyses of our peptide provide new insights to our current understanding on the structural aspect of the binding of γc-cytokines the γc-molecule. Furthermore, we provide evidence that our peptide, when conjugated to polyethylene glycol to gain stability in vivo, efficiently blocks the action of one of the target cytokines in animal models. Collectively, our technology can be expanded to target various combinations of γc-cytokines and thereby will provide a novel strategy to the current anti-cytokine therapies against immune, inflammatory, and malignant diseases.

  4. Plasma cytokines in acute stroke

    DEFF Research Database (Denmark)

    Christensen, Hanne Krarup; Boysen, Gudrun; Christensen, Erik

    2011-01-01

    GOALS: The aim of this study was to test the relations between plasma cytokines and the clinical characteristics, course, and risk factors in acute stroke. PATIENTS AND METHODS: The analysis was based on 179 patients with acute stroke included within 24 hours of stroke onset. On inclusion and 3...... measured by enzyme-linked immunoassay (ELISA). FINDINGS: The levels of most cytokines were significantly different in acute stroke from the levels 3 months later; but only IL-10 was positively associated with stroke severity. C-reactive protein and white blood cell count were positively associated...... with the cytokine response. CONCLUSIONS: We found a substantial overall cytokine reaction that reflected the stroke incident. However, these results do not, at present, suggest a potential for clinical use, as they do not seem to add to the information obtained from the clinical workup of the individual patient....

  5. Th2 cytokines inhibit lymphangiogenesis.

    Directory of Open Access Journals (Sweden)

    Ira L Savetsky

    Full Text Available Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2 cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes in the extracellular matrix. However, while the evidence supporting a role for T cells and Th2 cytokines as negative regulators of lymphatic function is clear, the direct effects of Th2 cytokines on isolated LECs remains poorly understood. Using in vitro and in vivo studies, we show that physiologic doses of interleukin-4 (IL-4 and interleukin-13 (IL-13 have profound anti-lymphangiogenic effects and potently impair LEC survival, proliferation, migration, and tubule formation. Inhibition of these cytokines with targeted monoclonal antibodies in the cornea suture model specifically increases inflammatory lymphangiogenesis without concomitant changes in angiogenesis. These findings suggest that manipulation of anti-lymphangiogenic pathways may represent a novel and potent means of improving lymphangiogenesis.

  6. Systematic analysis of reportedly distinct populations of multipotent bone marrow-derived stem cells reveals a lack of distinction.

    Science.gov (United States)

    Lodie, Tracey A; Blickarz, Courtney E; Devarakonda, Tara J; He, Chufa; Dash, Ajeeta B; Clarke, Jennifer; Gleneck, Kristen; Shihabuddin, Lamya; Tubo, Ross

    2002-10-01

    Adult human bone marrow-derived stem cells, having the ability to differentiate into cells of multiple lineages, have been isolated and propagated by varied protocols, including positive (CD105(+))/negative (CD45(-)GlyA(-)) selection with immunomagnetic beads, or direct plating into selective culture media. Each substratum-adherent cell population was subjected to a systematic analysis of their cell surface markers and differentiation potential. In the initial stages of culture, each cell population proliferated slowly, reaching confluence in 10-14 days. Adherent cells proliferated at similar rates whether cultured in serum-free medium supplemented with basic fibroblast growth factor, medium containing 2% fetal bovine serum (FBS) supplemented with epidermal growth factor and platelet-derived growth factor, or medium containing 10% FBS alone. Cell surface marker analysis revealed that more than 95% of the cells were positive for CD105/endoglin, a putative mesenchymal stem cell marker, and negative for CD34, CD31, and CD133, markers of hematopoietic, endothelial, and neural stem cells, respectively, regardless of cell isolation and propagation method. CD44 expression was variable, apparently dependent on serum concentration. Functional similarity of the stem cell populations was also observed, with each different cell population expressing the cell type-specific markers beta-tubulin, type II collagen, and desmin, and demonstrating endothelial tube formation when cultured under conditions favoring neural, cartilage, muscle, and endothelial cell differentiation, respectively. On the basis of these data, adult human bone marrow-derived stem cells cultured in adherent monolayer are virtually indistinguishable, both physically and functionally, regardless of the method of isolation or proliferative expansion.

  7. Instruction of hematopoietic lineage choice by cytokine signaling

    Energy Technology Data Exchange (ETDEWEB)

    Endele, Max; Etzrodt, Martin; Schroeder, Timm, E-mail: timm.schroeder@bsse.ethz.ch

    2014-12-10

    Hematopoiesis is the cumulative consequence of finely tuned signaling pathways activated through extrinsic factors, such as local niche signals and systemic hematopoietic cytokines. Whether extrinsic factors actively instruct the lineage choice of hematopoietic stem and progenitor cells or are only selectively allowing survival and proliferation of already intrinsically lineage-committed cells has been debated over decades. Recent results demonstrated that cytokines can instruct lineage choice. However, the precise function of individual cytokine-triggered signaling molecules in inducing cellular events like proliferation, lineage choice, and differentiation remains largely elusive. Signal transduction pathways activated by different cytokine receptors are highly overlapping, but support the production of distinct hematopoietic lineages. Cellular context, signaling dynamics, and the crosstalk of different signaling pathways determine the cellular response of a given extrinsic signal. New tools to manipulate and continuously quantify signaling events at the single cell level are therefore required to thoroughly interrogate how dynamic signaling networks yield a specific cellular response. - Highlights: • Recent studies provided definite proof for lineage-instructive action of cytokines. • Signaling pathways involved in hematopoietic lineage instruction remain elusive. • New tools are emerging to quantitatively study dynamic signaling networks over time.

  8. Circadian Rhythm in Cytokines Administration.

    Science.gov (United States)

    Trufakin, Valery A; Shurlygina, Anna V

    2016-01-01

    In recent times, a number of diseases involving immune system dysfunction have appeared. This increases the importance of research aimed at finding and developing optimized methods for immune system correction. Numerous studies have found a positive effect in using cytokines to treat a variety of diseases, yet the clinical use of cytokines is limited by their toxicity. Research in the field of chronotherapy, aimed at designing schedules of medicine intake using circadian biorhythms of endogenous production of factors, and receptors' expression to the factors on the target cells, as well as chronopharmacodynamics and chronopharmacokinetics of medicines may contribute to the solution of this problem. Advantages of chronotherapy include a greater effectiveness of treatment, reduced dose of required drugs, and minimized adverse effects. This review presents data on the presence of circadian rhythms of spontaneous and induced cytokine production, as well as the expression of cytokine receptors in the healthy body and in a number of diseases. The article reviews various effects of cytokines, used at different times of the day in humans and experimental animals, as well as possible mechanisms underlying the chronodependent effects of cytokines. The article presents the results of chronotherapeutic modes of administering IL-2, interferons, G-CSF, and GM-CSF in treatment of various types of cancer as well as in experimental models of immune suppression and inflammation, which lead to a greater effectiveness of therapy, the possibility of reducing or increasing the dosage, and reduced drug toxicity. Further research in this field will contribute to the effectiveness and safety of cytokine therapy.

  9. Cytokines in Sjogren's syndrome: potential therapeutic targets

    NARCIS (Netherlands)

    Roescher, N.; Tak, P.P.; Illei, G.G.

    2010-01-01

    The dysregulated cytokine network in Sjogren's Syndrome (SS) is reflected by local and systemic overexpression of pro-inflammatory cytokines and absent or low levels of anti-inflammatory cytokines. To date, the use of cytokine based therapies in SS has been disappointing. Oral administration of low

  10. Angiogenesis meets immunology: cytokine gene therapy of cancer.

    Science.gov (United States)

    Minuzzo, Sonia; Moserle, Lidia; Indraccolo, Stefano; Amadori, Alberto

    2007-02-01

    Delivery of cytokine genes at the tumor site in pre-clinical models has been shown to recruit host inflammatory cells followed by inhibition of tumor growth. This local effect is often accompanied by systemic protection mediated by the immune system, mainly by CD8(+) T and NK cells. On this basis, cytokine gene-transduced tumor cells have widely been used as vaccines in clinical trials, which have shown good safety profiles and some local responses but substantial lack of systemic efficacy. Are these findings the end of the story? Possibly not, if major improvements will be attained in the coming years. These should be directed at the level of gene selection and delivery, in order to identify the optimal cytokine and achieve efficient and durable cytokine expression, and at the level of improving immune stimulation, i.e. by co-administration of co-stimulatory molecules including B7 and CD40, or boosting the expression of tumor antigens or MHC class I molecules. Interestingly, some of the cytokines which have shown encouraging anti-tumor activity, including IFNs, IL-4, IL-12 and TNF-alpha, are endowed with anti-angiogenic or vasculotoxic effects, which may significantly contribute to local tumor control. Therapeutic exploitation of this property may result in the design of novel approaches which, by maximizing immune-stimulating and anti-angiogenic effects, could possibly lead to starvation of established tumors in patients.

  11. Computational visual distinctness metric

    NARCIS (Netherlands)

    Martínez-Baena, J.; Toet, A.; Fdez-Vidal, X.R.; Garrido, A.; Rodríguez-Sánchez, R.

    1998-01-01

    A new computational visual distinctness metric based on principles of the early human visual system is presented. The metric is applied to quantify (1) the visual distinctness of targets in complex natural scenes and (2) the perceptual differences between compressed and uncompressed images. The new

  12. Grima: A Distinct Emotion Concept?

    Science.gov (United States)

    Schweiger Gallo, Inge; Fernández-Dols, José-Miguel; Gollwitzer, Peter M.; Keil, Andreas

    2017-01-01

    People experience an unpleasant sensation when hearing a scratch on a board or plate. The present research focuses on this aversive experience known in Spanish as ‘grima’ with no equivalent term in English and German. We hypothesized that this aversive experience constitutes a distinctive, separate emotional concept. In Study 1, we found that the affective meaning of ‘grima’ was closer to disgust than to other emotion concepts. Thus, in Study 2 we explored the features of grima and compared them with disgust. As grima was reported to be predominantly elicited by certain auditory stimuli and associated with a distinctive physiological pattern, Study 3 used direct measures of physiological arousal to test the assumption of a distinctive pattern of physiological responses elicited by auditory stimuli of grima and disgust, and found different effects on heart rate but not on skin conductance. In Study 4, we hypothesized that only participants with an implementation intention geared toward down-regulating grima would be able to successfully weaken the grima- but not disgust- experience. Importantly, this effect was specific as it held true for the grima-eliciting sounds only, but did not affect disgust-related sounds. Finally, Study 5 found that English and German speakers lack a single accessible linguistic label for the pattern of aversive reactions termed by Spanish speaking individuals as ‘grima’, whereas the elicitors of other emotions were accessible and accurately identified by German, English, as well as Spanish speakers. PMID:28217102

  13. Cytokine profile in murine toxoplasmosis

    Institute of Scientific and Technical Information of China (English)

    Funda Dogruman-Al; Isil Fidan; Bekir Celebi; Emine Yesilyurt; Berna Erdal; Cahit Babur; Semra Kustimur

    2011-01-01

    Objective: To investigate which cytokines are produced after acute infection of mice withToxoplasma gondii (T. Gondii) RH strain. Methods: Mus domesticus domesticus mice in infected group were inoculated with with highly virulent T. Gondii RH strain by intraperitoneally. Serum samples were obtained from infected and non-infected mice for cytokine levels for ELISA assay. Results: The concentrations of tumor necrosis factor-α, interferonγ, interleukin (IL)-10 and IL-12 in the cardiac blood sample of the infected mice were significantly higher than those in uninfected controls (P0.05). Conclusions: According to our findings, immune response into T helper type 1 was predominant during acute T. gondii infection. Further characterization and purification of Toxoplasma molecule(s) implicated in the regulation of cytokines could lead to the development of new drug prospects to control Toxoplasma infection.

  14. Leucocytes, cytokines and satellite cells

    DEFF Research Database (Denmark)

    Paulsen, Gøran; Mikkelsen, Ulla Ramer; Raastad, Truls

    2012-01-01

    -damaging exercise', primarily eccentric exercise. We review the evidence for the notion that the degree of muscle damage is related to the magnitude of the cytokine response. In the third and final section, we look at the satellite cell response to a single bout of eccentric exercise, as well as the role...... damage. With the exception of IL-6, the sources of systemic cytokines following exercise remain unclear The satellite cell response to severe muscle damage is related to regeneration, whereas the biological significance of satellite cell proliferation after mild damage or non-damaging exercise remains...

  15. Cytokines, STATs and Liver Disease

    Institute of Scientific and Technical Information of China (English)

    BinGao

    2005-01-01

    The Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway, activated by more than 50 cytokines or growth factors, plays critical roles in a wide variety of cellular functions in the hematopoietic, immune, neuronal and hepatic systems. In the liver, this signaling pathway, activated by more than 20 cytokines, growth factors, hormones, and hepatitis viral proteins, plays critical roles in antiviral defense, acute phase response, hepatic injury, repair, inflammation, transformation, and hepatitis. This article reviews the biological significance of STAT1, 2, 3, 4, 5, 6 in hepatic functions and diseases. Cellular & Molecular Immunology. 2005;2(2):92-100.

  16. Cytokines, STATs and Liver Disease

    Institute of Scientific and Technical Information of China (English)

    Bin Gao

    2005-01-01

    The Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway, activated by more than 50 cytokines or growth factors, plays critical roles in a wide variety of cellular functions in the hematopoietic, immune, neuronal and hepatic systems. In the liver, this signaling pathway, activated by more than 20 cytokines, growth factors, hormones, and hepatitis viral proteins, plays critical roles in antiviral defense, acute phase response, hepatic injury, repair, inflammation, transformation, and hepatitis. This article reviews the biological significance of STAT1, 2, 3, 4, 5, 6 in hepatic functions and diseases. Cellular & Molecular Immunology.2005;2(2):92-100.

  17. Cytokine crowdsourcing: multicellular production of TH17-associated cytokines.

    Science.gov (United States)

    Busman-Sahay, Kathleen O; Walrath, Travis; Huber, Samuel; O'Connor, William

    2015-03-01

    In the 2 decades since its discovery, IL-17A has become appreciated for mounting robust, protective responses against bacterial and fungal pathogens. When improperly regulated, however, IL-17A can play a profoundly pathogenic role in perpetuating inflammation and has been linked to a wide variety of debilitating diseases. IL-17A is often present in a composite milieu that includes cytokines produced by TH17 cells (i.e., IL-17F, IL-21, IL-22, and IL-26) or associated with other T cell lineages (e.g., IFN-γ). These combinatorial effects add mechanistic complexity and more importantly, contribute differentially to disease outcome. Whereas TH17 cells are among the best-understood cell types that secrete IL-17A, they are frequently neither the earliest nor dominant producers. Indeed, non-TH17 cell sources of IL-17A can dramatically alter the course and severity of inflammatory episodes. The dissection of the temporal regulation of TH17-associated cytokines and the resulting net signaling outcomes will be critical toward understanding the increasingly intricate role of IL-17A and TH17-associated cytokines in disease, informing our therapeutic decisions. Herein, we discuss important non-TH17 cell sources of IL-17A and other TH17-associated cytokines relevant to inflammatory events in mucosal tissues.

  18. Cytokine and chemokine inter-regulation in the inflamed or injured CNS

    DEFF Research Database (Denmark)

    Owens, Trevor; Babcock, Alicia A; Millward, Jason M;

    2005-01-01

    The distinction between immune-regulatory and effector cytokines and chemokines, and neural growth and survival factors (neurotrophins) becomes increasingly blurred. We discuss here the role of immune cytokines and chemokines as mediators of innate glial responses in the central nervous system...... the earliest responses are the expression of a wide profile of chemokines, and of the cytokine tumor necrosis factor-alpha (TNFalpha). The cytokine interferon-gamma (IFNgamma) is not normally produced in the CNS, but TNFalpha levels are enhanced if it is present. Viral vector-derived IFNgamma directly induces...... are directed by Toll-like receptors (TLR). Our recent studies focus on specific TLR signals as upstream on-switches for glial cytokine and chemokine responses. The biological activity of chemokines is regulated by matrix metalloproteinase enzymes (MMPs) and specific members of this family are expressed...

  19. Cytokines and the Skin Barrier

    Directory of Open Access Journals (Sweden)

    Jens Malte Baron

    2013-03-01

    Full Text Available The skin is the largest organ of the human body and builds a barrier to protect us from the harmful environment and also from unregulated loss of water. Keratinocytes form the skin barrier by undergoing a highly complex differentiation process that involves changing their morphology and structural integrity, a process referred to as cornification. Alterations in the epidermal cornification process affect the formation of the skin barrier. Typically, this results in a disturbed barrier, which allows the entry of substances into the skin that are immunologically reactive. This contributes to and promotes inflammatory processes in the skin but also affects other organs. In many common skin diseases, including atopic dermatitis and psoriasis, a defect in the formation of the skin barrier is observed. In these diseases the cytokine composition within the skin is different compared to normal human skin. This is the result of resident skin cells that produce cytokines, but also because additional immune cells are recruited. Many of the cytokines found in defective skin are able to influence various processes of differentiation and cornification. Here we summarize the current knowledge on cytokines and their functions in healthy skin and their contributions to inflammatory skin diseases.

  20. Anesthesiology and the cytokine network

    Directory of Open Access Journals (Sweden)

    Barbara Lisowska

    2013-08-01

    Full Text Available The immune response is a highly specific reaction carried out by means of specialized cells that belong to the immune system. There are two types of immune response mechanisms aimed towards pathogens: non-specific, innate reactions, and specific, acquired reactions. Acquired immunity, characterized by its specificity, is comprised of lymphocytes, including both T cell and B cell populations. The role of B lymphocytes is not limited to the humoral response, though the cellular immune response is carried out mainly by various T lymphocyte subpopulations. The reactions of the humoral and cellular responses complement and stimulate one another mutually – cytokines are their common linking element. The attachment of cytokines to their specific receptors activates a sequence of signals – either intracellular or between the cells of various systems. This organization of respective connections and reactions, including the functional relations between cells of the immune response, in its complexity, is best described as a cytokine network. The response of the immune system to surgical trauma can be looked at from both a local and a general perspective. Not only surgical trauma caused by tissue damage, however, influences the functioning of the immune system, but also the drugs and techniques used during anesthesia. Our article is a presentation of the effects of medications used in anesthesia with respect to their influence on the cytokine network.

  1. Cytokines in human lung fibrosis.

    Science.gov (United States)

    Martinet, Y; Menard, O; Vaillant, P; Vignaud, J M; Martinet, N

    1996-01-01

    Fibrosis is a pathological process characterized by the replacement of normal tissue by mesenchymal cells and the extracellular matrix produced by these cells. The sequence of events leading to fibrosis of an organ involves the subsequent processes of injury with inflammation and disruption of the normal tissue architecture, followed by tissue repair with accumulation of mesenchymal cells in the area of derangement. The same sequence of events occurs in wound healing with normal granulation tissue and scar formation, but, while normal scar formation is very localized and transient, in contrast, in fibrosis, the repair process is exaggerated and usually widespread and can be chronic. Inflammatory cells (mainly mononuclear phagocytes), platelets, endothelial cells, and type II pneumocytes play a direct and indirect role in tissue injury and repair. The evaluation of three human fibrotic lung diseases, two diffuse [idiopathic pulmonary fibrosis (IPF), and the adult respiratory distress syndrome (ARDS)], and one focal (tumor stroma in lung cancer), has shown that several cytokines participate to the local injury and inflammatory reaction [interleukin-1 (IL-1), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha)], while other cytokines are involved in tissue repair and fibrosis [platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta), and basic-fibroblast growth factor (b-FGF)]. A better understanding of the cytokines and cytokine networks involved in lung fibrosis leads to the possibility of new therapeutic approaches.

  2. 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 hypoglyc...

  3. Cytokine responses during chronic denervation

    Directory of Open Access Journals (Sweden)

    Olsson Tomas

    2005-11-01

    Full Text Available Abstract Background The aim of the present study was to examine inflammatory responses during Wallerian degeneration in rat peripheral nerve when the regrowth of axons was prevented by suturing. Methods Transected rat sciatic nerve was sutured and ligated to prevent reinnervation. The samples were collected from the left sciatic nerve distally and proximally from the point of transection. The endoneurium was separated from the surrounding epi- and perineurium to examine the expression of cytokines in both of these compartments. Macrophage invasion into endoneurium was investigated and Schwann cell proliferation was followed as well as the expression of cytokines IL-1β, IL-10, IFN-γ and TNF-α mRNA. The samples were collected from 1 day up to 5 weeks after the primary operation. Results At days 1 to 3 after injury in the epi-/perineurium of the proximal and distal stump, a marked expression of the pro-inflammatory cytokines TNF-α and IL-1β and of the anti-inflammatory cytokine IL-10 was observed. Concurrently, numerous macrophages started to gather into the epineurium of both proximal and distal stumps. At day 7 the number of macrophages decreased in the perineurium and increased markedly in the endoneurium of both stumps. At this time point marked expression of TNF-α and IFN-γ mRNA was observed in the endo- and epi-/perineurium of the proximal stump. At day 14 a marked increase in the expression of IL-1β could be noted in the proximal stump epi-/perineurium and in the distal stump endoneurium. At that time point many macrophages were observed in the longitudinally sectioned epineurium of the proximal 2 area as well as in the cross-section slides from the distal stump. At day 35 TNF-α, IL-1β and IL-10 mRNA appeared abundantly in the proximal epi-/perineurium together with macrophages. Conclusion The present studies show that even during chronic denervation there is a cyclic expression pattern for the studied cytokines. Contrary to the

  4. Formulation and stability of cytokine therapeutics.

    Science.gov (United States)

    Lipiäinen, Tiina; Peltoniemi, Marikki; Sarkhel, Sanjay; Yrjönen, Teijo; Vuorela, Heikki; Urtti, Arto; Juppo, Anne

    2015-02-01

    Cytokines are messenger proteins that regulate the proliferation and differentiation of cells and control immune responses. Interferons, interleukins, and growth factors have applications in cancer, autoimmune, and viral disease treatment. The cytokines are susceptible to chemical and physical instability. This article reviews the structure and stability issues of clinically used cytokines, as well as formulation strategies for improved stability. Some general aspects for identifying most probable stability concerns, selecting excipients, and developing stable cytokine formulations are presented. The vast group of cytokines offers possibilities for new biopharmaceuticals. The formulation approaches of the current cytokine products could facilitate development of new biopharmaceuticals.

  5. The local cytokine and chemokine milieu within malignant effusions.

    Science.gov (United States)

    Atanackovic, Djordje; Cao, Yanran; Kim, Ji-Won; Brandl, Stephan; Thom, Ina; Faltz, Christiane; Hildebrandt, York; Bartels, Katrin; de Weerth, Andreas; Hegewisch-Becker, Susanna; Hossfeld, Dieter Kurt; Bokemeyer, Carsten

    2008-01-01

    Malignant effusions offer a unique opportunity for the study of interactions between the human immune system and cancer. We have recently demonstrated that malignant effusions are characterized by an accumulation of T cells expressing chemokine receptors such as CCR4, which is commonly found on Th2 cells. In contrast, effector T cells expressing chemokine receptors typical for Th1 cells, such as CCR5, showed a diminished homing into malignant effusions. We analyzed concentrations of 12 different cytokines and 9 chemokines within malignant and nonmalignant effusions and investigated cytokine expression by effusion-infiltrating leukocytes. We observed that concentrations of the immunoregulatory cytokine TGF-beta(1) and of angiogenic factors VEGF and IL-8 were markedly increased within effusions caused by malignancies. However, we did not observe signs of a typical Th1 or Th2 milieu. Analyzing concentrations of 9 different chemokines, we found elevated concentrations of the chemokines MDC, eotaxin, I-TAC, and MCP-1 in malignant effusions. Interestingly, tumor-infiltrating leukocytes themselves seemed to contribute strongly to the creation of a distinct cytokine/chemokine pattern within cancer-related effusions. Additional analyses suggested that this cytokine/chemokine milieu might support an enrichment of immunosuppressive leukocytes. The local cytokine and chemokine milieu within malignant effusions seems to promote angiogenesis and to block an efficient immune-mediated antitumor response. An elimination of such tumor-promoting influences will be necessary in order to transform local immunotolerance into clinically relevant immune recognition of tumors causing malignant effusions. (c) 2008 S. Karger AG, Basel

  6. Interferon-alpha induces transient suppressors of cytokine signalling expression in human T cells

    DEFF Research Database (Denmark)

    Brender, C; Nielsen, M; Röpke, C;

    2001-01-01

    The suppressors of cytokine signalling (SOCS) proteins comprise a newly identified family of negative feedback regulators of cytokine signalling. SOCS expression is differentially induced upon cytokine stimulation in different cell types. Here we show that interferon-alpha (IFNalpha) is a potent...... induction neither CIS, SOCS-1, nor SOCS-2 expression levels declined after 6 h. In conclusion, we provide the first evidence that IFNalpha induces SOCS expression in human T cells. Moreover, we show that IFNalpha and IL-2 induce distinct patterns of expression kinetics, suggesting that dynamic changes...

  7. Heterogeneity of inflammatory and cytokine networks in chronic plaque psoriasis.

    Directory of Open Access Journals (Sweden)

    William R Swindell

    Full Text Available The clinical features of psoriasis, characterized by sharply demarcated scaly erythematous plaques, are typically so distinctive that a diagnosis can easily be made on these grounds alone. However, there is great variability in treatment response between individual patients, and this may reflect heterogeneity of inflammatory networks driving the disease. In this study, whole-genome transcriptional profiling was used to characterize inflammatory and cytokine networks in 62 lesional skin samples obtained from patients with stable chronic plaque psoriasis. We were able to stratify lesions according to their inflammatory gene expression signatures, identifying those associated with strong (37% of patients, moderate (39% and weak inflammatory infiltrates (24%. Additionally, we identified differences in cytokine signatures with heightened cytokine-response patterns in one sub-group of lesions (IL-13-strong; 50% and attenuation of these patterns in a second sub-group (IL-13-weak; 50%. These sub-groups correlated with the composition of the inflammatory infiltrate, but were only weakly associated with increased risk allele frequency at some psoriasis susceptibility loci (e.g., REL, TRAF3IP2 and NOS2. Our findings highlight variable points in the inflammatory and cytokine networks known to drive chronic plaque psoriasis. Such heterogeneous aspects may shape clinical course and treatment responses, and can provide avenues for development of personalized treatments.

  8. Nociceptive neurons detect cytokines in arthritis

    OpenAIRE

    Schaible, Hans-Georg

    2014-01-01

    Proinflammatory cytokines are major mediators in the pathogenesis of diseases of joints such as rheumatoid arthritis and osteoarthritis. This review emphasizes that proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6 and interleukin-17 are also mediators of pain by directly acting on the nociceptive system. Proportions of nociceptive sensory neurons express receptors for these cytokines, and the application of cytokines rapidly changes the excitabil...

  9. Substance, Reality, and Distinctness

    Directory of Open Access Journals (Sweden)

    Boris Hennig

    2008-04-01

    Full Text Available Descartes claims that God is a substance, and that mind and body are two different and separable substances. This paper provides some background that renders these claims intelligible. For Descartes, that something is real means it can exist in separation, and something is a substance if it does not depend on other substances for its existence. Further, separable objects are correlates of distinct ideas, for an idea is distinct (in an objective sense if its object may be easily and clearly separated from everything that is not its object. It follows that if our idea of God is our most distinct idea, as Descartes claims, then God must be a substance in the Cartesian sense of the term. Also, if we can have an idea of a thinking subject which does not in any sense refer to bodily things, and if bodily things are substances, then mind and body must be two different substances.

  10. Two biologically distinct isolates of Zucchini yellow mosaic virus lack seed transmissibility in cucumber.

    Science.gov (United States)

    Glasa, M; Kollerova, E

    2007-01-01

    The seed transmission of the Zucchini yellow mosaic virus (ZYMV) was studied in cucumber using two isolates unrelated in their biological characteristics. Although the virus could be readily detected in mature seeds harvested from infected cucumbers, the seedlings obtained from infected germinated seeds tested negative for ZYMV using both ELISA and RT-PCR assays. No evidence was obtained for transmission of two ZYMV isolates through seeds.

  11. Avian cytokines in health and disease

    Directory of Open Access Journals (Sweden)

    P Wigley

    2003-04-01

    Full Text Available Cytokines are proteins secreted by cells that play an important role in the activation and regulation of other cells and tissues during inflammation and immune responses. Although well described in several mammalian species, the role of cytokines and other related proteins is poorly understood in avian species. Recent advances in avian genetics and immunology have begun to allow the exploration of cytokines in health and disease. Cytokines may be classified in a number of ways, but may be conveniently arranged into four broad groups on the basis of their function. Proinflammatory cytokines such as interleukin-6 and interleukin-1beta play a role in mediating inflammation during disease or injury. Th1 cytokines, including interleukin-12 and interferon-gamma, are involved in the induction of cell-mediated immunity, whereas Th2 cytokines such as interleukin-4 are involved in the induction of humoral immunity. The final group Th3 or Tr cytokines play a role in regulation of immunity. The role of various cytokines in infectious and non-infectious diseases of chickens and turkeys is now being investigated. Although there are only a few reliable ELISAs or bioassays developed for avian cytokines, the use of molecular techniques, and in particular quantitative RT-PCR (Taqman has allowed investigation of cytokine responses in a number of diseases including salmonellosis, coccidiosis and autoimmune thyroiditis. In addition the use of recombinant cytokines as therapeutic agents or as vaccine adjuvants is now being explored.

  12. Cytokines, Neovascularization and Breast Cancer

    Science.gov (United States)

    1996-10-01

    obtained. Eight micron histologic sections were prepared and analyzed by immunohistochemistry using chicken-anti human IL-8 antibody and the Avidin -Biotin... Egg yolks containing antibody were processed as previously described (need ref). Antibody titer and specificity were assessed by double-immunodiffusion...vitro cytokine paper Scott H. Kurtzman, M.D. Hill, NJ) prepared in Hunger’s Titer Max (CYTRX Corp., Norcross, GA). Egg yolks containing antibody were

  13. Cytokines and perinatal brain injury.

    Science.gov (United States)

    Silverstein, F S; Barks, J D; Hagan, P; Liu, X H; Ivacko, J; Szaflarski, J

    1997-01-01

    A rapidly expanding body of data provides support for the hypothesis that pro-inflammatory cytokines including interleukin-1 beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) are expressed acutely in injured brain and contribute to progressive neuronal damage. Little is known about the pathogenetic role of these cytokines in perinatal brain injury. Recent experimental studies have incorporated two closely related in vivo perinatal rodent brain injury models to evaluate the role(s) of pro-inflammatory cytokines in the progression of neuronal injury: a perinatal stroke model, elicited by unilateral carotid artery ligation and subsequent timed exposure to 8% oxygen in 7-day-old rats, and a model of excitotoxic injury, elicited by stereotactic intra-cerebral injection of the selective excitatory amino acid agonist NMDA. Each of these lesioning methods results in reproducible, quantifiable focal forebrain injury at this developmental stage. Acute brain injury, evoked by cerebral hypoxia-ischemia or excitotoxin lesioning, results in transient marked increases in expression of IL-1 beta, and TNF-alpha mRNA in brain regions susceptible to irreversible injury, and there is evidence that pharmacological antagonism of IL-1 receptors can attenuate injury in both models. Recent studies also suggest that complementary strategies, based on pharmacological antagonism of platelet activating factor and on neutrophil depletion can also limit the extent of irreversible injury. In summary, current data suggest that pro-inflammatory cytokines contribute to the progression of perinatal brain injury, and that these mediators are important targets for neuroprotective interventions in the acute post-injury period.

  14. A designer hyper interleukin 11 (H11 is a biologically active cytokine

    Directory of Open Access Journals (Sweden)

    Dams-Kozlowska Hanna

    2012-03-01

    Full Text Available Abstract Background Interleukin 11 (IL-11 is a pleiotropic cytokine with anti-apoptotic, anti-inflammatory and hematopoietic potential. The IL-11 activity is determined by the expression of the IL-11R receptor alpha (IL-11Rα and the signal transducing subunit β (gp130 on the cell membrane. A recombinant soluble form of the IL-11Rα (sIL-11Rα in combination with IL-11 acts as an agonist on cells expressing the gp130 molecule. We constructed a designer cytokine Hyper IL-11 (H11, which is exclusively composed of naturally existing components. It contains the full length sIL-11Rα connected with the mature IL-11 protein using their natural sequences only. Such a construct has two major advantages: (i its components are as close as possible to the natural forms of both proteins and (ii it lacks an artificial linker what should avoid induction of antibody production. Results The H11 construct was generated, the protein was produced in a baculovirus expression system and was then purified by using ion exchange chromatography. The H11 protein displayed activity in three independent bioassays, (i it induced acute phase proteins production in HepG2 cells expressing IL-11, IL-11Rα and gp130, (ii it stimulated the proliferation of B9 cells (cells expressing IL-11Rα and gp130 and (iii proliferation of Baf/3-gp130 cells (cells not expressing IL-11 and IL-11Rα but gp130. Moreover, the preliminary data indicated that H11 was functionally distinct from Hyper-IL-6, a molecule which utilizes the same homodimer of signal transducing receptor (gp130. Conclusions The biologically active H11 may be potentially useful for treatment of thrombocytopenia, infertility, multiple sclerosis, cardiovascular diseases or inflammatory disorders.

  15. Insulin Influences Autophagy Response Distinctively in Macrophages of Different Compartments

    Directory of Open Access Journals (Sweden)

    Karen K. S. Sunahara

    2014-11-01

    Full Text Available Background/Aims: Diabetes mellitus (DM is characterized by hyperglycemia, associated to a lack or inefficiency of the insulin to regulate glucose metabolism. DM is also marked by alterations in a diversity of cellular processes that need to be further unraveled. In this study, we examined the autophagy pathway in diabetic rat macrophages before and after treatment with insulin. Methods: Bone marrow-derived macrophages (BMM, bronchoalveolar lavage (BAL and splenic tissue of diabetic male Wistar rats (alloxan, 42 mg/kg, i.v., 10 days and control rats (physiological saline, i.v.. Some diabetic rats were given neutral protamine Hagedorn insulin (4 IU, s.c. 8 h before experiments. For characterization of the model and evaluation of the effect of insulin on the autophagic process, the following analyzes were performed: (a concentrations of cytokines: interleukin (IL-1β, tumor necrosis factor (TNF-α, IL-6, IL-4, IL-10, cytokine-induced neutrophil chemoattractant (CINC-1 and CINC-2 in the BAL supernatant was measured by ELISA; (b characterization of alveolar macrophage (AM of the BAL as surface antigens (MHCII, pan-macrophage KiM2R, CD11b and autophagic markers (protein microtubule-associated light chain (LC3, autophagy protein (Atg12 by flow cytometry and confocal microscopy (c study of macrophages differentiated from the bone marrow by flow cytometry and confocal microscopy (d histology of the spleen by immunohistochemistry associated with confocal microscopy. Results: Interestingly, insulin exerted antagonistic effects on macrophages from different tissues. Macrophages from bronchoalveolar lavage (BAL enhanced their LC3 autophagosome bound content after treatment with insulin whereas splenic macrophages from red pulp in diabetic rats failed to enhance their Atg 12 levels compared to control animals. Insulin treatment in diabetic rats did not change LC3 content in bone marrow derived macrophages (BMM. M1 and M2 macrophages behaved accordingly to the

  16. The role of cytokine deficiencies and cytokine autoantibodies in clinical dermatology

    DEFF Research Database (Denmark)

    Liszewski, Walter; Gniadecki, Robert

    2016-01-01

    Cytokines are small, secreted proteins that are essential for promoting and maintaining a normal immune response. Upregulation of cytokines frequently occurs in autoimmune and inflammatory diseases. Conversely, several immunodeficiency, autoimmune and autoinflammatory disorders are known to occur...... review the role of cytokine deficiencies and cytokine autoantibodies in immunodeficiency syndromes, as well as in autoimmune disorders. Finally, we will examine autoinflammatory disorders due to cytokine deficiencies....

  17. Distinct functional programming of human fetal and adult monocytes.

    Science.gov (United States)

    Krow-Lucal, Elisabeth R; Kim, Charles C; Burt, Trevor D; McCune, Joseph M

    2014-03-20

    Preterm birth affects 1 out of 9 infants in the United States and is the leading cause of long-term neurologic handicap and infant mortality, accounting for 35% of all infant deaths in 2008. Although cytokines including interferon-γ (IFN-γ), interleukin-10 (IL-10), IL-6, and IL-1 are produced in response to in utero infection and are strongly associated with preterm labor, little is known about how human fetal immune cells respond to these cytokines. We demonstrate that fetal and adult CD14(+)CD16(-) classical monocytes are distinct in terms of basal transcriptional profiles and in phosphorylation of signal transducers and activators of transcription (STATs) in response to cytokines. Fetal monocytes phosphorylate canonical and noncanonical STATs and respond more strongly to IFN-γ, IL-6, and IL-4 than adult monocytes. We demonstrate a higher ratio of SOCS3 to IL-6 receptor in adult monocytes than in fetal monocytes, potentially explaining differences in STAT phosphorylation. Additionally, IFN-γ signaling results in upregulation of antigen presentation and costimulatory machinery in adult, but not fetal, monocytes. These findings represent the first evidence that primary human fetal and adult monocytes are functionally distinct, potentially explaining how these cells respond differentially to cytokines implicated in development, in utero infections, and the pathogenesis of preterm labor.

  18. Cytokine-mediated FOXO3a phosphorylation suppresses FasL expression in hemopoietic cell lines: investigations of the role of Fas in apoptosis due to cytokine starvation.

    Science.gov (United States)

    Behzad, Hayedeh; Jamil, Sarwat; Denny, Trisha A; Duronio, Vincent

    2007-05-01

    We have investigated phosphatidylinositol 3-kinase (PI3K)-dependent survival signalling pathways using several cytokines in three different hemopoietic cell lines, MC/9, FDC-P1, and TF-1. Cytokines caused PI3K- and PKB-dependent phosphorylation of FOXO3a (previously known as FKHRL1) at three distinct sites. Following cytokine withdrawal or PI3K inhibition, both of which are known to lead to apoptosis, there was a loss of FOXO3a phosphorylation, and a resulting increase in forkhead transcriptional activity, along with increased expression of Fas Ligand (FasL), which could be detected at the cell surface. Concurrently, an increase in cell surface expression of Fas was also detected. Despite the presence of both FasL and Fas, there was no detectable evidence that activation of Fas-mediated apoptotic events was contributing to apoptosis resulting from cytokine starvation or inhibition of PI3K activity. Thus, inhibition of FOXO3a activity is mediated by the PI3K-PKB pathway, but regulation of FasL is not the primary means by which cell survival is regulated in cytokine-dependent hemopoietic cells. We were also able to confirm increased expression of known FOXO3a targets, Bim and p27kip1. Together, these results support the conclusion that mitochondrial-mediated signals play the major role in apoptosis of hemopoietic cells due to loss of cytokine signalling.

  19. Transcriptional Crosstalk between Nuclear Receptors and Cytokine Signal Transduction Pathways in Immunity

    Institute of Scientific and Technical Information of China (English)

    Lihua Wang; Xiaohu Zhang; William L. Farrar; Xiaoyi Yang

    2004-01-01

    The nuclear receptor superfamily and the transcriptional factors associated with cytokines are inherently different families of signaling molecules and activate gene transcription by binding to their respective responsive element. However, it has become increasingly clear from our works and others that nuclear receptors are important regulators of cytokine production and function through complex and varied interactions between these distinct transcriptional factors. This review provides a general overview of the mechanism of action of nuclear receptors and their transcriptional crosstalk with transcriptional factors associated with cytokine transduction pathways. One of the most important mechanistic aspects is protein to protein interaction through a direct or co-regulator-mediated indirect manner. Such crosstalk is crucially involved in physiological and therapeutic roles of nuclear receptors and their ligands in immunity,inflammation and cytokine-related tumors. Cellular & Molecular Immunology. 2004;1(6):416-424.

  20. Cytokine Gene Expression in CD4 Positive Cells of the Japanese Pufferfish, Takifugu rubripes.

    Directory of Open Access Journals (Sweden)

    Tomoya Kono

    Full Text Available CD4(+ T (Th cells are a central component of the adaptive immune response and are divided into distinct sets based on their specific cytokine production pattern. Several reports have suggested that fish possess Th subset activity similar to that of mammals. The aim of the present study was to isolate CD4(+ T cells from the blood of Japanese pufferfish, Fugu rubripes, and to characterize their cytokine expression profile. We produced a specific antibody against Fugu CD4 and performed cell sorting with the magnetic activated cell sorting system. Sorted Fugu CD4(+ cells were characterized by morphology and expression analysis of cell marker genes. Fugu CD4(+ cells expressed T-cell marker genes but not macrophage or B-cell marker genes. In addition, peripheral blood lymphocytes were stimulated with lipopolysaccharide (LPS, polycytidylic acid (polyI:C, concanavalin A (ConA prior to sorting, and then Multiplex RT-PCR was used to examine the expression of Th cytokines by the stimulated Fugu CD4(+ cells. LPS and polyI:C stimulation upregulated the expression of Th1, Th17 and Treg cytokines and downregulated the expression of Th2 cytokines. ConA stimulation upregulated the expression of all Th cytokines. These results suggest that fish exhibit the same upregulation of Th-specific cytokine expression as in mammals.

  1. Differential regulation of monocyte cytokine release by αV and β2 integrins that bind CD23

    Science.gov (United States)

    Edkins, Adrienne L; Borland, Gillian; Acharya, Mridu; Cogdell, Richard J; Ozanne, Bradford W; Cushley, William

    2012-01-01

    The human soluble CD23 (sCD23) protein displays highly pleiotropic cytokine-like activity. Monocytic cells express the sCD23-binding integrins αVβ3, αVβ5, αMβ2 and αXβ2, but it is unclear which of these four integrins most acutely regulates sCD23-driven cytokine release. The hypothesis that ligation of different sCD23-binding integrins promoted release of distinct subsets of cytokines was tested. Lipopolysaccharide (LPS) and sCD23 promoted release of distinct groups of cytokines from the THP-1 model cell line. The sCD23-driven cytokine release signature was characterized by elevated amounts of RANTES (CCL5) and a striking increase in interleukin-8 (IL-8; CXCL8) secretion, but little release of macrophage inflammatory protein 1β (MIP-1β; CCL4). Antibodies to αVβ3 or αXβ2 both promoted IL-8 release, consistent with the sCD23-driven pattern, but both also evoked strong MIP-1β secretion; simultaneous ligation of these two integrins further increased cytokine secretion but did not alter the pattern of cytokine output. In both model cell lines and primary tissue, integrin-mediated cytokine release was more pronounced in immature monocyte cells than in mature cells. The capacity of anti-integrin monoclonal antibodies to elicit a cytokine release response is epitope-dependent and also reflects the differentiation state of the cell. Although a pattern of cytokine release identical to that provoked by sCD23 could not be elicited with any individual anti-integrin monoclonal antibody, αXβ2 and αVβ3 appear to regulate IL-8 release, a hallmark feature of sCD23-driven cytokine secretion, more acutely than αMβ2 or αVβ5. PMID:22348662

  2. 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...

  3. Bioanalytical chemistry of cytokines--a review.

    Science.gov (United States)

    Stenken, Julie A; Poschenrieder, Andreas J

    2015-01-01

    Cytokines are bioactive proteins produced by many different cells of the immune system. Due to their role in different inflammatory disease states and maintaining homeostasis, there is enormous clinical interest in the quantitation of cytokines. The typical standard methods for quantitation of cytokines are immunoassay-based techniques including enzyme-linked immusorbent assays (ELISA) and bead-based immunoassays read by either standard or modified flow cytometers. A review of recent developments in analytical methods for measurements of cytokine proteins is provided. This review briefly covers cytokine biology and the analysis challenges associated with measurement of these biomarker proteins for understanding both health and disease. New techniques applied to immunoassay-based assays are presented along with the uses of aptamers, electrochemistry, mass spectrometry, optical resonator-based methods. Methods used for elucidating the release of cytokines from single cells as well as in vivo collection methods are described.

  4. CYTOKINE REGULATION OF ULCEROGENESIS IN GASTRODUODENAL MUCOSA

    Directory of Open Access Journals (Sweden)

    L. V. Matveeva

    2013-01-01

    Full Text Available Ulcerogenesis in gastroduodenal mucosa area is a complex multistep process. Its, phases arecontrolled by interaction and activation of pro­ and antiinflammatory cytokine cascade. Present review article summarizes scientific data on impact of cytokines upon ulcerative and reparatory processes, a variety of their diagnostic and therapeutic options is defined. Evaluation of cytokine status, or, in some cases, cytokine genotyping in patients with stomach and duodenal ulcers, may predict clinical course of the disease, as well as efficiency of basic and eradication therapy, correction of the treatment.

  5. Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

    Directory of Open Access Journals (Sweden)

    Hideaki Hasegawa

    2016-11-01

    Full Text Available The interleukin (IL-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics in that they are composed of two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing; currently, there are more than 6 cytokines, including the tentatively named cytokines IL-Y (p28/p40, IL-12 (p35/p40, IL-23 (p19/p40, IL-27 p28/Epstein-Barr virus-induced protein 3 (EBI3, IL-35 (p35/EBI3, and IL-39 (p19/EBI3. This family of cytokines covers a very broad range of immune responses, including pro-inflammatory responses such as helper T (Th1, Th2, and Th17 to anti-inflammatory responses such as regulatory T (Treg cells and IL-10-producing Treg cells. IL-12 is the first member of this family, and IL-12, IL-23, and IL-27 are mainly produced by activated antigen-presenting cells such as dendritic cells and macrophages. IL-12 plays a critical role in the promotion of Th1 immune responses by inducing interferon-γ production to combat pathogens and malignant tumors. IL-23 induces IL-17 production and is necessary to maintain pathogenic Th17 cells that cause inflammatory and autoimmune diseases. IL-27 was initially reported to play a critical role in promotion of Th1 differentiation; however, subsequent studies revealed that IL-27 has broader stimulatory and inhibitory roles by inducing IL-10-producing Treg cells. IL-35 is produced by forkhead box P3+ Treg cells and activated B cells and has immunosuppressive functions to maintain immune tolerance. The most recently identified cytokine, IL-39, is produced by activated B cells and has pro-inflammatory functions. The cytokine tentatively named IL-Y seems to have anti-inflammatory functions by inhibiting Th1 and Th17 differentiation. In addition, individual cytokine subunits were also shown to have self-standing activities. Thus

  6. Touch communicates distinct emotions.

    Science.gov (United States)

    Hertenstein, Matthew J; Keltner, Dacher; App, Betsy; Bulleit, Brittany A; Jaskolka, Ariane R

    2006-08-01

    The study of emotional signaling has focused almost exclusively on the face and voice. In 2 studies, the authors investigated whether people can identify emotions from the experience of being touched by a stranger on the arm (without seeing the touch). In the 3rd study, they investigated whether observers can identify emotions from watching someone being touched on the arm. Two kinds of evidence suggest that humans can communicate numerous emotions with touch. First, participants in the United States (Study 1) and Spain (Study 2) could decode anger, fear, disgust, love, gratitude, and sympathy via touch at much-better-than-chance levels. Second, fine-grained coding documented specific touch behaviors associated with different emotions. In Study 3, the authors provide evidence that participants can accurately decode distinct emotions by merely watching others communicate via touch. The findings are discussed in terms of their contributions to affective science and the evolution of altruism and cooperation. (c) 2006 APA, all rights reserved

  7. Bringing distinctive TV drama?

    DEFF Research Database (Denmark)

    Jensen, Pia Majbritt; Raats, Tim

    roles of PSB. (2) Comparing public service media strategies for TV drama financing and distribution in two markets: the Flemish (i.e. Dutch-speaking part of Belgium) and the Danish market. Both cases are characterized by huge popularity of domestic tv drama and both markets are non......-Anglophone with a limited market size and hence, theoretically, limited capacity for production and export. Both cases furthermore show a crucial role of the public broadcasters as part of developing and sustaining tv drama in those markets. However, the underlying policy impetus reflect clearly different views on TV drama...... strategies, with policymakers employing TV drama in Flanders as a driver for a ‘healthy’ independent production sector (especially in VRT’s most recent management contract) and DR drama clearly driven by distinct public service characteristics. Having the said that, the latter case in recently proved its...

  8. Role of cytokines in Trypanosoma brucei-induced anaemia: A review of the literature.

    Science.gov (United States)

    Musaya, J; Matovu, E; Nyirenda, M; Chisi, J

    2015-06-01

    Anaemia is an important complication of trypanosomiasis. The mechanisms through which trypanosomal infection leads to anaemia are poorly defined. A number of studies have implicated inflammatory cytokines, but these data are limited and inconsistent. In this article, we reviewed the published literature on cytokines associated with Trypanosoma brucei infections and their role in the immunopathology leading to anaemia. Articles were searched in PubMed through screening of titles and abstracts with no limitation on date of publishing and study design. Articles in English were searched using keywords "African trypanosomiasis", "sleeping sickness", "Trypanosoma brucei", in all possible combinations with "anaemia" and/or "cytokines". Twelve articles examining cytokines and their role in trypanosomeinduced anaemia were identified out of 1095 originally retrieved from PubMed. None of the articles identified were from human-based studies. A total of eight cytokines were implicated, with four cytokines (IFN-γ, IL-10, TNF-α, IL-12) showing an association with anaemia. These articles reported that mice lacking TNF-α were able to control anaemia, and that IFN-γ was linked to severe anaemia given its capacity to suppress erythropoiesis, while IL-10 was shown to regulate IFN-γ and TNF-α, providing a balance that was associated with severity of anaemia. IFN-γ and TNF-α have also been reported to work in concert with other factors such as nitric oxide and iron in order to induce anaemia. IFN-γ, IL-10, and TNF-α were the three major cytokines identified to be heavily involved in anaemia caused by Trypanosoma brucei infection. The anti-inflammatory cytokine, IL-10, was shown to counter the effects of proinflammatory cytokines in order to balance the severity of anaemia. The mechanism of anaemia is multifactorial and therefore requires further, more elaborate research. Data from human subjects would also shed more light.

  9. Cytokine profile of cervical cancer cells

    NARCIS (Netherlands)

    Hazelbag, S; Fleuren, GJ; Baelde, JJ; Schuuring, E; Kenter, GG; Gorter, A

    2001-01-01

    Objective. In patients with cervical carcinoma, the presence of cytokines produced by T(H)2 cells, and the presence of an eosinophilic inflammatory infiltrate, has been associated with a less effective immune response and tumor progression. In the present study, we have investigated the cytokine pro

  10. Cytokines and organ failure in acute pancreatitis

    DEFF Research Database (Denmark)

    Malmstrøm, Marie Louise; Hansen, Mark Berner; Andersen, Anders Møller

    2012-01-01

    We aimed at synchronously examining the early time course of 4 proinflammatory cytokines as predictive factors for development of organ failure in patients with acute pancreatitis (AP).......We aimed at synchronously examining the early time course of 4 proinflammatory cytokines as predictive factors for development of organ failure in patients with acute pancreatitis (AP)....

  11. 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 deve

  12. Cytokines and mood in healthy young adults

    NARCIS (Netherlands)

    Jansen, J.; Fernstrand, A.M.; Van De Loo, A.J.A.E.|info:eu-repo/dai/nl/369403649; Garssen, J.|info:eu-repo/dai/nl/086369962; Verster, J.C.|info:eu-repo/dai/nl/241442702

    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 deve

  13. Compartmentalized Cytokine Responses in Hidradenitis Suppurativa.

    Directory of Open Access Journals (Sweden)

    Theodora Kanni

    Full Text Available Favorable treatment outcomes with TNF blockade led us to explore cytokine responses in hidradenitis suppurativa (HS.Blood monocytes of 120 patients and 24 healthy volunteers were subtyped by flow cytometry. Isolated blood mononuclear cells (PBMCs were stimulated for cytokine production; this was repeated in 13 severe patients during treatment with etanercept. Cytokines in pus were measured.CD14brightCD16dim inflammatory monocytes and patrolling monocytes were increased in Hurley III patients. Cytokine production by stimulated PBMCs was low compared to controls but the cytokine gene copies did not differ, indicating post-translational inhibition. The low production of IL-17 was restored, when cells were incubated with adalimumab. In pus, high concentrations of pro-inflammatory cytokines were detected. Based on the patterns, six different cytokine profiles were discerned, which are potentially relevant for the choice of treatment. Clinical improvement with etanercept was predicted by increased production of IL-1β and IL-17 by PBMCs at week 8.Findings indicate compartmentalized cytokine expression in HS; high in pus but suppressed in PBMCs. This is modulated through blockade of TNF.

  14. Cytokines in clinical and experimental transplantation

    NARCIS (Netherlands)

    A.C.Th.M. Vossen (Ann); H.F.J. Savelkoul (Huub)

    1994-01-01

    textabstractAllograft rejection is a complex process, which requires interactions between different cell types and a variety of soluble factors, such as cytokines. In this review we discuss the role of cytokines in the induction and effector phases of the rejection process and in the induction and m

  15. Interactions between Autophagy and Inhibitory Cytokines

    Science.gov (United States)

    Wu, Tian-tian; Li, Wei-Min; Yao, Yong-Ming

    2016-01-01

    Autophagy is a degradative pathway that plays an essential role in maintaining cellular homeostasis. Most early studies of autophagy focused on its involvement in age-associated degeneration and nutrient deprivation. However, the immunological functions of autophagy have become more widely studied in recent years. Autophagy has been shown to be an intrinsic cellular defense mechanism in the innate and adaptive immune responses. Cytokines belong to a broad and loose category of proteins and are crucial for innate and adaptive immunity. Inhibitory cytokines have evolved to permit tolerance to self while also contributing to the eradication of invading pathogens. Interactions between inhibitory cytokines and autophagy have recently been reported, revealing a novel mechanism by which autophagy controls the immune response. In this review, we discuss interactions between autophagy and the regulatory cytokines IL-10, transforming growth factor-β, and IL-27. We also mention possible interactions between two newly discovered cytokines, IL-35 and IL-37, and autophagy. PMID:27313501

  16. Interactions between Autophagy and Inhibitory Cytokines.

    Science.gov (United States)

    Wu, Tian-Tian; Li, Wei-Min; Yao, Yong-Ming

    2016-01-01

    Autophagy is a degradative pathway that plays an essential role in maintaining cellular homeostasis. Most early studies of autophagy focused on its involvement in age-associated degeneration and nutrient deprivation. However, the immunological functions of autophagy have become more widely studied in recent years. Autophagy has been shown to be an intrinsic cellular defense mechanism in the innate and adaptive immune responses. Cytokines belong to a broad and loose category of proteins and are crucial for innate and adaptive immunity. Inhibitory cytokines have evolved to permit tolerance to self while also contributing to the eradication of invading pathogens. Interactions between inhibitory cytokines and autophagy have recently been reported, revealing a novel mechanism by which autophagy controls the immune response. In this review, we discuss interactions between autophagy and the regulatory cytokines IL-10, transforming growth factor-β, and IL-27. We also mention possible interactions between two newly discovered cytokines, IL-35 and IL-37, and autophagy.

  17. Cytokines in juvenile rheumatoid arthritis (JRA).

    Science.gov (United States)

    Mangge, H; Schauenstein, K

    1998-06-01

    Juvenile rheumatoid arthritis (JRA), unlike rheumatoid arthritis of adulthood (RA), is a heterogenous disease comprising at least five subtypes that differ in clinical course and prognosis, and require different therapeutical approaches. As compared to RA, the production of local and systemic cytokines in JRA have not yet been as extensively investigated. In this article we review the available literature on cytokine expression in serum and synovial fluid in all five different subtypes of JRA. Even though the data are still fragmentary, the evidence so far suggests that the determination of serum cytokines yields relevant information as to clinical subtype and inflammatory activity of the disease. Furthermore, the cytokine data suggest that the pathogenesis of JRA may even by more heterogenous than defined by the clinical subtypes. Finally, future directions of research in this area are proposed, and-based on the latest results-arguments for (anti)cytokine therapies in JRA are critically discussed.

  18. Cytokines and Immune Responses in Murine Atherosclerosis.

    Science.gov (United States)

    Kusters, Pascal J H; Lutgens, Esther

    2015-01-01

    Atherosclerosis is an inflammatory disease of the vessel wall characterized by activation of the innate immune system, with macrophages as the main players, as well as the adaptive immune system, characterized by a Th1-dominant immune response. Cytokines play a major role in the initiation and regulation of inflammation. In recent years, many studies have investigated the role of these molecules in experimental models of atherosclerosis. While some cytokines such as TNF or IFNγ clearly had atherogenic effects, others such as IL-10 were found to be atheroprotective. However, studies investigating the different cytokines in experimental atherosclerosis revealed that the cytokine system is complex with both disease stage-dependent and site-specific effects. In this review, we strive to provide an overview of the main cytokines involved in atherosclerosis and to shed light on their individual role during atherogenesis.

  19. Cytokine signalling in embryonic stem cells

    DEFF Research Database (Denmark)

    Kristensen, David Møbjerg; Kalisz, Mark; Nielsen, Jens Høiriis

    2006-01-01

    Cytokines play a central role in maintaining self-renewal in mouse embryonic stem (ES) cells through a member of the interleukin-6 type cytokine family termed leukemia inhibitory factor (LIF). LIF activates the JAK-STAT3 pathway through the class I cytokine receptor gp130, which forms a trimeric...... pathways seem to converge on c-myc as a common target to promote self-renewal. Whereas LIF does not seem to stimulate self-renewal in human embryonic stem cells it cannot be excluded that other cytokines are involved. The pleiotropic actions of the increasing number of cytokines and receptors signalling...... via JAKs, STATs and SOCS exhibit considerable redundancy, compensation and plasticity in stem cells in accordance with the view that stem cells are governed by quantitative variations in strength and duration of signalling events known from other cell types rather than qualitatively different stem...

  20. Distinctive Cytokines as Biomarkers Predicting Fatal Outcome of Severe Staphylococcus aureus Bacteremia in Mice

    NARCIS (Netherlands)

    S. van den Berg (Sanne); J.D. Laman (Jon); L. Boon (Louis); M.T. ten Kate (Marian); G.J. de Knegt (Gerjo); R.M. Verdijk (Robert); H.A. Verbrugh (Henri); J.L. Nouwen (Jan); I.A.J.M. Bakker-Woudenberg (Irma)

    2013-01-01

    textabstractInvasive Staphylococcus aureus infections are frequently associated with bacteraemia. To support clinical decisions on antibiotic therapy, there is an urgent need for reliable markers as predictors of infection outcome. In the present study in mice, bacteraemia was established by intrave

  1. Distinct patterns of cytokine regulation in discrete clinical forms of Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Akanmori, B D; Kurtzhals, J A; Goka, B Q;

    2000-01-01

    The pathogenesis of two of the most severe complications of Plasmodium falciparum malaria, cerebral malaria (CM) and severe malarial anaemia (SA) both appear to involve dysregulation of the immune system. We have measured plasma levels of TNF and its two receptors in Ghanaian children with strictly...... defined cerebral malaria (CM), severe malarial anaemia (SA), or uncomplicated malaria (UM) in two independent studies in an area of seasonal, hyperendemic transmission of P. falciparum. Levels of TNF, soluble TNF receptor 1 (sTNF-R1) and 2 (sTNF-R2) were found to be significantly higher in CM than...... in the other clinical categories of P. falciparum malaria patients. Levels of both receptors depended on clinical category, whereas only sTNF-R1 levels were significantly dependent on parasitemia. Detailed analysis of the interrelationship between these variables resolved this pattern further, and identified...

  2. Cytokines and pregnancy in rheumatic disease.

    Science.gov (United States)

    Østensen, Monika; Förger, Frauke; Villiger, Peter M

    2006-06-01

    Cytokines are important mediators involved in the successful outcome of pregnancy. The concept of pregnancy as biased toward a Th2 immune response states that Th1 type cytokines are associated with pregnancy failure and that Th2 cytokines are protective and counteract pregnancy-related disorders. Studies at the level of the maternal-fetal interface, in the maternal circulation and in cells of peripheral blood have shown that the Th2 concept of pregnancy is an oversimplification. Both Th1 and Th2 type cytokines play a role at different stages of pregnancy and are adapted to the localization and function of cells and tissues. The changes of local and systemic cytokine patterns during pregnancy correspond to neuroendocrine changes with hormones as powerful modulators of cytokine expression. Several autoimmune disorders show a modulation of disease activity during and after pregnancy. In rheumatic diseases with a predominance of a Th1 immune response, a shift to a Th2 type immune response during pregnancy has been regarded as beneficial. Studies of pregnant patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have shown a cytokine expression similar to that found in healthy pregnant women. Significant differences were present only for a few cytokines and seemed related to the activity of the underlying disease. Interestingly, a gestational increase of cytokine inhibitors interleukin 1 receptor antagonist (IL-1ra) and soluble tumor necrosis factor receptor (sTNFR) in the circulation corresponded to low disease activity in RA. The influence of hormones and cytokines on autoimmune disease is an issue for further study.

  3. Tc17 cells mediate vaccine immunity against lethal fungal pneumonia in immune deficient hosts lacking CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Som Gowda Nanjappa

    Full Text Available Vaccines may help reduce the growing incidence of fungal infections in immune-suppressed patients. We have found that, even in the absence of CD4(+ T-cell help, vaccine-induced CD8(+ T cells persist and confer resistance against Blastomyces dermatitidis and Histoplasma capsulatum. Type 1 cytokines contribute to that resistance, but they also are dispensable. Although the role of T helper 17 cells in immunity to fungi is debated, IL-17 producing CD8(+ T cells (Tc17 cells have not been investigated. Here, we show that Tc17 cells are indispensable in antifungal vaccine immunity in hosts lacking CD4(+ T cells. Tc17 cells are induced upon vaccination, recruited to the lung on pulmonary infection, and act non-redundantly in mediating protection in a manner that requires neutrophils. Tc17 cells did not influence type I immunity, nor did the lack of IL-12 signaling augment Tc17 cells, indicating a distinct lineage and function. IL-6 was required for Tc17 differentiation and immunity, but IL-1R1 and Dectin-1 signaling was unexpectedly dispensable. Tc17 cells expressed surface CXCR3 and CCR6, but only the latter was essential in recruitment to the lung. Although IL-17 producing T cells are believed to be short-lived, effector Tc17 cells expressed low levels of KLRG1 and high levels of the transcription factor TCF-1, predicting their long-term survival and stem-cell like behavior. Our work has implications for designing vaccines against fungal infections in immune suppressed patients.

  4. Tc17 cells mediate vaccine immunity against lethal fungal pneumonia in immune deficient hosts lacking CD4+ T cells.

    Science.gov (United States)

    Nanjappa, Som Gowda; Heninger, Erika; Wüthrich, Marcel; Gasper, David Joseph; Klein, Bruce S

    2012-01-01

    Vaccines may help reduce the growing incidence of fungal infections in immune-suppressed patients. We have found that, even in the absence of CD4(+) T-cell help, vaccine-induced CD8(+) T cells persist and confer resistance against Blastomyces dermatitidis and Histoplasma capsulatum. Type 1 cytokines contribute to that resistance, but they also are dispensable. Although the role of T helper 17 cells in immunity to fungi is debated, IL-17 producing CD8(+) T cells (Tc17 cells) have not been investigated. Here, we show that Tc17 cells are indispensable in antifungal vaccine immunity in hosts lacking CD4(+) T cells. Tc17 cells are induced upon vaccination, recruited to the lung on pulmonary infection, and act non-redundantly in mediating protection in a manner that requires neutrophils. Tc17 cells did not influence type I immunity, nor did the lack of IL-12 signaling augment Tc17 cells, indicating a distinct lineage and function. IL-6 was required for Tc17 differentiation and immunity, but IL-1R1 and Dectin-1 signaling was unexpectedly dispensable. Tc17 cells expressed surface CXCR3 and CCR6, but only the latter was essential in recruitment to the lung. Although IL-17 producing T cells are believed to be short-lived, effector Tc17 cells expressed low levels of KLRG1 and high levels of the transcription factor TCF-1, predicting their long-term survival and stem-cell like behavior. Our work has implications for designing vaccines against fungal infections in immune suppressed patients.

  5. Differential cytokine profiles in juvenile idiopathic arthritis subtypes revealed by cluster analysis.

    Science.gov (United States)

    van den Ham, Henk-Jan; de Jager, Wilco; Bijlsma, Johannes W J; Prakken, Berent J; de Boer, Rob J

    2009-08-01

    With the introduction of high-throughput biomarker measurements, traditional analysis of these markers is increasingly difficult. Using samples from a diverse group of patients, we tested the applicability of cluster analysis to these data. Using this method, we aim to visualize some of the patterns specific to certain disease groups. In particular, we focus on juvenile idiopathic arthritis (JIA), a multifactorial autoimmune disorder that ultimately leads to chronic inflammation of the joints. Cytokine measurements were performed using multiplex immunoassays. Using heuristic clustering methods, we set out to compare the pattern of 30 cytokines in plasma and SF of JIA, RA, OA, or diabetes type II patients and healthy controls. Analysis shows that oligo- and polyarticular JIA have similar biomarker profiles, both in plasma and SF. Systemic onset JIA (SoJIA) has a profile distinct from other JIA subtypes, suggesting that they involve different inflammatory processes. SoJIA samples do, however, cluster together with RA in SF, suggesting that these two conditions have similar cytokine profiles. Furthermore, we identify several clusters of ILs and chemokines that are co-expressed, suggesting that they are co-regulated. We show that previously undetected clusters of cytokines and patients can be identified by applying cluster analysis to multiplex data. Cytokine clusters identified in plasma and SF samples were quite different, which underscore the differential cytokine signalling in these two compartments, and suggest that plasma samples may not be suitable for estimating joint biomarker profiles and inflammation.

  6. Cytokines profiling by multiplex analysis in experimental arthritis: which pathophysiological relevance for articular versus systemic mediators?

    Science.gov (United States)

    Paquet, Joseph; Goebel, Jean-Christophe; Delaunay, Camille; Pinzano, Astrid; Grossin, Laurent; Cournil-Henrionnet, Christel; Gillet, Pierre; Netter, Patrick; Jouzeau, Jean-Yves; Moulin, David

    2012-03-13

    We have taken advantage of the large screening capacity of a multiplex immunoassay to better define the respective contribution of articular versus systemic cytokines in experimental arthritis. We performed a follow up (from 7 hours to 14 days) multiplex analysis of 24 cytokines in synovial fluid and sera of rats developing Antigen-Induced Arthritis (AIA) and confronted their protein level changes with molecular, biochemical, histological and clinical events occurring in the course of the disease. The time-scheduled findings in arthritic joints correlated with time-dependent changes of cytokine amounts in joint effusions but not with their blood levels. From seven hours after sensitization, high levels of chemokines (MCP-1, MIP1α, GRO/KC, RANTES, eotaxin) were found in synovial fluid of arthritic knees whereas perivascular infiltration occurred in the synovium; local release of inflammatory cytokines (IFNγ, IL-1β, IL-6) preceded the spreading of inflammation and resulted in progressive degradation of cartilage and bone. Finally a local overexpression of several cytokines/adipocytokines poorly described in arthritis (IL-13, IL-18, leptin) was observed. Distinct panels of cytokines were found in arthritic fluid during AIA, and the expected effect of mediators correlated well with changes occurring in joint tissues. Moreover, multiplex analysis could be helpful to identify new pathogenic mediators and to elucidate the mechanisms supporting the efficacy of putative targeted therapies.

  7. Detection of inflammatory cytokines using a fiber optic microsphere immunoassay array

    Science.gov (United States)

    Blicharz, Timothy M.; Walt, David R.

    2006-10-01

    A multiplexed fiber optic microsphere-based immunoassay array capable of simultaneously measuring five inflammatory cytokines has been developed. Five groups of amine-functionalized 3.1 micron microspheres were internally encoded with five distinct concentrations of a europium dye and converted to cytokine probes by covalently coupling monoclonal capture antibodies specific for human VEGF, IFN-gamma, RANTES, IP-10, and Eotaxin-3 to the microspheres via glutaraldehyde chemistry. The microspheres were pooled and loaded into a 1 mm diameter fiber optic bundle containing ~50,000 individual etched microwells, producing the multiplexed cytokine immunoassay array. Multiple arrays can be created from a single microsphere pool for high throughput sample analysis. Sandwich fluoroimmunoassays were performed by incubating the probe array in a sample, followed by incubation in a mixture of biotin-labeled detection antibodies that are complementary to the five cytokines. Finally, universal detection of each protein was performed using a fluorescence imaging system after briefly immersing the array in a solution of fluorophore-labeled streptavidin. The multiplexed cytokine array has been shown to respond selectively to VEGF, IFNgamma, RANTES, IP-10, and Eotaxin-3, permitting multiplexed quantitative analysis. Ultimately, the multiplexed cytokine array will be utilized to evaluate the potential of using saliva as a noninvasive diagnostic fluid for pulmonary inflammatory diseases such as asthma.

  8. 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.

  9. Global Cytokine Profiles and Association With Clinical Characteristics in Patients With Irritable Bowel Syndrome.

    Science.gov (United States)

    Bennet, Sean M P; Polster, Annikka; Törnblom, Hans; Isaksson, Stefan; Capronnier, Sandrine; Tessier, Aurore; Le Nevé, Boris; Simrén, Magnus; Öhman, Lena

    2016-08-01

    Evidence suggests that patients with irritable bowel syndrome (IBS) have an altered cytokine profile, although it is unclear whether cytokines are linked with symptom severity. We aimed to determine whether global serum and mucosal cytokine profiles differ between IBS patients and healthy subjects and whether cytokines are associated with IBS symptoms. Serum from 144 IBS patients and 42 healthy subjects was analyzed for cytokine levels of interleukin (IL)-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, interferon (IFN)-γ, and tumor necrosis factor (TNF) by MSD MULTI-ARRAY. In total, 109 IBS and 36 healthy sigmoid colon biopsies were analyzed for mRNA expression of IL-8, IL-10, TNF, and FOXP3 by quantitative reverse transcription PCR. Multivariate discrimination analysis evaluated global cytokine profiles. Rectal sensitivity, oroanal transit time, and psychological and gastrointestinal symptom severity were also assessed. Global cytokine profiles of IBS patients and healthy subjects overlapped, but cytokine levels varied more in IBS patients. Serum levels of IL-6 and IL-8 tended to be increased and levels of IFN-γ tended to be decreased in IBS patients. Mucosal mRNA expression of IL-10 and FOXP3 tended to be decreased in IBS patients. Within both the full study cohort and IBS patients alone, serum level of TNF was associated with looser stool pattern, while subjects with more widespread somatic symptoms had increased serum levels of IL-6. Although neither IBS bowel habit subgroups nor patients with possible post-infectious IBS were associated with distinct cytokine profiles, a small cluster of IBS patients with comparatively elevated immune markers was identified. Global cytokine profiles did not discriminate IBS patients from healthy subjects, but cytokine profiles were more varied among IBS patients than among healthy subjects, and a small subgroup of patients with enhanced immune activity was identified. Also, association of inflammatory cytokines with some

  10. Photonic crystal enhanced cytokine immunoassay.

    Science.gov (United States)

    Mathias, Patrick C; Ganesh, Nikhil; Cunningham, Brian T

    2009-01-01

    Photonic crystal surfaces are demonstrated as a means for enhancing the detection sensitivity and resolution for assays that use a fluorescent tag to quantify the concentration of an analyte protein molecule in a liquid test sample. Computer modeling of the spatial distribution of resonantly coupled electromagnetic fields on the photonic crystal surface are used to estimate the magnitude of enhancement factor compared to performing the same fluorescent assay on a plain glass surface, and the photonic crystal structure is fabricated and tested to experimentally verify the performance using a sandwich immunoassay for the protein Tumor Necrosis Factor-alpha (TNF-alpha). The demonstrated photonic crystal fabrication method utilizes a nanoreplica molding technique that allows for large-area inexpensive fabrication of the structure in a format that is compatible with confocal microarray laser scanners. The signal-to-noise ratio for fluorescent spots on the photonic crystal is increased by at least five-fold relative to the glass slide, allowing a TNF-alpha concentration of 1.6 pg/ml to be distinguished from noise on a photonic crystal surface. In addition, the minimum quantitative limit of detection on the photonic crystal surface is one-third the limit on the glass slide - a decrease from 18 pg/ml to 6 pg/ml. The increased performance of the immunoassay allows for more accurate quantitation of physiologically relevant concentrations of TNF-alpha in a protein microarray format that can be expanded to multiple cytokines.

  11. Inflammatory cytokines in newborn infants

    Directory of Open Access Journals (Sweden)

    A. Sarandakou

    1998-01-01

    Full Text Available Serum levels of IL-1β, IL-6 and TNF-α were measured in 48 healthy, termed neonates on the 1st (N1, 5th (N5 and 40th (N40 day after birth, compared with those in maternal serum (MS, umbilical cord (UC and adult controls. Cytokine values in N1 and N5 were significantly elevated, than those in UC and in controls (p<0.0001. IL-1β and IL-6 declined significantly from N1 to N40 (p<0.0001, while TNF-α increased significantly from N1 to N5 and declined thereafter. MS ∞ IL-1β and IL-6, but not MS ∞ TNF-α, were significantly higher than those of controls (p<0.0001. IL-1β values depended on the mode of delivery. In conclusion, the increased concentrations of IL-1 β, IL-6 and TNF-α during the perinatal period might suggest their involvement in an inflammation like process during normal parturition, and reflect also a newborn immune response to the stress of delivery and environmental changes.

  12. Lack of Set Theory Relevant Prerequisite Knowledge

    Science.gov (United States)

    Dogan-Dunlap, Hamide

    2006-01-01

    Many students struggle with college mathematics topics due to a lack of mastery of prerequisite knowledge. Set theory language is one such prerequisite for linear algebra courses. Many students' mistakes on linear algebra questions reveal a lack of mastery of set theory knowledge. This paper reports the findings of a qualitative analysis of a…

  13. Cytokine medicines in clinical practice: current issues.

    Science.gov (United States)

    Barnes, Theresa; Moots, Robert J; Goodacre, John

    2005-10-21

    Cytokine medicines have been licensed for the treatment of rheumatoid arthritis since 2000. The rheumatology community has accrued a large amount of experience in the use of these medications. This experience has led to the development of guidelines for their use that include ongoing vigilance for long term adverse events and efficacy using the Biologics Register. Delivery of these expensive therapies has prompted extensive system developments within rheumatology. The cytokine medicines have provided important tools to probe the pathogenesis of rheumatoid and other inflammatory diseases. Further cytokine medicines, in various stages of development, are on the horizon and continue to stimulate excitement within this fast expanding field.

  14. Th17 cytokines induce pro-fibrotic cytokines release from human eosinophils.

    Science.gov (United States)

    Al-Muhsen, Saleh; Letuve, Severine; Vazquez-Tello, Alejandro; Pureza, Mary Angeline; Al-Jahdali, Hamdan; Bahammam, Ahmed S; Hamid, Qutayba; Halwani, Rabih

    2013-03-13

    Subepithelial fibrosis is one of the most critical structural changes affecting bronchial airway function during asthma. Eosinophils have been shown to contribute to the production of pro-fibrotic cytokines, TGF-β and IL-11, however, the mechanism regulating this process is not fully understood. In this report, we investigated whether cytokines associated with inflammation during asthma may induce eosinophils to produce pro-fibrotic cytokines. Eosinophils were isolated from peripheral blood of 10 asthmatics and 10 normal control subjects. Eosinophils were stimulated with Th1, Th2 and Th17 cytokines and the production of TGF-β and IL-11 was determined using real time PCR and ELISA assays. The basal expression levels of eosinophil derived TGF-β and IL-11 cytokines were comparable between asthmatic and healthy individuals. Stimulating eosinophils with Th1 and Th2 cytokines did not induce expression of pro-fibrotic cytokines. However, stimulating eosinophils with Th17 cytokines resulted in the enhancement of TGF-β and IL-11 expression in asthmatic but not healthy individuals. This effect of IL-17 on eosinophils was dependent on p38 MAPK activation as inhibiting the phosphorylation of p38 MAPK, but not other kinases, inhibited IL-17 induced pro-fibrotic cytokine release. Th17 cytokines might contribute to airway fibrosis during asthma by enhancing production of eosinophil derived pro-fibrotic cytokines. Preventing the release of pro-fibrotic cytokines by blocking the effect of Th17 cytokines on eosinophils may prove to be beneficial in controlling fibrosis for disorders with IL-17 driven inflammation such as allergic and autoimmune diseases.

  15. Whole Blood Activation Results in Enhanced Detection of T Cell and Monocyte Cytokine Production by Flow Cytometry

    Science.gov (United States)

    Sams, Clarence F.; Crucian, Brian E.

    2001-01-01

    An excellent monitor of the immune balance of peripheral circulating cells is to determine their cytokine production patterns in response to stimuli. Using flow cytometry a positive identification of cytokine producing cells in a mixed culture may be achieved. Recently, the ability to assess cytokine production following a wholeblood activation culture has been described. We compared whole blood culture to standard PBMC culture and determined the individual cytokine secretion patterns for both T cells and monocytes via flow cytometry. For T cells cytokine assessment following PMA +ionomycin activation: (1) a significantly greater percentages of T cells producing IFNgamma and IL-2 were observed following whole-blood culture; (2) altered T cell cytokine production kinetics were observed by varying whole blood culture times. In addition, a four-color cytometric analysis was used to allow accurate phenotyping and quantitation of cytokine producing lymphocyte populations. Using this technique we found IFNgamma production to be significantly elevated in the CD3+/CD8+ T cell population as compared to the CD3+/CD8- population following five hours of whole blood activation. Conversely, IL-2 and IL-10 production were significantly elevated in the CD3+/CD8- T cell population as compared to the CD3+/CD8+ population. Monocyte cytokine production was assessed in both culture systems following LPS activation for 24 hours. A three-color flow cytometric was used to assess two cytokines in conjunction with CD 14. The cytokine pairs used for analysis were IL-1a/IL-12, and IL-10ITNFa. Nearly all monocytes were stimulated to produce IL-1a, IL-12 and TNFalpha equally well in both culture systems. Monocyte production of IL-10 was significantly elevated following whole blood culture as compared to PBMC culture. IL-12 producing monocytes appeared to be a distinct subpopulation of the IL-1a producing set, whereas IL-10 and TNFa producing monocytes were largely mutually exclusive. IL-10 and

  16. Ex vivo PBMC cytokine profile in familial Mediterranean fever patients: Involvement of IL-1β, IL-1α and Th17-associated cytokines and decrease of Th1 and Th2 cytokines.

    Science.gov (United States)

    Ibrahim, José-Noel; Jounblat, Rania; Delwail, Adriana; Abou-Ghoch, Joelle; Salem, Nabiha; Chouery, Eliane; Megarbane, André; Medlej-Hashim, Myrna; Lecron, Jean-Claude

    2014-10-01

    In order to clarify the inflammatory mechanism underlying familial Mediterranean fever (FMF), we aimed to evaluate the ex vivo cytokine profile of FMF patients during acute attacks and attack-free periods, and compare it with that of healthy controls. The study included 34 FMF patients, of whom 9 were studied during attack and remission and 24 healthy controls. Cytokine levels were evaluated by Luminex technology in serum and supernatants of PBMC (Peripheral Blood Mononuclear Cells) cultures with and without 24h stimulation of monocytes by LPS and T lymphocytes by anti-CD3/CD28 beads. Levels of IL-6 and TNF-α were higher in unstimulated and LPS-stimulated PBMC supernatants of FMF patients in crises compared to controls. In response to LPS stimulation, higher levels of IL-1β and IL-1α were found in PBMC supernatants of patients during crises compared to those in remission and to controls. IFN-γ and IL-4 levels were the lowest in unstimulated and anti-CD3/CD28 stimulated PBMCs supernatants of patients during crises compared to remission and controls. The Th17 cytokines IL-17 and IL-22 were respectively higher in anti-CD3/CD28 stimulated PBMC supernatants of FMF patients during and between crises compared to controls. Amongst cytokines tested in serum, only IL-6 and TNFα were enhanced in FMF patients. The ex vivo study represents an interesting approach to evaluate cytokines' involvement in FMF. Our results suggest an ongoing subclinical inflammation and define an elevated inflammatory cytokine signature, distinctly for M694V homozygous patients. The absence of spontaneous IL-1β release by PBMCs reflects no constitutive activation of the inflammasome in FMF physiopathology.

  17. Multiplex Serum Cytokine Immunoassay Using Nanoplasmonic Biosensor Microarrays

    Science.gov (United States)

    Chen, Pengyu; Chung, Meng Ting; McHugh, Walker; Nidetz, Robert; Li, Yuwei; Fu, Jianping; Cornell, Timothy T.; Shanley, Thomas P.; Kurabayashi, Katsuo

    2015-01-01

    Precise monitoring of the rapidly changing immune status during the course of a disease requires multiplex analysis of cytokines from frequently sampled human blood. However, the current lack of rapid, multiplex, and low volume assays makes immune monitoring for clinical decision-making (e.g., critically ill patients) impractical. Without such assays, immune monitoring is even virtually impossible for infants and neonates with infectious diseases and/or immune mediated disorders as access to their blood in large quantities is prohibited. Localized surface plasmon resonance (LSPR)-based microfluidic optical biosensing is a promising approach to fill this technical gap as it could potentially permit real-time refractometric detection of biomolecular binding on a metallic nanoparticle surface and sensor miniaturization, both leading to rapid and sample-sparing analyte analysis. Despite this promise, practical implementation of such a microfluidic assay for cytokine biomarker detection in serum samples has not been established primarily due to the limited sensitivity of LSPR biosensing. Here, we developed a high-throughput, label-free, multiarrayed LSPR optical biosensor device with 480 nanoplasmonic sensing spots in microfluidic channel arrays and demonstrated parallel multiplex immunoassays of six cytokines in a complex serum matrix on a single device chip while overcoming technical limitations. The device was fabricated using easy-to-implement, one-step microfluidic patterning and antibody conjugation of gold nanorods (AuNRs). When scanning the scattering light intensity across the microarrays of AuNR ensembles with dark-field imaging optics, our LSPR biosensing technique allowed for high-sensitivity quantitative cytokine measurements at concentrations down to 5–20 pg/mL from a 1 µL serum sample. Using the nanoplasmonic biosensor microarray device, we demonstrated the ability to monitor the inflammatory responses of infants following cardiopulmonary bypass (CPB

  18. Cytokines and HCV-Related Disorders

    Directory of Open Access Journals (Sweden)

    Poupak Fallahi

    2012-01-01

    However, HCV interferes with cytokines at various levels and escapes immune response by inducing a T-helper (Th2/T cytotoxic 2 cytokine profile. Inability to control infection leads to the recruitment of inflammatory infiltrates into the liver parenchyma by interferon (IFN-gamma-inducible CXC chemokine ligand (CXCL-9, -10, and -11 chemokines, which results in sustained liver damage and eventually in liver cirrhosis. The most important systemic HCV-related extrahepatic diseases—mixed cryoglobulinemia, lymphoproliferative disorders, thyroid autoimmune disorders, and type 2 diabetes—are associated with a complex dysregulation of the cytokine/chemokine network, involving proinflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN-alpha may result in viral clearance during persistent infection and reverts this process.

  19. Dynamical Systems, Cytokine Storms, and Blood Filtration

    Science.gov (United States)

    Foster, Glenn; Hubler, Alfred

    2008-03-01

    Various infections and non-infectious diseases can trigger immune cells and the proteins (cytokines) the cells use to communicate with each other to be caught in a positive feedback loop; this ``cytokine storm'' is frequently fatal. By examining the network of cytokine-immune cell interactions we will illustrate why anti-mediator drugs have been generally ineffective in stopping this feedback. A more effective approach may be to try and reduce interactions by dampening many signals at once by filtering the cytokines out of the blood directly (think dialysis). We will argue that feedback on an out of control nonlinear dynamical system is easier to understand than its normal healthy state and apply filtration to a toy model of immune response.

  20. Lack of Exercise Might Invite Dementia

    Science.gov (United States)

    ... fullstory_163264.html Lack of Exercise Might Invite Dementia Study found being sedentary may make you as ... TV may make you as likely to develop dementia as people genetically predisposed to the condition, a ...

  1. LACK - a VoIP Steganographic Method

    CERN Document Server

    Mazurczyk, Wojciech

    2008-01-01

    The paper presents a new steganographic method called LACK (Lost Audio PaCKets Steganography) which is intended mainly for VoIP. The method is presented in a broader context of network steganography and of VoIP steganography in particular. The analytical results presented in the paper concern the influence of LACK's hidden data insertion procedure on the method's impact on quality of voice transmission and its resistance to steganalysis.

  2. Treatment of Cancer Pain by Targeting Cytokines

    OpenAIRE

    Vendrell, I.; Macedo, D.; I. Alho; Dionísio, M. R.; Costa, L.

    2015-01-01

    Inflammation is one of the most important causes of the majority of cancer symptoms, including pain, fatigue, cachexia, and anorexia. Cancer pain affects 17 million people worldwide and can be caused by different mediators which act in primary efferent neurons directly or indirectly. Cytokines can be aberrantly produced by cancer and immune system cells and are of particular relevance in pain. Currently, there are very few strategies to control the release of cytokines that seems to be relate...

  3. Native thrombocidin-1 and unfolded thrombocidin-1 exert antimicrobial activity via distinct structural elements

    NARCIS (Netherlands)

    Kwakman, P.H.S.; Krijgsveld, J.; de Boer, L.; Nguyen, L.T.; Boszhard, L.; Vreede, J.; Dekker, H.L.; Speijer, D.; Drijfhout, J.W.; te Velde, A.A.; Crielaard, W.; Vogel, H.J.; Vandenbroucke-Grauls, C.M.J.E.; Zaat, S.A.J.

    2011-01-01

    Chemokines (chemotactic cytokines) can have direct antimicrobial activity, which is apparently related to the presence of a distinct positively charged patch on the surface. However, chemokines can retain antimicrobial activity upon linearization despite the loss of their positive patch, thus questi

  4. [Proinflammatory cytokines in patients with pyelonephritis].

    Science.gov (United States)

    Gaĭseniuk, F Z; Driianskaia, V E; Drannik, G N; Rudenko, M Iu; Lavrenchuk, O V; Stepanova, N M; Stashevskaia, N V; Busygina, Iu S

    2013-09-01

    The antiinflammatory cytokines participate in antiinfective immunity, that is why it is advisable to study their peculiarities in determination of the role in immunologic pathogenesis of pyelonephritis. Of the work is to study the levels of pro-inflammatory blood cytokines in the patients with pyelonephritis (PN), to determine the peculiarities in acute and chronic its course in children and adults. The immuno-enzymic method ELISA and the corresponding test-systems were used to study the levels of cytokines in blood. There were studied the levels of pro-inflammatory cytokines (TNF, MCP and IL-23) in blood serum of patients with acute (APN) and chronic (CPN) pyelonephritis. The analysis showed the reliable increase in levels of all studied findings in both forms of PN--both in all 173 patients and in every group--children (87) and adults (86). The MCP-1 levels in APN are reliably higher than in CPN, while in TNF-b and IL-23--do not differ. The levels of all three cytokines in blood of adults were higher than in children in APN, but TNF--in CPN as well. The high level of TNF, MCP-1 and IL-23 in blood of adults and children confirm their important role both in APN and CPN, but MCP-1 can be considered as a predictor of acute/exacerbation of chronic pyelonephritis. By the findings of the studied cytokines, more expressed immune response was noted in the adults.

  5. Yeast modulation of human dendritic cell cytokine secretion: an in vitro study.

    Science.gov (United States)

    Smith, Ida M; Christensen, Jeffrey E; Arneborg, Nils; Jespersen, Lene

    2014-01-01

    Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. The concept of individual microorganisms influencing the makeup of T cell subsets via interactions with intestinal dendritic cells (DCs) appears to constitute the foundation for immunoregulatory effects of probiotics, and several studies have reported probiotic strains resulting in reduction of intestinal inflammation through modulation of DC function. Consequent to a focus on Saccharomyces boulardii as the fundamental probiotic yeast, very little is known about hundreds of non-Saccharomyces yeasts in terms of their interaction with the human gastrointestinal immune system. The aim of the present study was to evaluate 170 yeast strains representing 75 diverse species for modulation of inflammatory cytokine secretion by human DCs in vitro, as compared to cytokine responses induced by a S. boulardii reference strain with probiotic properties documented in clinical trials. Furthermore, we investigated whether cytokine inducing interactions between yeasts and human DCs are dependent upon yeast viability or rather a product of membrane interactions regardless of yeast metabolic function. We demonstrate high diversity in yeast induced cytokine profiles and employ multivariate data analysis to reveal distinct clustering of yeasts inducing similar cytokine profiles in DCs, highlighting clear species distinction within specific yeast genera. The observed differences in induced DC cytokine profiles add to the currently very limited knowledge of the cross-talk between yeasts and human immune cells and provide a foundation for selecting yeast strains for further characterization and development toward potentially novel yeast probiotics. Additionally, we present data to support a hypothesis that the interaction between yeasts and human DCs does not solely depend on yeast viability, a concept which may suggest a need for further classifications beyond the current

  6. Yeast modulation of human dendritic cell cytokine secretion: an in vitro study.

    Directory of Open Access Journals (Sweden)

    Ida M Smith

    Full Text Available Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. The concept of individual microorganisms influencing the makeup of T cell subsets via interactions with intestinal dendritic cells (DCs appears to constitute the foundation for immunoregulatory effects of probiotics, and several studies have reported probiotic strains resulting in reduction of intestinal inflammation through modulation of DC function. Consequent to a focus on Saccharomyces boulardii as the fundamental probiotic yeast, very little is known about hundreds of non-Saccharomyces yeasts in terms of their interaction with the human gastrointestinal immune system. The aim of the present study was to evaluate 170 yeast strains representing 75 diverse species for modulation of inflammatory cytokine secretion by human DCs in vitro, as compared to cytokine responses induced by a S. boulardii reference strain with probiotic properties documented in clinical trials. Furthermore, we investigated whether cytokine inducing interactions between yeasts and human DCs are dependent upon yeast viability or rather a product of membrane interactions regardless of yeast metabolic function. We demonstrate high diversity in yeast induced cytokine profiles and employ multivariate data analysis to reveal distinct clustering of yeasts inducing similar cytokine profiles in DCs, highlighting clear species distinction within specific yeast genera. The observed differences in induced DC cytokine profiles add to the currently very limited knowledge of the cross-talk between yeasts and human immune cells and provide a foundation for selecting yeast strains for further characterization and development toward potentially novel yeast probiotics. Additionally, we present data to support a hypothesis that the interaction between yeasts and human DCs does not solely depend on yeast viability, a concept which may suggest a need for further classifications

  7. Cytokine Immunopathogenesis of Enterovirus 71 Brain Stem Encephalitis

    Directory of Open Access Journals (Sweden)

    Shih-Min Wang

    2012-01-01

    Full Text Available Enterovirus 71 (EV71 is one of the most important causes of herpangina and hand, foot, and mouth disease. It can also cause severe complications of the central nervous system (CNS. Brain stem encephalitis with pulmonary edema is the severe complication that can lead to death. EV71 replicates in leukocytes, endothelial cells, and dendritic cells resulting in the production of immune and inflammatory mediators that shape innate and acquired immune responses and the complications of disease. Cytokines, as a part of innate immunity, favor the development of antiviral and Th1 immune responses. Cytokines and chemokines play an important role in the pathogenesis EV71 brain stem encephalitis. Both the CNS and the systemic inflammatory responses to infection play important, but distinctly different, roles in the pathogenesis of EV71 pulmonary edema. Administration of intravenous immunoglobulin and milrinone, a phosphodiesterase inhibitor, has been shown to modulate inflammation, to reduce sympathetic overactivity, and to improve survival in patients with EV71 autonomic nervous system dysregulation and pulmonary edema.

  8. Cytokine Regulation of Microenvironmental Cells in Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Gregor Hoermann

    2015-01-01

    Full Text Available The term myeloproliferative neoplasms (MPN refers to a heterogeneous group of diseases including not only polycythemia vera (PV, essential thrombocythemia (ET, and primary myelofibrosis (PMF, but also chronic myeloid leukemia (CML, and systemic mastocytosis (SM. Despite the clinical and biological differences between these diseases, common pathophysiological mechanisms have been identified in MPN. First, aberrant tyrosine kinase signaling due to somatic mutations in certain driver genes is common to these MPN. Second, alterations of the bone marrow microenvironment are found in all MPN types and have been implicated in the pathogenesis of the diseases. Finally, elevated levels of proinflammatory and microenvironment-regulating cytokines are commonly found in all MPN-variants. In this paper, we review the effects of MPN-related oncogenes on cytokine expression and release and describe common as well as distinct pathogenetic mechanisms underlying microenvironmental changes in various MPN. Furthermore, targeting of the microenvironment in MPN is discussed. Such novel therapies may enhance the efficacy and may overcome resistance to established tyrosine kinase inhibitor treatment in these patients. Nevertheless, additional basic studies on the complex interplay of neoplastic and stromal cells are required in order to optimize targeting strategies and to translate these concepts into clinical application.

  9. Counselor Identity: Conformity or Distinction?

    Science.gov (United States)

    McLaughlin, Jerry E.; Boettcher, Kathryn

    2009-01-01

    The authors explore 3 debates in other disciplines similar to counseling's identity debate in order to learn about common themes and outcomes. Conformity, distinction, and cohesion emerged as common themes. They conclude that counselors should retain their distinctive, humanistic approach rather than conforming to the dominant, medical approach.

  10. Counselor Identity: Conformity or Distinction?

    Science.gov (United States)

    McLaughlin, Jerry E.; Boettcher, Kathryn

    2009-01-01

    The authors explore 3 debates in other disciplines similar to counseling's identity debate in order to learn about common themes and outcomes. Conformity, distinction, and cohesion emerged as common themes. They conclude that counselors should retain their distinctive, humanistic approach rather than conforming to the dominant, medical approach.

  11. Is Face Distinctiveness Gender Based?

    Science.gov (United States)

    Baudouin, Jean-Yves; Gallay, Mathieu

    2006-01-01

    Two experiments were carried out to study the role of gender category in evaluations of face distinctiveness. In Experiment 1, participants had to evaluate the distinctiveness and the femininity-masculinity of real or artificial composite faces. The composite faces were created by blending either faces of the same gender (sexed composite faces,…

  12. THE LEVELS OF VALUE IN BUSINESS VALUATION. THE DISCOUNT FOR LACK OF MARKETABILITY

    Directory of Open Access Journals (Sweden)

    Szatmary Miclea Camelia

    2012-12-01

    Full Text Available This paper approaches the subject of levels of value used in business valuation and adjustments (discounts and prime that enable professional business valuers to relate these in order to determine the value of a business or ownerships interests in a business. Marketability and control over business decision have a profound impact on the value of an ownership interest. Valuators, regularly, reduce the value of an investment interest if it lacks a ready market. In this paper, I highlight the difference between the marketability and liquidity and, the differences between the the discount for lack of marketability and discount for lack of control. A discount for lack of marketability is closely associated with, but, conceptually, distinct from, the discount for lack of control. I present the characteristics of discount for lack of marketability and the rational of applying it in valuation of minority and majority interest.

  13. Optimal Distinctiveness Signals Membership Trust.

    Science.gov (United States)

    Leonardelli, Geoffrey J; Loyd, Denise Lewin

    2016-07-01

    According to optimal distinctiveness theory, sufficiently small minority groups are associated with greater membership trust, even among members otherwise unknown, because the groups are seen as optimally distinctive. This article elaborates on the prediction's motivational and cognitive processes and tests whether sufficiently small minorities (defined by relative size; for example, 20%) are associated with greater membership trust relative to mere minorities (45%), and whether such trust is a function of optimal distinctiveness. Two experiments, examining observers' perceptions of minority and majority groups and using minimal groups and (in Experiment 2) a trust game, revealed greater membership trust in minorities than majorities. In Experiment 2, participants also preferred joining minorities over more powerful majorities. Both effects occurred only when minorities were 20% rather than 45%. In both studies, perceptions of optimal distinctiveness mediated effects. Discussion focuses on the value of relative size and optimal distinctiveness, and when membership trust manifests.

  14. Cytokine expression in the rat central nervous system following perinatal Borna disease virus infection.

    Science.gov (United States)

    Sauder, C; de la Torre, J C

    1999-04-01

    Borna disease virus (BDV) causes central nervous system (CNS) disease in several vertebrate species, which is frequently accompanied by behavioral abnormalities. In the adult rat, intracerebral (i.c.) BDV infection leads to immunomediated meningoencephalitis. In contrast, i.c. infection of neonates causes a persistent infection in the absence of overt signs of brain inflammation. These rats (designated PTI-NB) display distinct behavioral and neurodevelopmental abnormalities. However, the molecular mechanisms for these virally induced CNS disturbances are unknown. Cytokines play an important role in CNS function, both under normal physiological and pathological conditions. Astrocytes and microglia are the primary resident cells of the central nervous system with the capacity to produce cytokines. Strong reactive astrocytosis is observed in the PTI-NB rat brain. We have used a ribonuclease protection assay to investigate the mRNA expression levels of proinflammatory cytokines in different brain regions of PTI-NB and control rats. We show here evidence of a chronic upregulation of proinflammatory cytokines interleukin-6, tumor necrosis factor alpha, interleukins-1alpha, and -1beta in the hippocampus and cerebellum of the PTI-NB rat brain. These brain regions exhibited only a very mild and transient immune infiltration. In contrast, in addition to reactive astrocytes, a strong and sustained microgliosis was observed in the PTI-NB rat brains. Our data suggest that CNS resident cells, namely astrocytes and microglia, are the major source of cytokine expression in the PTI-NB rat brain. The possible implications of these findings are discussed.

  15. Structural Pathways of Cytokines May Illuminate Their Roles in Regulation of Cancer Development and Immunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Guven-Maiorov, Emine; Acuner-Ozbabacan, Saliha Ece; Keskin, Ozlem; Gursoy, Attila [Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer Istanbul (Turkey); Nussinov, Ruth, E-mail: nussinor@helix.nih.gov [Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702 (United States); Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel)

    2014-03-25

    Cytokines are messengers between tissues and the immune system. They play essential roles in cancer initiation, promotion, metastasis, and immunotherapy. Structural pathways of cytokine signaling which contain their interactions can help understand their action in the tumor microenvironment. Here, our aim is to provide an overview of the role of cytokines in tumor development from a structural perspective. Atomic details of protein-protein interactions can help in understanding how an upstream signal is transduced; how higher-order oligomerization modes of proteins can influence their function; how mutations, inhibitors or antagonists can change cellular consequences; why the same protein can lead to distinct outcomes, and which alternative parallel pathways can take over. They also help to design drugs/inhibitors against proteins de novo or by mimicking natural antagonists as in the case of interferon-γ. Since the structural database (PDB) is limited, structural pathways are largely built from a series of predicted binary protein-protein interactions. Below, to illustrate how protein-protein interactions can help illuminate roles played by cytokines, we model some cytokine interaction complexes exploiting a powerful algorithm (PRotein Interactions by Structural Matching—PRISM)

  16. Structural pathways of cytokines may illuminate their roles in regulation of cancer development and immunotherapy.

    Science.gov (United States)

    Guven-Maiorov, Emine; Acuner-Ozbabacan, Saliha Ece; Keskin, Ozlem; Gursoy, Attila; Nussinov, Ruth

    2014-03-25

    Cytokines are messengers between tissues and the immune system. They play essential roles in cancer initiation, promotion, metastasis, and immunotherapy. Structural pathways of cytokine signaling which contain their interactions can help understand their action in the tumor microenvironment. Here, our aim is to provide an overview of the role of cytokines in tumor development from a structural perspective. Atomic details of protein-protein interactions can help in understanding how an upstream signal is transduced; how higher-order oligomerization modes of proteins can influence their function; how mutations, inhibitors or antagonists can change cellular consequences; why the same protein can lead to distinct outcomes, and which alternative parallel pathways can take over. They also help to design drugs/inhibitors against proteins de novo or by mimicking natural antagonists as in the case of interferon-γ. Since the structural database (PDB) is limited, structural pathways are largely built from a series of predicted binary protein-protein interactions. Below, to illustrate how protein-protein interactions can help illuminate roles played by cytokines, we model some cytokine interaction complexes exploiting a powerful algorithm (PRotein Interactions by Structural Matching-PRISM).

  17. The expression pattern of two novel cytokines (IL-24 and IL-29) in human fetal membranes.

    Science.gov (United States)

    Nace, Judith; Fortunato, Stephen J; Maul, Holger; Menon, Ramkumar

    2010-11-01

    interleukin (IL)-24 and -29 are novel cytokines, produced by immune cells in response to microbial antigens. The functions of these cytokines in the reproductive system are unknown. We examined the expression pattern of IL-24 and IL-29 in human fetal membranes from preterm and term births and in in vitro in response to microbial antigens. fetal membranes collected from cesarean sections at term (normal, not in labor) were placed in culture for 48 h. These membranes were then stimulated with bacterial lipopolysaccharide (LPS) or viral antigen poly-inosinic and cytidylic acid (polyIC) for an additional 24 h. Amniotic fluids (AF) and fetal membranes were also collected from preterm and term deliveries. IL-24 and IL-29 expressions were studied by RT-PCR. ELISA documented culture media and AF cytokine concentrations. IL-24 and IL-29 expressions were seen in cultured fetal membranes regardless of stimulation. Expressions were also found in preterm and term labor membranes, but not in non-labor tissues at term. IL-24 concentrations were higher after LPS stimulation whereas IL-29 concentrations were higher after polyIC-stimulation. AF analysis did not detect either of the cytokines either preterm or term. this is the first study to report IL-24 and IL-29 expressions in human fetal membranes. Higher concentrations of these cytokines in response to distinct infectious stimuli suggest different pathways for fetal immune response during infection.

  18. A genetic contribution to circulating cytokines and obesity in children

    Science.gov (United States)

    Cytokines are considered to be involved in obesity-related metabolic diseases. Study objectives are to determine the heritability of circulating cytokine levels, to investigate pleiotropy between cytokines and obesity traits, and to present genome scan results for cytokines in 1030 Hispanic children...

  19. Cytokines in common variable immunodeficiency as signs of immune dysregulation and potential therapeutic targets - a review of the current knowledge.

    Science.gov (United States)

    Varzaneh, Farnaz Najmi; Keller, Bärbel; Unger, Susanne; Aghamohammadi, Asghar; Warnatz, Klaus; Rezaei, Nima

    2014-07-01

    Common variable immunodeficiency (CVID) is characterized by low levels of circulating immunoglobulins and compromised specific antibody response leading to frequent infections. Cytokines play an important role in the orchestration of the antibody response. Several previous studies have attempted to identify distinct cytokines responsible for the inflammatory changes and different manifestations of CVID, but there are conflicting results regarding the cytokine profiles in CVID patients. In light of this, an extensive review regarding the level of various cytokines and their potential therapeutic role in CVID patients was performed. This review delineates the contribution of interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-21, interferons, tumor necrosis factor (TNF)-α, IL-17, APRIL (a proliferation inducing ligand) and BAFF (B cell activating factor) in CVID disease and outline their potential therapeutic implications in these patients.

  20. Lacking control increases illusory pattern perception.

    Science.gov (United States)

    Whitson, Jennifer A; Galinsky, Adam D

    2008-10-03

    We present six experiments that tested whether lacking control increases illusory pattern perception, which we define as the identification of a coherent and meaningful interrelationship among a set of random or unrelated stimuli. Participants who lacked control were more likely to perceive a variety of illusory patterns, including seeing images in noise, forming illusory correlations in stock market information, perceiving conspiracies, and developing superstitions. Additionally, we demonstrated that increased pattern perception has a motivational basis by measuring the need for structure directly and showing that the causal link between lack of control and illusory pattern perception is reduced by affirming the self. Although these many disparate forms of pattern perception are typically discussed as separate phenomena, the current results suggest that there is a common motive underlying them.

  1. Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia

    DEFF Research Database (Denmark)

    Ejlerskov, Patrick; Hultberg, Jeanette Göransdotter; Wang, JunYang;

    2015-01-01

    -causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying α-synuclein-containing Lewy bodies in the brain, as well as a reduction in dopaminergic neurons and defective dopamine signaling in the nigrostriatal region. Lack of IFN-β signaling caused...... neuron loss in a familial Parkinson's disease model. These results indicate a protective role for IFN-β in neuronal homeostasis and validate Ifnb mutant mice as a model for sporadic Lewy body and Parkinson's disease dementia.......Neurodegenerative diseases have been linked to inflammation, but whether altered immunomodulation plays a causative role in neurodegeneration is not clear. We show that lack of cytokine interferon-β (IFN-β) signaling causes spontaneous neurodegeneration in the absence of neurodegenerative disease...

  2. Dynamic and Static Exercises Differentially Affect Plasma Cytokine Content in Elite Endurance- and Strength-Trained Athletes and Untrained Volunteers

    Science.gov (United States)

    Kapilevich, Leonid V.; Zakharova, Anna N.; Kabachkova, Anastasia V.; Kironenko, Tatyana A.; Orlov, Sergei N.

    2017-01-01

    Extensive exercise increases the plasma content of IL-6, IL-8, IL-15, leukemia inhibitory factor (LIF), and several other cytokines via their augmented transcription in skeletal muscle cells. However, the relative impact of aerobic and resistant training interventions on cytokine production remains poorly defined. In this study, we compared effects of dynamic and static load on cytokine plasma content in elite strength- and endurance-trained athletes vs. healthy untrained volunteers. The plasma cytokine content was measured before, immediately after, and 30 min post-exercise using enzyme-linked immunosorbent assay. Pedaling on a bicycle ergometer increased IL-6 and IL-8 content in the plasma of trained athletes by about 4- and 2-fold, respectively. In contrast to dynamic load, weightlifting had negligible impact on these parameters in strength exercise-trained athletes. Unlike IL-6 and IL-8, dynamic exercise had no impact on IL-15 and LIF, whereas static load increases the content of these cytokines by ~50%. Two-fold increment of IL-8 content seen in athletes subjected to dynamic exercise was absent in untrained individuals, whereas the ~50% increase in IL-15 triggered by static load in the plasma of weightlifting athletes was not registered in the control group. Thus, our results show the distinct impact of static and dynamic exercises on cytokine content in the plasma of trained athletes. They also demonstrate that both types of exercises differentially affect cytokine content in plasma of athletes and untrained persons.

  3. Dynamic and Static Exercises Differentially Affect Plasma Cytokine Content in Elite Endurance- and Strength-Trained Athletes and Untrained Volunteers.

    Science.gov (United States)

    Kapilevich, Leonid V; Zakharova, Anna N; Kabachkova, Anastasia V; Kironenko, Tatyana A; Orlov, Sergei N

    2017-01-01

    Extensive exercise increases the plasma content of IL-6, IL-8, IL-15, leukemia inhibitory factor (LIF), and several other cytokines via their augmented transcription in skeletal muscle cells. However, the relative impact of aerobic and resistant training interventions on cytokine production remains poorly defined. In this study, we compared effects of dynamic and static load on cytokine plasma content in elite strength- and endurance-trained athletes vs. healthy untrained volunteers. The plasma cytokine content was measured before, immediately after, and 30 min post-exercise using enzyme-linked immunosorbent assay. Pedaling on a bicycle ergometer increased IL-6 and IL-8 content in the plasma of trained athletes by about 4- and 2-fold, respectively. In contrast to dynamic load, weightlifting had negligible impact on these parameters in strength exercise-trained athletes. Unlike IL-6 and IL-8, dynamic exercise had no impact on IL-15 and LIF, whereas static load increases the content of these cytokines by ~50%. Two-fold increment of IL-8 content seen in athletes subjected to dynamic exercise was absent in untrained individuals, whereas the ~50% increase in IL-15 triggered by static load in the plasma of weightlifting athletes was not registered in the control group. Thus, our results show the distinct impact of static and dynamic exercises on cytokine content in the plasma of trained athletes. They also demonstrate that both types of exercises differentially affect cytokine content in plasma of athletes and untrained persons.

  4. PATHOGENETIC ROLE OF CYTOKINES IN CHILDHOOD ROTAVIRUS INFECTION

    Directory of Open Access Journals (Sweden)

    S. N. Benyova

    2007-01-01

    Full Text Available Abstract. Results of cytokine network studies system in children with rotavirus infection are presented. Concentrations of cytokines were determined at both local and systemic levels. Analysis of cytokine levels was performed at initial terms (day 1 to 3, and in the course of disease (day 7 to 10. It was revealed that mild and mid-severe cases of rotavirus infection in the children are characterized by early increase in proinflammatory cytokines with restricted overshoot of proinflammatory cytokines at early recovery period. Meanwhile, the patients with severe forms of viral gastroenteritis exhibited high levels of proinflammatory cytokines. However, this balance was shifted towards anti-inflammatory cytokines during early reconvalescence.

  5. Dnase1L3 Regulates Inflammasome-Dependent Cytokine Secretion

    Directory of Open Access Journals (Sweden)

    Guilan Shi

    2017-05-01

    Full Text Available Pediatric-onset systemic lupus erythematosus arises in humans and mice lacking the endonuclease Dnase1L3. When Dnase1L3 is absent, DNA from circulating apoptotic bodies is not cleared, leading to anti-DNA antibody production. Compared to early anti-DNA and anti-chromatin responses, other autoantibody responses and general immune activation in Dnase1L3−/− mice are greatly delayed. We investigated the possibility that immune activation, specifically inflammasome activation, is regulated by Dnase1L3. Here, we report that Dnase1L3 inhibition blocked both NLR family, pyrin domain containing 3 (NLRP3 and NLRC4 inflammasome-mediated release of high-mobility group box 1 protein and IL-1β. In contrast to IL-1β release, Dnase1L3 inhibition only mildly impaired NLRP3-dependent pyroptosis, as measured by propidium iodide uptake or LDH release. Mechanistically, we found that Dnase1L3 was needed to promote apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC nuclear export and speck formation. Our results demonstrate that Dnase1L3 inhibition separates cytokine secretion from pyroptosis by targeting ASC. These findings suggest that Dnase1L3 is necessary for cytokine secretion following inflammasome activation.

  6. Th1 cytokine-based immunotherapy for cancer

    Institute of Scientific and Technical Information of China (English)

    Hong-Mei Xu

    2014-01-01

    Cytokine-based immunotherapy is executed by harnessing cytokines to activate the immune system to suppress tumors. Th1-type cytokines including IL-1, IL-2, IL-12 and granulocyte-macrophage colony-stimulating factor are potent stimulators of Th1 differentiation and Th1-based antitumor response. Many preclinical studies demonstrated the antitumor effects of Th1 cytokines but their clinical efficacy is limited. Multiple factors influence the efficacy of immunotherapy for tumors. For instance immunosuppressive cells in the tumor microenvironment can produce inhibitory cytokines which suppress antitumor immune response. Most studies on cytokine immunotherapy focused on how to boost Th1 response; many studies combined cytokine-based therapy with other treatments to reverse immunosuppression in tumor microenvironment. In addition, cytokines have pleiotropic functions and some cytokines show paradoxical activities under different settings. Better understanding the physiological and pathological functions of cytokines helps clinicians to design Th1-based cancer therapy in clinical practice.

  7. 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.

  8. Staphylococcus aureus Biofilm and Planktonic cultures differentially impact gene expression, mapk phosphorylation, and cytokine production in human keratinocytes

    Directory of Open Access Journals (Sweden)

    Olerud John E

    2011-06-01

    Full Text Available Abstract Background Many chronic diseases, such as non-healing wounds are characterized by prolonged inflammation and respond poorly to conventional treatment. Bacterial biofilms are a major impediment to wound healing. Persistent infection of the skin allows the formation of complex bacterial communities termed biofilm. Bacteria living in biofilms are phenotypically distinct from their planktonic counterparts and are orders of magnitude more resistant to antibiotics, host immune response, and environmental stress. Staphylococcus aureus is prevalent in cutaneous infections such as chronic wounds and is an important human pathogen. Results The impact of S. aureus soluble products in biofilm-conditioned medium (BCM or in planktonic-conditioned medium (PCM on human keratinocytes was investigated. Proteomic analysis of BCM and PCM revealed differential protein compositions with PCM containing several enzymes involved in glycolysis. Global gene expression of keratinocytes exposed to biofilm and planktonic S. aureus was analyzed after four hours of exposure. Gene ontology terms associated with responses to bacteria, inflammation, apoptosis, chemotaxis, and signal transduction were enriched in BCM treated keratinocytes. Several transcripts encoding cytokines were also upregulated by BCM after four hours. ELISA analysis of cytokines confirmed microarray results at four hours and revealed that after 24 hours of exposure, S. aureus biofilm induced sustained low level cytokine production compared to near exponential increases of cytokines in planktonic treated keratinocytes. The reduction in cytokines produced by keratinocytes exposed to biofilm was accompanied by suppressed phosphorylation of MAPKs. Chemical inhibition of MAPKs did not drastically reduce cytokine production in BCM-treated keratinocytes suggesting that the majority of cytokine production is mediated through MAPK-independent mechanisms. Conclusions Collectively the results indicate that S

  9. Cytokines in Neuropathic Pain and Associated Depression.

    Science.gov (United States)

    Lees, Justin G; Fivelman, Brett; Duffy, Samuel S; Makker, Preet G S; Perera, Chamini J; Moalem-Taylor, Gila

    2015-01-01

    Neuropathic pain occurs as a result of lesion or disease affecting the somatosensory nervous system and is present in a diverse set of peripheral and central pathologies such as nerve trauma, diabetic neuropathy, post-herpetic neuralgia, chemotherapy-induced peripheral neuropathy, spinal cord injury and multiple sclerosis. Debilitating symptoms including allodynia, hyperalgesia and spontaneous pain have a substantial negative impact on patients' quality of life. The currently available therapeutic treatments are generally ineffective and characterised by poor response rates. Accumulating evidence suggests that neuroinflammation and cytokine signalling play a critical role in neuropathic pain. Numerous experimental studies have demonstrated that certain pro-inflammatory cytokines are elevated in neuropathic pain conditions, and administration of these cytokines can elicit pain hypersensitivity in the absence of injury or disease. This phenomenon is also apparent in the 'sickness response', which encompasses a broad inflammatory response to disease and injury and involves a series of physiological and behavioural changes including pain hypersensitivity. Interestingly, the 'sickness response' is also similar in nature to some of the defining characteristics of the depressed state of affective disorder. In this review, we explore links that may relate the co-existence of depression in neuropathic pain patients with the activity of cytokines and discuss the role of several key pro-inflammatory and anti-inflammatory cytokines in neuropathic pain.

  10. Interleukin-1 Family Cytokines in Liver Diseases.

    Science.gov (United States)

    Tsutsui, Hiroko; Cai, Xianbin; Hayashi, Shuhei

    2015-01-01

    The gene encoding IL-1 was sequenced more than 30 years ago, and many related cytokines, such as IL-18, IL-33, IL-36, IL-37, IL-38, IL-1 receptor antagonist (IL-1Ra), and IL-36Ra, have since been identified. IL-1 is a potent proinflammatory cytokine and is involved in various inflammatory diseases. Other IL-1 family ligands are critical for the development of diverse diseases, including inflammatory and allergic diseases. Only IL-1Ra possesses the leader peptide required for secretion from cells, and many ligands require posttranslational processing for activation. Some require inflammasome-mediated processing for activation and release, whereas others serve as alarmins and are released following cell membrane rupture, for example, by pyroptosis or necroptosis. Thus, each ligand has the proper molecular process to exert its own biological functions. In this review, we will give a brief introduction to the IL-1 family cytokines and discuss their pivotal roles in the development of various liver diseases in association with immune responses. For example, an excess of IL-33 causes liver fibrosis in mice via activation and expansion of group 2 innate lymphoid cells to produce type 2 cytokines, resulting in cell conversion into pro-fibrotic M2 macrophages. Finally, we will discuss the importance of IL-1 family cytokine-mediated molecular and cellular networks in the development of acute and chronic liver diseases.

  11. Methodological issues in cytokine measurement in schizophrenia

    Directory of Open Access Journals (Sweden)

    Maju Mathew Koola

    2016-01-01

    Full Text Available There is mounting evidence that inflammation is a major factor in the pathophysiology of schizophrenia. Inflammatory status is commonly ascertained by measuring peripheral cytokine concentrations. An issue concerning research on inflammation and schizophrenia relates to assay methodology. Enzyme-linked immunosorbent assay (ELISA is the most widely used and the gold standard method used to measure cytokine concentrations. ELISA has a number of limitations. Both ELISA and multiplex are limited by not being able to distinguish between bioactive and inactive molecules and the matrix and heterophilic (auto- antibody interference. Multiplex assays when combined with gene expression analysis and flow cytometry techniques such as fluorescence-activated cell sorting may be useful to detect abnormalities in specific immune pathways. Peripheral blood mononuclear cells cultures, to evaluate in vitro lipopolysaccharide-induced cytokine production, may be a better technology than measuring cytokines in the serum. The purpose of this paper is to shed light on major methodological issues that need to be addressed in order to advance the study of cytokines in schizophrenia. We make a few recommendations on how to address these issues.

  12. Cytokines in rheumatoid arthritis and osteoarthrosis

    Directory of Open Access Journals (Sweden)

    Petrović-Rackov Ljiljana

    2005-01-01

    Full Text Available The aim of this research was to determine the clinical significance of tumor necrosis factor-alpha (TNF-alpha, IL-12, IL-15 and IL-18 in evaluation of the activity of rheumatoid arthritis. Cytokine concentrations in serum samples and synovial fluid were measured by immnnoenzymatic methods using kits for human interleukins and the Disease Activity Score 28 in 64 patients with active disease. The control group consisted of 25 subjects with arthritis of the knee and osteoarthrosis. Patients with rheumatoid arthritis have significantly high (p<0.01 concentrations of examined cytokines in relation to patients with osteoarthritis. By comparing concentrations in 30 patients with high, 14 patients with moderate and 20 patients with mild activity of rheumatoid arthritis, it was established that patients with high degree of disease activity have significantly high (p<0.01; p<0.05 concentrations of examined cytokines in the blood and synovial fluid in relation to patients with moderate and mild disease. We have concluded that cytokine concentrations are good indicators of the degree of rheumatoid arthritis activity. This research is a contribution to understanding the insufficiently known pathogenetic mechanisms of cytokines, especially IL-18, in active disease. .

  13. An elevated pro-inflammatory cytokine response is linked to development of amphotericin B-induced nephrotoxicity

    NARCIS (Netherlands)

    Chai, L.Y.; Netea, M.G.; Tai, B.C.; Khin, L.W.; Vonk, A.G.; Teo, B.W.; Schlamm, H.T.; Herbrecht, R.; Donnelly, J.P.; Troke, P.F.; Kullberg, B.J.

    2013-01-01

    OBJECTIVES: The underlying mechanism for amphotericin B-induced acute kidney injury (AKI) remains poorly understood and may be immunologically mediated. We assessed whether the development of nephrotoxicity is linked to a distinct cytokine profile in patients receiving amphotericin B deoxycholate (A

  14. Relationship between T-lymphocyte cytokine levels and sero-response to hepatitis B vaccines

    Institute of Scientific and Technical Information of China (English)

    Vijayakumar Velu; Shanmugam Saravanan; Subhadra Nandakumar; Esaki Muthu Shankar; Appasamy Vengatesan; Suresh Sakharam Jadhav; Prasad Suryakant Kulkarni; Sadras Panchatcharam Thyagarajan

    2008-01-01

    AIM: TO investigate the cellular defects by analyzing the (Th1/Th2) cytokine levels in vaccine responders and non-responders.METHODS: Peripheral blood mononuclear cell (PBMC) from responders and non-responders were stimulated with or with out recombinant HBsAg or PHA. Broad spectrum of cytokines viz (Th1) IFN-γ, IL-2, TNF-α, IL-12 and (Th2) IL-10, IL-4 were measured after in vitro stimulation with recombinant HBsAg and were compared with respective antibody titers.RESULTS: A significant decrease (P = 0.001) in Th1 and Th2 cytokines namely, IL-2, INF-γ, TNF-α and IL-10 in non-responders was observed. The level of IL-4 was not significant between the three groups. Furthermore, despite a strong Th1 and Th2 cytokine response, the level of IL-12 was elevated in high-responders compared to other groups (P=0.001) and demonstrated a positive correlation with anti-HBs titers and Th1 cytokine response.CONCLUSION: Our findings suggest that unresponsiveness to recombinant hepatitis B vaccines (rHB) is multifactorial, including specific failure of antigen presentation or the lack of both T helper Th1 and Th2 response.

  15. A distinct bacterial dysbiosis associated skin inflammation in ovine footrot

    Science.gov (United States)

    Maboni, Grazieli; Blanchard, Adam; Frosth, Sara; Stewart, Ceri; Emes, Richard; Tötemeyer, Sabine

    2017-03-01

    Ovine footrot is a highly prevalent bacterial disease caused by Dichelobacter nodosus and characterised by the separation of the hoof horn from the underlying skin. The role of innate immune molecules and other bacterial communities in the development of footrot lesions remains unclear. This study shows a significant association between the high expression of IL1β and high D. nodosus load in footrot samples. Investigation of the microbial population identified distinct bacterial populations in the different disease stages and also depending on the level of inflammation. Treponema (34%), Mycoplasma (29%) and Porphyromonas (15%) were the most abundant genera associated with high levels of inflammation in footrot. In contrast, Acinetobacter (25%), Corynebacteria (17%) and Flavobacterium (17%) were the most abundant genera associated with high levels of inflammation in healthy feet. This demonstrates for the first time there is a distinct microbial community associated with footrot and high cytokine expression.

  16. Misoprostol Inhibits Lipopolysaccharide-Induced Pro-inflammatory Cytokine Production by Equine Leukocytes

    Directory of Open Access Journals (Sweden)

    Emily Medlin Martin

    2017-09-01

    Full Text Available Pro-inflammatory cytokines including tumor necrosis factor α (TNFα, IL-1β, IL-6, and IL-8 are potent immune mediators that exacerbate multiple equine diseases such as sepsis and laminitis. Unfortunately, safe and effective cytokine-targeting therapies are lacking in horses; therefore, novel mechanisms of inhibiting cytokine production are critically needed. One potential mechanism for inhibiting cytokine synthesis is elevation of intracellular cyclic AMP (cAMP. In human leukocytes, intracellular cAMP production is induced by activation of E-prostanoid (EP receptors 2 and 4. These receptors can be targeted by the EP2/4 agonist and prostaglandin E1 analog, misoprostol. Misoprostol is currently used as a gastroprotectant in horses but has not been evaluated as a cytokine-targeting therapeutic. Thus, we hypothesized that misoprostol treatment would inhibit pro-inflammatory cytokine production by lipopolysaccharide (LPS-stimulated equine leukocytes in an in vitro inflammation model. To test this hypothesis, equine leukocyte-rich plasma (LRP was collected from 12 healthy adult horses and used to model LPS-mediated inflammatory signaling. LRP was treated with varying concentrations of misoprostol either before (pretreated or following (posttreated LPS stimulation. LRP supernatants were assayed for 23 cytokines using an equine-specific multiplex bead immunoassay. Leukocytes were isolated from LRP, and leukocyte mRNA levels of four important cytokines were evaluated via RT-PCR. Statistical differences between treatments were determined using one-way RM ANOVA (Holm–Sidak post hoc testing or Friedman’s RM ANOVA on Ranks (SNK post hoc testing, where appropriate (p < 0.05, n = 3–6 horses. These studies revealed that misoprostol pre- and posttreatment inhibited LPS-induced TNFα and IL-6 protein production in equine leukocytes but had no effect on IL-8 protein. Interestingly, misoprostol pretreatment enhanced IL-1β protein synthesis

  17. Cytokines and Pancreatic β-Cell Apoptosis

    DEFF Research Database (Denmark)

    Berchtold, L A; Prause, M; Størling, J

    2016-01-01

    The discovery 30 years ago that inflammatory cytokines cause a concentration, activity, and time-dependent bimodal response in pancreatic β-cell function and viability has been a game-changer in the fields of research directed at understanding inflammatory regulation of β-cell function and survival...... and the causes of β-cell failure and destruction in diabetes. Having until then been confined to the use of pathophysiologically irrelevant β-cell toxic chemicals as a model of β-cell death, researchers could now mimic endocrine and paracrine effects of the cytokine response in vitro by titrating concentrations...... to gene expressional changes, endoplasmic reticulum stress, and triggering of mitochondrial dysfunction. Preclinical studies have shown preventive effects of cytokine antagonism in animal models of diabetes, and clinical trials demonstrating proof of concept are emerging. The full clinical potential...

  18. Cytokine production associated with smallpox vaccine responses.

    Science.gov (United States)

    Simon, Whitney L; Salk, Hannah M; Ovsyannikova, Inna G; Kennedy, Richard B; Poland, Gregory A

    2014-01-01

    Smallpox was eradicated 34 years ago due to the success of the smallpox vaccine; yet, the vaccine continues to be studied because of its importance in responding to potential biological warfare and the adverse events associated with current smallpox vaccines. Interindividual variations in vaccine response are observed and are, in part, due to genetic variation. In some cases, these varying responses lead to adverse events, which occur at a relatively high rate for the smallpox vaccine compared with other vaccines. Here, we aim to summarize the cytokine responses associated with smallpox vaccine response to date. Along with a description of each of these cytokines, we describe the genetic and adverse event data associated with cytokine responses to smallpox vaccination.

  19. The role of cytokines in postmenopausal osteoporosis.

    Science.gov (United States)

    Brincat, S D; Borg, M; Camilleri, G; Calleja-Agius, J

    2014-08-01

    Postmenopausal osteoporosis is a silent systemic progressive disease characterised by a decrease in bone mass per unit volume. This condition compromises the physical strength of the skeleton and increases the susceptibility to fractures on minor trauma. The imbalance between bone formation and bone resorption is known to be responsible for postmenopausal bone loss. Estrogen deficiency contributes to bone loss by increasing the production of pro-inflammatory cytokines by bone marrow and bone cells. Clinical and molecular evidence indicates that estrogen-regulated cytokines exert regulatory effects on bone turnover implicating their role as being the primary mediators of the accelerated bone loss at menopause. The current perspective on the role and interaction of cytokines such as IL-1, IL-4, IL-6, IL-17, TNF, IFN-γ and TGF-β in bone loss linked with estrogen deficiency is reviewed. Current treatment options and emerging drug therapies in the management of postmenopausal osteoporosis are also evaluated.

  20. Th1/Th2 Cytokines in Psoriasis

    Directory of Open Access Journals (Sweden)

    Z Jadali

    2007-08-01

    Full Text Available Background: The aim of this study was to determine the Th1 and Th2 serum cytokines, in patients with psoriasis and to com¬pare their cytokine levels with those of normal control subjects. Methods: Serum levels of Interferon-gamma (IFN-γ, Interleukin-2 (IL-2, Interleukin-4 (IL-4, and Interleukin-10 (IL-10 were measured by enzyme linked immunosorbent assay in 40 patients with psoriasis and in 40 normal controls. Results: Compared with control subjects, patients with psoriasis had elevated levels of IFN-γ and IL-2 (P<0.001. In addi¬tion a positive correlation was found between the levels of IFN-γ, IL-2 and disease severity. Conclusion: Th1 secreting inflammatory cytokines may contribute to the pathogenesis of psoriasis.

  1. Cytokine and lipid mediator networks in tuberculosis.

    Science.gov (United States)

    Mayer-Barber, Katrin D; Sher, Alan

    2015-03-01

    A major approach for immunologic intervention in tuberculosis involves redirecting the outcome of the host immune response from the induction of disease to pathogen control. Cytokines and lipid mediators known as eicosanoids play key roles in regulating this balance and as such represent important targets for immunologic intervention. While the evidence for cytokine/eicosanoid function derives largely from the investigation of murine and zebrafish experimental infection models, clinical studies have confirmed the existence of many of the same pathways in tuberculosis patients. Here, we summarize new data that reveal important intersections between the cytokine and eicosanoid networks in the host response to mycobacteria and discuss how targeting this crosstalk can promote resistance to lethal Mycobacterium tuberculosis infection. This approach could lead to new host-directed therapies to be used either as an adjunct for improving the efficacy of standard antibiotic treatment or for the management of drug-resistant infections.

  2. Treatment of Cancer Pain by Targeting Cytokines.

    Science.gov (United States)

    Vendrell, I; Macedo, D; Alho, I; Dionísio, M R; Costa, L

    2015-01-01

    Inflammation is one of the most important causes of the majority of cancer symptoms, including pain, fatigue, cachexia, and anorexia. Cancer pain affects 17 million people worldwide and can be caused by different mediators which act in primary efferent neurons directly or indirectly. Cytokines can be aberrantly produced by cancer and immune system cells and are of particular relevance in pain. Currently, there are very few strategies to control the release of cytokines that seems to be related to cancer pain. Nevertheless, in some cases, targeted drugs are available and in use for other diseases. In this paper, we aim to review the importance of cytokines in cancer pain and targeted strategies that can have an impact on controlling this symptom.

  3. Distinction

    OpenAIRE

    2010-01-01

    Pr Serge Haroche La Médaille d’or 2009 du CNRS est décernée au Pr Serge Haroche, titulaire de la chaire de Physique quantique depuis 2001. Serge Haroche est spécialiste de physique atomique et d’optique quantique. Il est l’un des fondateurs de l’électrodynamique quantique en cavité, domaine qui permet, par des expériences conceptuellement simples, d’éclairer les fondements de la théorie quantique et de réaliser des prototypes de systèmes de traitement quantique de l’information. Serge Haroche...

  4. Cytokine polymorphisms in silicosis and other pneumoconioses

    Energy Technology Data Exchange (ETDEWEB)

    Yucesoy, B.; Vallyathan, V.; Landsittel, D.P.; Simeonova, P.; Luster, M.I. [NIOSH, Morgantown, WV (United States). Health Effects & Laboratory Division

    2002-06-01

    Silicosis and coal workers' pneumoconiosis are complex multifactorial lung diseases whose etiopathogenesis are not well defined. It is generally accepted that fibrotic lung disorders are mediated by macrophage-derived cytokines and growth factors. There is evidence showing a crucial role for tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) in inflammation caused by silica dust and in the transition from simple to progressive massive fibrosis. In this review genetic polymorphisms responsible for regulating the production of these proinflammatory cytokines and their role in modifying silicosis severity are discussed.

  5. Cytokine inhibition in the treatment of COPD

    Directory of Open Access Journals (Sweden)

    Caramori G

    2014-04-01

    Full Text Available Gaetano Caramori,1 Ian M Adcock,2,3 Antonino Di Stefano,4 Kian Fan Chung2,3 1Dipartimento di Scienze Mediche, Centro Interdipartimentale per lo Studio delle Malattie Infiammatorie delle Vie Aeree e Patologie Fumo-correlate (CEMICEF; formerly Centro di Ricerca su Asma e BPCO, Sezione di Medicina Interna e Cardiorespiratoria, Università di Ferrara, Ferrara, Italy; 2Airway Diseases Section, National Heart and Lung Institute, Imperial College London, UK; 3Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK; 4Divisione di Pneumologia e Laboratorio di Citoimmunopatologia dell'Apparato Cardio-Respiratorio, Fondazione Salvatore Maugeri, IRCCS, Veruno, Italy Abstract: Cytokines play an important part in many pathobiological processes of chronic obstructive pulmonary disease (COPD, including the chronic inflammatory process, emphysema, and altered innate immune response. Proinflammatory cytokines of potential importance include tumor necrosis factor (TNF-α, interferon-γ, interleukin (IL-1β, IL-6, IL-17, IL-18, IL-32, and thymic stromal lymphopoietin (TSLP, and growth factors such as transforming growth factor-β. The current objectives of COPD treatment are to reduce symptoms, and to prevent and reduce the number of exacerbations. While current treatments achieve these goals to a certain extent, preventing the decline in lung function is not currently achievable. In addition, reversal of corticosteroid insensitivity and control of the fibrotic process while reducing the emphysematous process could also be controlled by specific cytokines. The abnormal pathobiological process of COPD may contribute to these fundamental characteristics of COPD, and therefore targeting cytokines involved may be a fruitful endeavor. Although there has been much work that has implicated various cytokines as potentially playing an important role in COPD, there have been very few studies that have examined the effect of specific cytokine blockade in

  6. Proinflammatory Cytokines as Regulators of Vaginal Microbiota.

    Science.gov (United States)

    Kremleva, E A; Sgibnev, A V

    2016-11-01

    It was shown that IL-1β, IL-8, and IL-6 in concentrations similar to those in the vagina of healthy women stimulated the growth of normal microflora (Lactobacillus spp.) and suppressed the growth and biofilm production by S. aureus and E. coli. On the contrary, these cytokines in higher concentrations typical of vaginal dysbiosis suppressed normal microflora and stimulated the growth of opportunistic microorganisms. TGF-β1 in both doses produced a stimulating effects on study vaginal microsymbionts. It is hypothesized that pro-inflammatory cytokines serve as the molecules of interspecies communication coordinating the interactions of all components of the vaginal symbiotic system.

  7. Glia activation and cytokine increase in rat hippocampus by kainic acid-induced status epilepticus during postnatal development.

    Science.gov (United States)

    Rizzi, Massimo; Perego, Carlo; Aliprandi, Marisa; Richichi, Cristina; Ravizza, Teresa; Colella, Daniele; Velískŏvá, Jana; Moshé, Solomon L; De Simoni, M Grazia; Vezzani, Annamaria

    2003-12-01

    In adult rats, status epilepticus (SE) induces cytokine production by glia especially when seizures are associated with neuronal injury. This suggests that cytokines may play a role in seizure-induced neuronal damage. As SE-induced injury is age-specific, we used rats of different ages (with distinct susceptibilities to seizure-induced neuronal injury) to elucidate the role of cytokines in this process. Thus, we investigated the activation of microglia and astrocytes, induction of cytokines, and hippocampal neuronal injury 4 and 24 h following kainic acid-induced SE in postnatal day (PN) 9, 15, and 21 rats. At PN9, there was little activation of microglia and astrocytes at any time point studied. Interleukin-1beta (IL), tumor necrosis factor-alpha (TNF), and IL-6 or the naturally occurring IL-1 receptor antagonist (Ra) mRNA expression did not increase. No evidence of cell injury has been detected. At PN15, immunostaining of microglia and astrocytes was enhanced, but only IL-1beta mRNA expression was increased. These changes were observed 4 h after SE. Scattered injured neurons in CA3 and subiculum, but not in any other region, were present 24 h following SE. At PN21, immunostaining of microglia and astrocytes and the mRNA expression of all cytokines studied was significantly increased already 4 h after SE. At 24 h, many injured neurons were present in CA1 and CA3 regions and in 40% of rats in other forebrain areas. These data show that (i) the pattern of glia activation and cytokine gene transcription induced by SE is age-dependent and (ii) neuronal injury in the hippocampus occurs only when cytokines are induced and their synthesis precedes the appearance of neuronal damage. Thus, cytokine expression in immature brain is associated specifically with cell injury rather than with seizures per se, suggesting that proinflammatory cytokines may contribute to the occurence of SE-induced hippocampal damage.

  8. Whole Blood Activation Results in Altered T Cell and Monocyte Cytokine Production Profiles by Flow Cytometry

    Science.gov (United States)

    Crucian, Brian E.; Sams, Clarence F.

    2001-01-01

    An excellent monitor of the immune balance of peripheral circulating cells is to determine their cytokine production patterns in response to stimuli. Using flow cytometry, a positive identification of cytokine producing cells in a mixed culture may be achieved. Recently, the ability to assess cytokine production following a whole-blood activation culture has been described. In this study, whole blood activation was compared to traditional PBMC activation and the individual cytokine secretion patterns for both T cells, T cell subsets and monocytes was determined by flow cytometry. RESULTS: For T cell cytokine assessment (IFNg/IL-10 and IL-21/L-4) following PMA +ionomycin activation: (1) a Significantly greater percentages of T cells producing IFNgamma and IL-2 were observed following whole-blood culture and (2) altered T cell cytokine production kinetics were observed by varying whole blood culture times. Four-color analysiS was used to allow assessment of cytokine production by specific T cell subsets. It was found that IFNgamma production was significantly elevated in the CD3+/CD8+ T cell population as compared to the CD3+/CD8- population following five hours of whole blood activation. Conversely, IL-2 and IL-10 production were Significantly elevated in the CD3+/CD8- T cell population as compared to the CD3+/CD8+ population. Monocyte cytokine production was assessed in both culture systems following LPS activation for 24 hours. A three-color flow cytometric was used to assess two cytokines (IL-1a/IL-12 and TNFa/IL-10) in conjunction with CD14. Nearly all monocytes were stimulated to produce IL-1a, IL-12 and TNFa. equally well in both culture systems, however monocyte production of IL-10 was significantly elevated in whole blood culture as compared to PBMC culture. IL-12 producing monocytes appeared to be a distinct subpopulation of the IL-1a producing set, whereas IL-10 and TNFa producing monocytes were largely mutually exclusive. IL-10 and TNFa producing

  9. Laura: Soybean variety lacking Kunitz trypsin inhibitor

    Directory of Open Access Journals (Sweden)

    Srebrić Mirjana

    2010-01-01

    Full Text Available Grain of conventional soybean varieties requires heat processing to break down trypsin inhibitor's activity before using as food or animal feed. At the same time, protein denaturation and other qualitative changes occur in soybean grain, especially if the temperature of heating is not controlled. Two types of trypsin inhibitor were found in soybean grain the Kunitz trypsin inhibitor and the Bowman-Birk inhibitor. Mature grain of soybean Laura is lacking Kunitz trypsin inhibitor. Grain yield of variety Laura is equal to high yielding varieties from the maturity group I, where it belongs. Lacking of Kunitz-trypsin inhibitor makes soybean grain suitable for direct feeding in adult non ruminant animals without previous thermal processing. Grain of variety Laura can be processed for a shorter period of time than conventional soybeans. This way we save energy, and preserve valuable nutritional composition of soybean grain, which is of interest in industrial processing.

  10. Conceptualising the lack of health insurance coverage.

    Science.gov (United States)

    Davis, J B

    2000-01-01

    This paper examines the lack of health insurance coverage in the US as a public policy issue. It first compares the problem of health insurance coverage to the problem of unemployment to show that in terms of the numbers of individuals affected lack of health insurance is a problem comparable in importance to the problem of unemployment. Secondly, the paper discusses the methodology involved in measuring health insurance coverage, and argues that the current method of estimation of the uninsured underestimates the extent that individuals go without health insurance. Third, the paper briefly introduces Amartya Sen's functioning and capabilities framework to suggest a way of representing the extent to which individuals are uninsured. Fourth, the paper sketches a means of operationalizing the Sen representation of the uninsured in terms of the disability-adjusted life year (DALY) measure.

  11. IL-10 is excluded from the functional cytokine memory of human CD4+ memory T lymphocytes.

    Science.gov (United States)

    Dong, Jun; Ivascu, Claudia; Chang, Hyun-Dong; Wu, Peihua; Angeli, Roberta; Maggi, Laura; Eckhardt, Florian; Tykocinski, Lars; Haefliger, Carolina; Möwes, Beate; Sieper, Jochen; Radbruch, Andreas; Annunziato, Francesco; Thiel, Andreas

    2007-08-15

    Epigenetic modifications, including DNA methylation, profoundly influence gene expression of CD4(+) Th-specific cells thereby shaping memory Th cell function. We demonstrate here a correlation between a lacking fixed potential of human memory Th cells to re-express the immunoregulatory cytokine gene IL10 and its DNA methylation status. Memory Th cells secreting IL-10 or IFN-gamma were directly isolated ex vivo from peripheral blood of healthy volunteers, and the DNA methylation status of IL10 and IFNG was assessed. Limited difference in methylation was found for the IL10 gene locus in IL-10-secreting Th cells, as compared with Th cells not secreting IL-10 isolated directly ex vivo or from in vitro-established human Th1 and Th2 clones. In contrast, in IFN-gamma(+) memory Th cells the promoter of the IFNG gene was hypomethylated, as compared with IFN-gamma-nonsecreting memory Th cells. In accordance with the lack of epigenetic memory, almost 90% of ex vivo-isolated IL-10-secreting Th cells lacked a functional memory for IL-10 re-expression after restimulation. Our data indicate that IL10 does not become epigenetically marked in human memory Th cells unlike effector cytokine genes such as IFNG. The exclusion of IL-10, but not effector cytokines, from the functional memory of human CD4(+) T lymphocytes ex vivo may reflect the need for appropriate regulation of IL-10 secretion, due to its potent immunoregulatory potential.

  12. Cytokine profile of murine malaria: stage-related production of inflammatory and anti-inflammatory cytokines.

    Science.gov (United States)

    Bakir, Hanaa Y; Tomiyama, Chikako; Abo, Toru

    2011-06-01

    Balance between inflammatory and anti-inflammatory cytokines may be important in malaria presentation and outcome. To clarify cytokine interactions that produce pathology of malaria and control infection, C57BL/6 mice were infected with 10(4) parasitized RBCs from a non-lethal strain of Plasmodium yoelii. Kinetics was monitored showing the course of parasitemia, and cytokines were determined by RT-PCR from liver and spleen tissues. Inflammatory cytokines such as interferon-γ (IFNγ), interleukin (IL)-12, IL-6, tumor necrosis factor-α (TNFα) and anti-inflammatory cytokines, including IL-4 and IL-10, were investigated as key molecules that interact with immune cells in the activation of the immune responses. The production of IFNγ mRNA was found to be higher on day 7 than on day 21 after infection, and IL-12 and IL-6 showed higher expression in the liver than in the spleen. Though TNFα was highly expressed on day 14 after infection and on day 21 in the liver, such expression was decreased on day 21 in the spleen. Anti-inflammatory cytokines showed high expression in both the liver and spleen. The results suggest that a relative balance between inflammatory and anti-inflammatory cytokines is crucial and that the increase of inflammatory cytokine levels during the acute phase of malaria may reflect an early and effective immune response.The counteraction effect of anti-inflammatory cytokines is thought to play a role in limiting progression from uncomplicated malaria to severe life-threatening complications.

  13. Cytokines and Organ Failure in Acute Pancreatitis

    DEFF Research Database (Denmark)

    Malmstrøm, Marie Louise; Hansen, Mark Berner; Andersen, Anders Møller

    2012-01-01

    Objectives: We aimed at synchronously examining the early time course of 4 proinflammatory cytokines as predictive factors for development of organ failure in patients with acute pancreatitis (AP). Methods: Interleukin (IL) 6, IL-8, IL-18, and tumor necrosis factor > were measured on admission...

  14. Role of cytokines in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), rep- resents a group of chronic disorders characterized by inflammation of the gastrointestinal tract, typically with a relapsing and remitting clinical course. Mucosal mac- rophages play an important role in the mucosal im- mune system, and an increase in the number of newly recruited monocytes and activated macrophages has been noted in the inflamed gut of patients with IBD. Activated macrophages are thought to be major con- tributors to the production of inflammatory cytokines in the gut, and imbalance of cytokines is contributing to the pathogenesis of IBD. The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Cytokines play a key role in IBD that determine T cell differentiation of Th1, Th2, T regulatory and newly described Th17 cells. Cytokines levels in time and space orchestrate the development, recurrence and exacerbation of theinflammatory process in IBD. Therefore, several cyto- kine therapies have been developed and tested for the treatment of IBD patients.

  15. Cytokines in atherosclerosis: an intricate balance

    NARCIS (Netherlands)

    Boshuizen, M.C.S.

    2016-01-01

    Atherosclerosis is the underlying pathology in the majority of clinical manifestations of cardiovascular diseases, which are nowadays the main global cause of mortality. Atherosclerosis is a lipid-driven chronic inflammatory disease of the arterial wall. This inflammatory response, with cytokines as

  16. Cytokines and immune surveillance in humans

    Science.gov (United States)

    Sonnenfeld, Gerald

    1994-01-01

    Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. Among the parameters shown, by us and others, to be affected is the production of interferons. Interferons are a family of cytokines that are antiviral and play a major role in regulating immune responses that control resistance to infection. Alterations in interferon and other cytokine production and activity could result in changes in immunity and a possible compromise of host defenses against both opportunistic and external infections. The purpose of the present study is to explore further the effects of space flight on cyotokines and cytokine-directed immunological function. Among the tests carried out are interferon-alpha production, interferon-gamma production, interleukin-1 and -2 production, signal transduction in neutrophils, signal transduction in monocytes, and monocyte phagocytic activity. The experiments will be performed using peripheral blood obtained from human subjects. It is our intent to eventually carry out these experiments using astronauts as subjects to determine the effects of space flight on cytokine production and activity. However, these subjects are not currently available. Until they become available, we will carry out these experiments using subjects maintained in the bed-rest model for microgravity.

  17. IFN-gamma: Novel antiviral cytokines

    DEFF Research Database (Denmark)

    Ank, Nina; West, Hans; Paludan, Søren Riis

    2006-01-01

    and adaptive immune responses. Recently, a novel class of cytokines was discovered and named IFN-lambda (alternatively type III IFN or interleukin-28/29 [IL- 28/29]), based on IFN-like antiviral activity and induction of typical IFN-inducible genes. Here, we review the literature on IFN-lambda and discuss...

  18. Murine cytokine patterns following rubella vaccination.

    Science.gov (United States)

    Farzaneh, Parvarich; Ebtekar, Massoumeh; Hassan, Z M; Rafati, Sima

    2003-06-01

    Although thorough studies on the immune reponse to rubella have been performed, less attention has been given to the cellular mechanism and mediators that shape the process. Specifically, information concerning the nature ofcytokine patterns involved in the immune response to Rubella vaccination is not avaliable. This study deals with cytokine production patterns of spleen cells from Balb/c mice following vaccination with the Takahashi strain of Rubella vaccine. Mice were injected intraperitonealy with Rubella virus and PBS and 7, 10 or 14 days later, spleen cells were separated and cultured with varying doses of virus, con A or only the medium. ELISA assays were performed on supernatants for measurement of IL-4, INF-gamma and IL-5. LTT (Lymphocyte Transformation Test) was also performed. The data indicate variation in cytokine patterns during the time periods after vaccination. On day 7 a type 1 pattern was observed. The LTT response was also indicative of CMI (Cell Mediated Immunity) response on the 7th and 14th days while a transient suppression on day 10 was observed. These results indicate a time dependent cytokine response with variation ultimately leading o a dominant type 1 (Ti) cytokine response.

  19. Tracking the fate of antigen-specific versus cytokine-activated natural killer cells after cytomegalovirus infection.

    Science.gov (United States)

    Nabekura, Tsukasa; Lanier, Lewis L

    2016-11-14

    Natural killer (NK) cells provide important host defense and can generate long-lived memory NK cells. Here, by using novel transgenic mice carrying inducible Cre expressed under the control of Ncr1 gene, we demonstrated that two distinct long-lived NK cell subsets differentiate in a mouse model of cytomegalovirus (MCMV) infection. NK cells expressing the MCMV-specific Ly49H receptor differentiated into memory NK cells by an activating signaling through Ly49H and Ly49H(-) NK cells differentiated into cytokine-activated NK cells by exposure to inflammatory cytokines during infection. Interleukin-12 is indispensable for optimal generation of both antigen-specific memory NK cells and cytokine-activated NK cells. MCMV-specific memory NK cells show enhanced effector function and augmented antitumor activity in vivo as compared with cytokine-activated NK cells, whereas cytokine-activated NK cells exhibited a more robust response to IL-15 and persisted better in an MCMV-free environment. These findings reveal that NK cells are capable of differentiation into distinct long-lived subsets with different functional properties. © 2016 Nabekura and Lanier.

  20. Cytokines profile in hypertensive patients with left ventricular remodeling and dysfunction.

    Science.gov (United States)

    Kuznetsova, Tatiana; Haddad, Francois; Knez, Judita; Rosenberg-Hasson, Yael; Sung, Janine; Cauwenberghs, Nicholas; Thijs, Lutgarde; Karakikes, Ioannis; Maecker, Holden; Mahaffey, Kenneth W; Wu, Joseph C; Staessen, Jan A

    2015-12-01

    There is strong evidence that inflammatory mediators play a key role in the progression to heart failure in patients with systemic hypertension (HTN). The present study aimed to identify a set of cytokines that are associated with early left ventricular (LV) remodeling and dysfunction as captured by echocardiography in patients with HTN in a cross-sectional case-control study nested within the FLEMish study on ENvironment, Genes and Health Outcome. We identified three groups of participants from the cohort: normotensive subjects (normotension; n = 30), HTN with normal LV structure and function (HTN [LV-]; n = 30), and HTN with evidence of adverse LV remodeling (HTN [LV+]; n = 50). We measured cytokines using a 63-plex Luminex platform. Using partial least squares-discriminant analysis, we constructed three latent variables from the measured cytokines that explained 35%-45% of the variance between groups. We identified five common cytokines (interleukin 18, monokine induced by gamma interferon, hepatocyte growth factor, epithelial neutrophil-activating peptide 78, and vascular endothelial growth factor D) with a stable signal which had a major impact on the construction of the latent variables. Among these cytokines, after adjustment for confounders, interleukin 18 remained significantly different between HTN participants with and without LV involvement (P = .02). Moreover, granulocyte-macrophage colony-stimulating factor and leptin showed a consistent upward trend in all HTN patients compared with normotensive subjects. In conclusion, in HTN patients with LV remodeling or/and dysfunction, we identified a set of cytokines strongly associated with LV maladaptation. We also found a distinct profile of inflammatory biomarkers that characterize HTN.

  1. 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

  2. Why does Colombia lack agricultural commodity futures?

    Directory of Open Access Journals (Sweden)

    Pablo Moreno-Alemay

    2015-11-01

    Full Text Available This article explores the reasons why futures contracts are not traded as an alternative to price hedging for agricultural goods in Colombia. Based on surveys, interviews and statistical analysis, this study identified that conceptual gaps in contract negotiation, lack of consensus in the agricultural sector regarding the use of financial mechanisms and the sector’s infrequent contact with Colombia’s financial institutions, are the main reasons why a futures contracts market has not emerged.

  3. Defining poverty as distinctively human

    Directory of Open Access Journals (Sweden)

    H.P.P. Lötter

    2007-05-01

    Full Text Available While it is relatively easy for most people to identify human beings suffering from poverty, it is rather more difficult to come to a proper understanding of poverty. In this article the author wants to deepen our understanding of poverty by interpreting the conventional definitions of poverty in a new light. The article starts with a defence of a claim that poverty is a concept uniquely applicable to humans. It then present a critical discussion of the distinction between absolute and relative poverty and it is then argued that a revision of this distinction can provide general standards applicable to humans everywhere.

  4. Cytokine balance and cytokine-driven natural killer cell dysfunction in systemic juvenile idiopathic arthritis.

    Science.gov (United States)

    Avau, Anneleen; Put, Karen; Wouters, Carine H; Matthys, Patrick

    2015-02-01

    Systemic juvenile idiopathic arthritis (sJIA) is a severe inflammatory childhood disorder, characterized by a specific pattern of systemic features and a typical cytokine profile. Patients are at risk to develop macrophage activation syndrome (MAS), an acute life-threatening condition defined by excessive proliferation and activation of macrophages and T cells. Defects of unknown cause in the natural killer (NK) cell cytotoxic capacity are presumed to underlie the pathogenesis of MAS and have been detected in sJIA patients. Here, we provide an overview of the cytokine profiles in sJIA and related mouse models. We discuss the influence of cytokines on NK cell function, and hypothesize that NK cell dysfunction in sJIA is caused by altered cytokine profiles.

  5. Low pH Environmental Stress Inhibits LPS and LTA-Stimulated Proinflammatory Cytokine Production in Rat Alveolar Macrophages

    Directory of Open Access Journals (Sweden)

    Stanley F. Fernandez

    2013-01-01

    Full Text Available Gastric aspiration increases the risks for developing secondary bacterial pneumonia. Cytokine elaboration through pathogen recognition receptors (PRRs is an important mechanism in initiating innate immune host response. Effects of low pH stress, a critical component of aspiration pathogenesis, on the PRR pathways were examined, specifically toll-like receptor-2 (TLR2 and TLR4, using isolated rat alveolar macrophages (aMØs. We assessed the ability of aMØs after brief exposure to acidified saline to elaborate proinflammatory cytokines in response to lipopolysaccharide (LPS and lipoteichoic acid (LTA stimulation, known ligands of TLR4 and TLR2, respectively. Low pH stress reduced LPS- and LTA-mediated cytokine release (CINC-1, MIP-2, TNF-, MCP-1, and IFN-. LPS and LTA increased intracellular Ca2+ concentrations while Ca2+ chelation by BAPTA decreased LPS- and LTA-mediated cytokine responses. BAPTA blocked the effects of low pH stress on most of LPS-stimulated cytokines but not of LTA-stimulated responses. In vivo mouse model demonstrates suppressed E. coli and S. pneumoniae clearance following acid aspiration. In conclusion, low pH stress inhibits antibacterial cytokine response of aMØs due to impaired TLR2 (MyD88 pathway and TLR4 signaling (MyD88 and TRIF pathways. The role of Ca2+ in low pH stress-induced signaling is complex but appears to be distinct between LPS- and LTA-mediated responses.

  6. Analysing the lack of Demand Organisation

    Science.gov (United States)

    Boxer, Philip; Cohen, Bernard

    1998-07-01

    We seek to develop means of intervention in Enterprises that will enable them to react in an effective, sustainable and timely fashion to changes in the ways that markets and demand are organized; that is, to act strategically. We take an enterprise to be some entity that seeks to provide its clients with services that they value while maintaining its ability to do so in the face of changes in the demands of its clients and in the resources at its disposal. The services that clients value form around what the organization of their demands lack. The concept of strategy therefore rests on critically evaluating the ontology and semantics of the Enterprise in relation to these holes in demand organization. We access ontology and semantics by constructing and manipulating hypothetical, first-order, mathematical models of the Enterprise's services and of its value-adding processes. Because an enterprise is an anticipatory system, its semantic domain must include representations of the enterprise's model of itself and of the market and demand organizations within which it competes. First-order (set) theory provides adequate expressive power here, but alternative, higher order, mathematical frameworks, such as Dubois' hyperincursion, provide inadequate power, particularly in relation to the analysis of the properties of emergence. Knowing exactly why and where this mathematical lack manifests in the analysis process enables effective collaboration between systems analysts and psychoanalysts, and suggest directions for mathematical research.

  7. Quantum preparation uncertainty and lack of information

    Science.gov (United States)

    Rozpędek, Filip; Kaniewski, Jędrzej; Coles, Patrick J.; Wehner, Stephanie

    2017-02-01

    The quantum uncertainty principle famously predicts that there exist measurements that are inherently incompatible, in the sense that their outcomes cannot be predicted simultaneously. In contrast, no such uncertainty exists in the classical domain, where all uncertainty results from ignorance about the exact state of the physical system. Here, we critically examine the concept of preparation uncertainty and ask whether similarly in the quantum regime, some of the uncertainty that we observe can actually also be understood as a lack of information (LOI), albeit a lack of quantum information. We answer this question affirmatively by showing that for the well known measurements employed in BB84 quantum key distribution (Bennett and Brassard 1984 Int. Conf. on Computer System and Signal Processing), the amount of uncertainty can indeed be related to the amount of available information about additional registers determining the choice of the measurement. We proceed to show that also for other measurements the amount of uncertainty is in part connected to a LOI. Finally, we discuss the conceptual implications of our observation to the security of cryptographic protocols that make use of BB84 states.

  8. Clash of the Cytokine Titans: counter-regulation of interleukin-1 and type I interferon-mediated inflammatory responses.

    Science.gov (United States)

    Mayer-Barber, Katrin D; Yan, Bo

    2017-01-01

    Over the past decades the notion of 'inflammation' has been extended beyond the original hallmarks of rubor (redness), calor (heat), tumor (swelling) and dolor (pain) described by Celsus. We have gained a more detailed understanding of the cellular players and molecular mediators of inflammation which is now being applied and extended to areas of biomedical research such as cancer, obesity, heart disease, metabolism, auto-inflammatory disorders, autoimmunity and infectious diseases. Innate cytokines are often central components of inflammatory responses. Here, we discuss how the type I interferon and interleukin-1 cytokine pathways represent distinct and specialized categories of inflammatory responses and how these key mediators of inflammation counter-regulate each other.

  9. Educational Psychology: The Distinctive Contribution

    Science.gov (United States)

    Cameron, R. J.

    2006-01-01

    This paper, written in the twenty-first anniversary year of the journal "Educational Psychology in Practice", attempts to uncover those distinctive aspects of the discipline and the practice of applied psychology in general and educational psychology in particular. After considering some of the reasons for attempting this task at this point in…

  10. Educational Psychology: The Distinctive Contribution

    Science.gov (United States)

    Cameron, R. J.

    2006-01-01

    This paper, written in the twenty-first anniversary year of the journal "Educational Psychology in Practice", attempts to uncover those distinctive aspects of the discipline and the practice of applied psychology in general and educational psychology in particular. After considering some of the reasons for attempting this task at this point in…

  11. Scanning for Therapeutic Targets within the Cytokine Network of Idiopathic Inflammatory Myopathies

    Directory of Open Access Journals (Sweden)

    Boel De Paepe

    2015-08-01

    Full Text Available The idiopathic inflammatory myopathies (IIM constitute a heterogeneous group of chronic disorders that include dermatomyositis (DM, polymyositis (PM, sporadic inclusion body myositis (IBM and necrotizing autoimmune myopathy (NAM. They represent distinct pathological entities that, most often, share predominant inflammation in muscle tissue. Many of the immunopathogenic processes behind the IIM remain poorly understood, but the crucial role of cytokines as essential regulators of the intramuscular build-up of inflammation is undisputed. This review describes the extensive cytokine network within IIM muscle, characterized by strong expression of Tumor Necrosis Factors (TNFα, LTβ, BAFF, Interferons (IFNα/β/γ, Interleukins (IL-1/6/12/15/18/23 and Chemokines (CXCL9/10/11/13, CCL2/3/4/8/19/21. Current therapeutic strategies and the exploration of potential disease modifying agents based on manipulation of the cytokine network are provided. Reported responses to anti-TNFα treatment in IIM are conflicting and new onset DM/PM has been described after administration of anti-TNFα agents to treat other diseases, pointing to the complex effects of TNFα neutralization. Treatment with anti-IFNα has been shown to suppress the IFN type 1 gene signature in DM/PM patients and improve muscle strength. Beneficial effects of anti-IL-1 and anti-IL-6 therapy have also been reported. Cytokine profiling in IIM aids the development of therapeutic strategies and provides approaches to subtype patients for treatment outcome prediction.

  12. Therapeutic antibodies that target inflammatory cytokines in autoimmune diseases.

    Science.gov (United States)

    Lai, Yuping; Dong, Chen

    2016-04-01

    Inflammatory cytokines are key regulators of immune responses. Persistent and excessive production of inflammatory cytokines underscores the development of autoimmune diseases. Therefore, neutralizing inflammatory cytokines or antagonizing their receptor function is considered as a useful therapeutic strategy to treat autoimmune diseases. To achieve the success of such a strategy, understanding of the complex actions of these cytokines and cytokine networks is required. In this review we focus on four inflammatory cytokines--tumor necrosis factor α (TNFα), interleukin-6 (IL-6), IL-23 and IL-17--and dissect how the dysregulation of these cytokines regulates autoimmune diseases. On the basis of pre-clinical and clinical data, we specifically discuss the therapeutic rationale for targeting these cytokines and describe the potential adverse effects.

  13. Mechanism of cytokine modulation of epithelial tight junction barrier

    OpenAIRE

    Al-Sadi, Rana; Boivin, Michel; Ma, Thomas

    2009-01-01

    Cytokines play a crucial role in the modulation of inflammatory response in the gastrointestinal tract. Pro-inflammatory cytokines including tumor necrosis factor-α, interferon-γ, interleukin-1β (IL-1β), and interleukin-12 are essential in mediating the inflammatory response, while anti-inflammatory cytokines including interleukin-10 and transforming growth factor-β are important in the attenuation or containment of inflammatory process. It is increasingly recognized that cytokines have an im...

  14. Cytokines gene expression in newly diagnosed multiple sclerosis patients.

    OpenAIRE

    Seyed Javad Hasheminia; Sepideh Tolouei; Sayyed Hamid Zarkesh-Esfahani; Vahid Shaygannejad; Hedaiat Allah Shirzad; Reza Torabi; Morteza Hashem Zadeh Chaloshtory

    2015-01-01

    Multiple Sclerosis (MS) is characterized by multiple areas of inflammation, demyelination and neurodegeneration. Infiltrating Th1 CD4+ T cells secrete proinflammatory cytokines. They stimulate the release of some cytokines, expression of adhesion molecules and these cytokines may cause damage to the myelin sheath and axons. In this study, we analyzed plasma levels and gene expressions of five important cytokines in the new diagnosed MS Patients by ELISA and Real time PCR. PCR amplifications w...

  15. Lack of transplacental transmission of Bartonella bovis.

    Science.gov (United States)

    Chastant-Maillard, S; Boulouis, H-J; Reynaud, K; Thoumire, S; Gandoin, C; Bouillin, C; Cordonnier, N; Maillard, R

    2015-02-01

    Transplacental transmission of Bartonella spp. has been reported for rodents, but not for cats and has never been investigated in cattle. The objective of this study was to assess vertical transmission of Bartonella in cattle. Fifty-six cow-calf pairs were tested before (cows) and after (calves) caesarean section for Bartonella bacteremia and/or serology, and the cotyledons were checked for gross lesions and presence of the bacteria. None of the 29 (52%) bacteremic cows gave birth to bacteremic calves, and all calves were seronegative at birth. Neither placentitis nor vasculitis were observed in all collected cotyledons. Bartonella bovis was not detected in placental cotyledons. Therefore, transplacental transmission of B. bovis and multiplication of the bacteria in the placenta do not seem likely. The lack of transplacental transmission may be associated with the particular structure of the placenta in ruminants or to a poor affinity/agressiveness of B. bovis for this tissue.

  16. Mice lacking neurofibromin develop gastric hyperplasia

    Science.gov (United States)

    Lin, Lu; Chen, Jian; Richardson, James A.

    2009-01-01

    Gastrointestinal (GI) neoplasms are among many manifestations of the genetic disease neurofibromatosis type 1 (NF1). However, the physiological and pathological functions of the Nf1 gene in the GI system have not been fully studied, possibly because of a lack of mouse models. In this study, we generated conditional knockout mice with Nf1 deficiency in the GI tract. These mice develop gastric epithelial hyperplasia and inflammation together with increased cell proliferation and apoptosis. The gastric phenotypes observed in these mutant mice seem to be the consequence of loss of Nf1 in gastric fibroblasts, resulting in paracrine hyperactivation of the ERK pathway in the gastric epithelium. These mice provide a useful model to study the pathogenesis of GI lesions in a subset of patients with NF1 and to investigate the role of the Nf1 gene in the development of GI neoplasms. PMID:19661150

  17. Lack of a distinct gradient in biomarker responses in small mammals collected at different distances from a highway.

    Science.gov (United States)

    Hamers, T; Smit, L A M; Bosveld, A T C; van den Berg, J H J; Koeman, J H; van Schooten, F J; Murk, A J

    2002-10-01

    This study describes biomarker effects in small mammals exposed to traffic emissions. Animals were collected at 10-50 m (site 1), 150-200 m (site 2), and 5 km (site 3) from a very busy highway (A2). To distinguish between routes of exposure, strictly carnivorous common shrews ( Sorex araneus) and predominantly herbivorous bank voles ( Clethrionomys glareolus) were collected. As a measure of exposure to polycyclic aromatic hydrocarbons (PAHs), aromatic DNA adduct levels were determined by (32)P-postlabeling techniques in tissue from heart, lung, and liver. Lead (Pb), cadmium (Cd), and copper (Cu) levels were analyzed in kidney as a measure of exposure to heavy metals. EROD and PROD activity and retinoid levels were determined in liver as effect biomarkers for exposure to PAHs and polyhalogenated aromatic hydrocarbons (PHAHs). Relatively high Cd levels in S. araneus and in particular elevated DNA adduct levels in C. glareolus indicated that small mammals at site 3 were exposed to more compounds than at sites 1 and 2 (3 > or = 1 > 2). The latter effect is probably due to an incidental and actual input of airborne pollutants that is deposited on plant surfaces. By consumption of above-ground vegetation, voles are chronically exposed to this pollution. Relatively high background input of PAHs probably hinders that the traffic-related gradient of airborne PAH concentrations found in an earlier study is reflected in DNA adduct levels in small mammals in the present study. Moreover, historical biomarkers for exposure to traffic emissions, such as increased kidney Pb levels, increased hepatic EROD activity, and disturbed hepatic vitamin A homeostasis are no longer applicable to indicate differences in exposure. This is a result of the ban on addition of Pb and chlorinated scavengers to gasoline and of cleaner combustion techniques, which were enforced by law over the past decade. Finally, it is advisable to use only juvenile small mammals for in situ monitoring of diffuse pollution because DNA adduct levels increased with age.

  18. Lack of a distinct gradient in biomarker responses in small mammals collected at different distances from a highway

    NARCIS (Netherlands)

    Hamers, T.; Smit, L.A.M.; Bosveld, A.T.C.; Berg, van den J.H.J.; Koeman, J.H.; Schooten, van F.J.; Murk, A.J.

    2002-01-01

    This study describes biomarker effects in small mammals exposed to traffic emissions. Animals were collected at 10-50 m (site 1), 150-200 m (site 2), and 5 km (site 3) from a very busy highway (A2). To distinguish between routes of exposure, strictly carnivorous common shrews (Sorex araneus) and

  19. Proinflammatory and anti-inflammatory cytokines in meningococcal disease.

    OpenAIRE

    Riordan, F A; Marzouk, O; Thomson, A. P.; Sills, J A; Hart, C. A.

    1996-01-01

    Interleukin-10 (IL-10), an anti-inflammatory cytokine, was measured in 131 children with meningococcal disease. IL-10 concentrations were significantly higher in children who died and correlated positively with proinflammatory cytokines. Children who die from meningococcal disease have high IL-10 concentrations, which do not suppress proinflammatory cytokines.

  20. Intragraft Cytokine mRNA Expression After Clinical Organ Transplantation

    NARCIS (Netherlands)

    C.C. Baan (Carla)

    1998-01-01

    textabstractAs the knowledge of the cytokine network in experimental transplant models grows, we need to understand how and to what extent cytokines mediate the various donordirected immune events in clinical situations. This overview on clinical cytokine measurements shows that specific intragraft

  1. Screening the cytokines for diagnosis of tuberculous meningitis

    Institute of Scientific and Technical Information of China (English)

    王丽豪

    2014-01-01

    Objective To select cytokines for diagnosis of tuber-culous meningitis.Methods One hundred and twenty kinds of cytokines were detected with protein chips among two tuberculous meningitis cases,two viral meningitis cases and two noninfectious neurologic disease cases.The results were compared among different disease groups to select the differential cytokines,which were

  2. Cytokines: muscle protein and amino acid metabolism

    DEFF Research Database (Denmark)

    van Hall, Gerrit

    2012-01-01

    raises TNF-α and IL-6 to moderate levels, has only identified IL-6 as a potent cytokine, decreasing systemic amino acid levels and muscle protein metabolism. The marked decrease in circulatory and muscle amino acid concentrations was observed with a concomitant reduction in both the rates of muscle...... of IL-6 on the regulation of muscle protein metabolism but indirectly via IL-6 reducing amino acid availability. SUMMARY: Recent studies suggest that the best described cytokines TNF-α and IL-6 are unlikely to be the major direct mediators of muscle protein loss in inflammatory diseases. However...... protein synthesis and breakdown, that is, reduced turnover with a minor increase in net muscle degradation. Very similar observations have been made in models of acute inflammation, induced by high-dose endotoxin injection. However, these changes were suggested not to be attributed to a direct effect...

  3. Cytokines: muscle protein and amino acid metabolism

    DEFF Research Database (Denmark)

    van Hall, Gerrit

    2012-01-01

    raises TNF-α and IL-6 to moderate levels, has only identified IL-6 as a potent cytokine, decreasing systemic amino acid levels and muscle protein metabolism. The marked decrease in circulatory and muscle amino acid concentrations was observed with a concomitant reduction in both the rates of muscle...... protein synthesis and breakdown, that is, reduced turnover with a minor increase in net muscle degradation. Very similar observations have been made in models of acute inflammation, induced by high-dose endotoxin injection. However, these changes were suggested not to be attributed to a direct effect...... of IL-6 on the regulation of muscle protein metabolism but indirectly via IL-6 reducing amino acid availability. SUMMARY: Recent studies suggest that the best described cytokines TNF-α and IL-6 are unlikely to be the major direct mediators of muscle protein loss in inflammatory diseases. However...

  4. Role of cytokine therapy for renal cell carcinoma in the era of targeted agents

    Science.gov (United States)

    Koneru, R.; Hotte, S.J.

    2009-01-01

    Starting in the late 1980s, cytokines were considered the mainstay of treatment for locally advanced or metastatic renal cell carcinoma (rcc) because of a lack of improved survival with either chemotherapy or hormonal therapy alone. The cytokine agents interferon alfa (ifnα) and interleukin-2 (il-2) have been the most evaluated, but a low overall response rate and a marginal survival advantage, coupled with significant toxicity, make these therapies less than ideal. Although complete tumour responses have occasionally been seen with high-dose il-2, this therapy is associated with significant morbidity and mortality, and its approval has been based on limited nonrandomized evidence. Newer anti-angiogenesis agents have been evaluated as single agents and in combination with infα, and these are now considered the standard of care for most patients with rcc. However, cytokines may still occasionally be recommended when angiogenesis inhibitors are not available or are contraindicated. In the present paper, we discuss the evidence for the use of cytokine therapy in the setting of pre– and post–targeted therapy for rcc. PMID:19478896

  5. IL-10 and its related cytokines for treatment of inflammatory bowel disease.

    Science.gov (United States)

    Li, Ming-Cai; He, Shao-Heng

    2004-03-01

    Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis are chronic inflammatory disorders of gastrointestinal tract. Although the etiology is incompletely understood, initiation and aggravation of the inflammatory process seem to be due to a massive local mucosal immune response. Interleukin-10 (IL-10) is a regulatory cytokine which inhibits both antigen presentation and subsequent pro-inflammatory cytokine release, and it is proposed as a potent anti-inflammatory biological therapy in chronic IBD. Many methods of IL-10 as a treatment for IBD have been published. The new strategies of IL-10 treatment, including recombinant IL-10, the use of genetically modified bacteria, gelatine microsphere containing IL-10, adenoviral vectors encoding IL-10 and combining regulatory T cells are discussed in this review. The advantages and disadvantages of these IL-10 therapies are summarized. Although most results of recombinant IL-10 therapies are disappointing in clinical testing because of lacking efficacy or side effects, therapeutic strategies utilizing gene therapy may enhance mucosal delivery and increase therapeutic response. Novel IL-10-related cytokines, including IL-19, IL-20, IL-22, IL-24, IL-26, IL-28 and IL-29, are involved in regulation of inflammatory and immune responses. The use of IL-10 and IL-10-related cytokines will provide new insights into cell-based and gene-based treatment against IBD in near future.

  6. IL-10 and its related cytokines for treatment of inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Ming-Cai Li; Shao-Heng He

    2004-01-01

    Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis are chronic inflammatory disorders of gastrointestinal tract. Although the etiology is incompletely understood, initiation and aggravation of the inflammatory process seem to be due to a massive local mucosal immune response. Interleukin-10 (IL-10) is a regulatory cytokine which inhibits both antigen presentation and subsequent pro-inflammatory cytokine release, and it is proposed as a potent anti-inflammatory biological therapy in chronic IBD. Many methods of IL-10 as a treatment for IBD have been published. The new strategies of IL-10 treatment, including recombinant IL-10, the use of genetically modified bacteria, gelatine microsphere containing IL-10,adenoviral vectors encoding IL-10 and combining regulatory T cells are discussed in this review. The advantages and disadvantages of these IL-10 therapies are summarized.Although most results of recombinant IL-10 therapies are disappointing in clinical testing because of lacking efficacy or side effects, therapeutic strategies utilizing gene therapy may enhance mucosal delivery and increase therapeutic response. Novel IL-10-related cytokines, including IL-t9, IL-20, IL-22, IL-24, IL-26, IL-28 and IL-29, are involved in regulation of inflammatory and immune responses. The use of IL-10 and IL-10-related cytokines will provide new insights into cell-based and gene-based treatment against IBD in near future.

  7. Effects of hemorrhage on cytokine gene transcription.

    Science.gov (United States)

    Shenkar, R; Abraham, E

    1993-08-01

    Injury and blood loss are often followed by infection and the rapid development of organ system dysfunction, frequently involving mucosal sites, such as the lung and intestine. To examine possible mechanisms contributing to these conditions, we used semiquantitative polymerase chain reactions to determine cytokine mRNA expression among cellular populations isolated from mucosal and systemic anatomic sites of mice at predetermined time points following 30% blood volume hemorrhage with resuscitation 1 hr later. Within 1 hr after hemorrhage, significant increases were observed in mRNA levels for IL-1 alpha, IL-1 beta, IL-5, and TGF-beta in intraparenchymal pulmonary mononuclear cells. The levels of TGF-beta transcripts among alveolar macrophages were increased 1 hr following blood loss, and increase in IL-1 alpha transcripts was found starting 2 hr posthemorrhage. Cells from Peyer's patches showed significant increases in mRNA levels for IL-1 beta, IL-2, IL-5, IL-6, IFN-gamma, and TGF-beta during the 4 hr following hemorrhage. Significant increases in mRNA levels for IL-1 beta, TNF-alpha, and TGF-beta were present within 4 hr of blood loss among cells isolated from mesenteric lymph nodes. The expression of mRNA for most cytokines was not significantly altered in splenocytes or peripheral blood mononuclear cells at any time point following hemorrhage. These experiments demonstrate that blood loss, even if resuscitated, produces significant increases in proinflammatory and immunoregulatory cytokine gene transcription as early as 1 hr following hemorrhage. These posthemorrhage alterations in cytokine mRNA expression were particularly prominent at mucosal sites, suggesting a mechanism for the increased incidence of pulmonary and intestinal involvement in organ system failure following severe blood loss and injury.

  8. Acute pancreatitis and fibromyalgia: Cytokine link

    Directory of Open Access Journals (Sweden)

    Sadat Muzammil

    2011-01-01

    Full Text Available Context: Fibromyalgia is a widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, and has both genetic and environmental contribution. Acute pancreatitis is a severe condition and in most cases gallstones disease represents approximately half of the cases of acute pancreatitis, and 20-25% are related to alcohol abuse. Small numbers of cases are caused by a variety of other reasons but a few cases have no obvious cause, referred to as ′idiopathic′. Here we present a case where fibromyalgia might be linked to acute pancreatitis. We believe this has not been reported in this context in literature. Case Report: Fibromyalgia is a widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, and has both genetic and environmental contribution. Patient had a cholecystectomy eight years previously. Patient feels tired almost all the time due to her fibromyalgia and requires family support for daily routine. Patient′s blood results showed alanine transaminase 527 IU/L, alkaline phosphatase 604 IU/L, bilirubin 34 μmol/L, amylase 2257 IU/L, C-reactive protein 19 mg/L, Gamma-Glutamyl transpeptidase 851 IU/L, renal function and electrolytes were within normal limits. The patient was admitted to the high dependency unit with a diagnosis of acute pancreatitis. Conclusion: There is a known increase in levels of cytokines in patients with fibromyalgia. Part of the pathophysiology of acute pancreatitis is related to raised cytokines and immune deregulations. We hypothesize that elevated levels of cytokines in fibromyalgia has led to acute pancreatitis in our patient. Further epidemiological research on the incidence of pancreatitis in cytokine mediated conditions such as fibromyalgia is required.

  9. Cytokine-Induced Modulation of Colorectal Cancer.

    Science.gov (United States)

    Mager, Lukas F; Wasmer, Marie-Hélène; Rau, Tilman T; Krebs, Philippe

    2016-01-01

    The emergence of novel immunomodulatory cancer therapies over the last decade, above all immune checkpoint blockade, has significantly advanced tumor treatment. For colorectal cancer (CRC), a novel scoring system based on the immune cell infiltration in tumors has greatly improved disease prognostic evaluation and guidance to more specific therapy. These findings underline the relevance of tumor immunology in the future handling and therapeutic approach of malignant disease. Inflammation can either promote or suppress CRC pathogenesis and inflammatory mediators, mainly cytokines, critically determine the pro- or anti-tumorigenic signals within the tumor environment. Here, we review the current knowledge on the cytokines known to be critically involved in CRC development and illustrate their mechanisms of action. We also highlight similarities and differences between CRC patients and murine models of CRC and point out cytokines with an ambivalent role for intestinal cancer. We also identify some of the future challenges in the field that should be addressed for the development of more effective immunomodulatory therapies.

  10. Cytokines as biomarkers in rheumatoid arthritis.

    Science.gov (United States)

    Burska, Agata; Boissinot, Marjorie; Ponchel, Frederique

    2014-01-01

    RA is a complex disease that develops as a series of events often referred to as disease continuum. RA would benefit from novel biomarker development for diagnosis where new biomarkers are still needed (even if progresses have been made with the inclusion of ACPA into the ACR/EULAR 2010 diagnostic criteria) and for prognostic notably in at risk of evolution patients with autoantibody-positive arthralgia. Risk biomarkers for rapid evolution or cardiovascular complications are also highly desirable. Monitoring biomarkers would be useful in predicting relapse. Finally, predictive biomarkers for therapy outcome would allow tailoring therapy to the individual. Increasing numbers of cytokines have been involved in RA pathology. Many have the potential as biomarkers in RA especially as their clinical utility is already established in other diseases and could be easily transferable to rheumatology. We will review the current knowledge's relation to cytokine used as biomarker in RA. However, given the complexity and heterogeneous nature of RA, it is unlikely that a single cytokine may provide sufficient discrimination; therefore multiple biomarker signatures may represent more realistic approach for the future of personalised medicine in RA.

  11. Cytokines as Biomarkers in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Agata Burska

    2014-01-01

    Full Text Available RA is a complex disease that develops as a series of events often referred to as disease continuum. RA would benefit from novel biomarker development for diagnosis where new biomarkers are still needed (even if progresses have been made with the inclusion of ACPA into the ACR/EULAR 2010 diagnostic criteria and for prognostic notably in at risk of evolution patients with autoantibody-positive arthralgia. Risk biomarkers for rapid evolution or cardiovascular complications are also highly desirable. Monitoring biomarkers would be useful in predicting relapse. Finally, predictive biomarkers for therapy outcome would allow tailoring therapy to the individual. Increasing numbers of cytokines have been involved in RA pathology. Many have the potential as biomarkers in RA especially as their clinical utility is already established in other diseases and could be easily transferable to rheumatology. We will review the current knowledge’s relation to cytokine used as biomarker in RA. However, given the complexity and heterogeneous nature of RA, it is unlikely that a single cytokine may provide sufficient discrimination; therefore multiple biomarker signatures may represent more realistic approach for the future of personalised medicine in RA.

  12. The role of cytokines in skin aging.

    Science.gov (United States)

    Borg, M; Brincat, S; Camilleri, G; Schembri-Wismayer, P; Brincat, M; Calleja-Agius, J

    2013-10-01

    Cutaneous aging is one of the major noticeable menopausal complications that most women want to fight in their quest for an eternally youthful skin appearance. It may contribute to some maladies that occur in aging which, despite not being life-threatening, affect the well-being, psychological state and quality of life of aged women. Skin aging is mainly affected by three factors: chronological aging, decreased levels of estrogen after menopause, and environmental factors. Aged skin is characterized by a decrease in collagen content and skin thickness which result in dry, wrinkled skin that is easily bruised and takes a longer time to heal. Cytokines play a crucial role in the manifestation of these features of old skin. The pro-inflammatory cytokine tumor necrosis factor-alpha inhibits collagen synthesis and enhances collagen degradation by increasing the production of MMP-9. It also lowers the skin immunity and thus increases the risk of cutaneous infections in old age. Deranged levels of several interleukins and interferons also affect the aging process. The high level of CCN1 protein in aged skin gives dermal fibroblasts an 'age-associated secretory phenotype' that causes abnormal homeostasis of skin collagen and leads to the loss of the function and integrity of skin. Further research is required especially to establish the role of cytokines in the treatment of cutaneous aging.

  13. Aggressive periodontitis and chronic arthritis: blood mononuclear cell gene expression and plasma protein levels of cytokines and cytokine inhibitors

    DEFF Research Database (Denmark)

    Sørensen, Lars K; Havemose-Poulsen, Anne; Bendtzen, Klaus

    2009-01-01

    BACKGROUND: Cytokines and cytokine inhibitors have been associated with many immunoinflammatory diseases. In the present study, we examined whether peripheral blood mononuclear cell (PBMC) gene expression mirrors the corresponding plasma levels of clinically important pro- and anti-inflammatory c......BACKGROUND: Cytokines and cytokine inhibitors have been associated with many immunoinflammatory diseases. In the present study, we examined whether peripheral blood mononuclear cell (PBMC) gene expression mirrors the corresponding plasma levels of clinically important pro- and anti...

  14. Inflammatory cytokine detection in adenotonsill and peripheral blood mononuclear cells- culture in adenotonsillectomy patients: a comparative study

    Directory of Open Access Journals (Sweden)

    Farhadi M

    2013-04-01

    Full Text Available Background: Tonsils and adenoid hypertrophy is a major respiratory symptom in children which is partly due to recruitment of inflammatory cells in upper airway lymph nodes as a result of the effects of synthesis and release of different inflammatory cytokines. It seems that infections play role in concert with these cytokines leading to tonsilar hypertrophy and other pathologic consequences. It is proposed that cellular infiltrate of tonsils and adenoids may secrete different quantities of these cytokines compared with peripheral blood mononuclear cells (PBMC cultures.Methods: Among patients who were admitted for adenotonsillectomy to the ENT ward, 37 patients, under 1-12 years old patients with fulfill criteria selected to include the study. Excised adenoid and tonsils cultured and inflammatory cytokines Interferon-γ (INF-γ, Interlukine-1 (IL-1, IL-6, IL-8 and tumor necrosis factor-α (TNF-α measured in cellular culture supernatant. The same cytokines measured in PBMC cultures.Results: The data shows that there is a significant difference between IFN-γ and IL-8 amounts in adenoid tissue culture supernatant and PBMC culture of our patients. Furth-ermore, the amounts of IFN-γ, IL-1 and IL-8 showed considerable difference between tonsilar tissue culture supernatant and PBMC culture of these patients. Although there is a significant correlation between IL-6 amounts in tissue culture supernatant and PBMC culture (P=0.02, the respective data for TNF is only almost significant.Conclusion: Inflammatory cytokines may have significant role in the early provoke of inflammation occurred in hypertrophied tonsils and adenoid. The majority of these cyt-okines increase the expression of adhesion molecules on epithelial cells and influence the recruitment of leucocytes and inflamed tonsils. On the other hand lack of sufficient cytokine release may lead to persistent infections and may cause chronic inflammation and hypertrophied tissue.

  15. Plasma cytokine profiling in sibling pairs discordant for autism spectrum disorder

    Science.gov (United States)

    2013-01-01

    Objective Converging lines of evidence point to the existence of immune dysfunction in autism spectrum disorder (ASD), which could directly affect several key neurodevelopmental processes. Previous studies have shown higher cytokine levels in patients with autism compared with matched controls or subjects with other developmental disorders. In the current study, we used plasma-cytokine profiling for 25 discordant sibling pairs to evaluate whether these alterations occur within families with ASD. Methods Plasma-cytokine profiling was conducted using an array-based multiplex sandwich ELISA for simultaneous quantitative measurement of 40 unique targets. We also analyzed the correlations between cytokine levels and clinically relevant quantitative traits (Vineland Adaptive Behavior Scale in Autism (VABS) composite score, Social Responsiveness Scale (SRS) total T score, head circumference, and full intelligence quotient (IQ)). In addition, because of the high phenotypic heterogeneity of ASD, we defined four subgroups of subjects (those who were non-verbal, those with gastrointestinal issues, those with regressive autism, and those with a history of allergies), which encompass common and/or recurrent endophenotypes in ASD, and tested the cytokine levels in each group. Results None of the measured parameters showed significant differences between children with ASD and their related typically developing siblings. However, specific target levels did correlate with quantitative clinical traits, and these were significantly different when the ASD subgroups were analyzed. It is notable that these differences seem to be attributable to a predisposing immunogenetic background, as no other significant differences were noticed between discordant sibling pairs. Interleukin-1β appears to be the cytokine most involved in quantitative traits and clinical subgroups of ASD. Conclusions In the present study, we found a lack of significant differences in plasma-cytokine levels between

  16. Unique cytokine and chemokine patterns in bronchoalveolar lavage are associated with specific causative pathogen among HIV infected patients with pneumonia, in Medellin, Colombia.

    Science.gov (United States)

    Keynan, Yoav; Rueda, Zulma V; Aguilar, Yudy; Trajtman, Adriana; Vélez, Lázaro A

    2015-06-01

    We wanted to investigate the pro-inflammatory cytokine/chemokine profile associated with the etiological agents identified in HIV patients. Immunosuppressed patients admitted to two hospitals in Medellin, Colombia, with clinical and radiographic diagnosis of pneumonia were enrolled in the study. After consent, bronchoalveolar lavage (BAL) was collected for bacterial, mycobacterial and fungal diagnosis. All patients were followed for a year. A stored BAL sample was used for cytokine/chemokine detection and measurement using commercial, magnetic human cytokine bead-based 19-plex assays. Statistical analysis was performed by assigning cytokine/chemokine concentrations levels into 75 percentile (higher). Principal component analysis (PCA) and Kruskal-Wallis analysis were conducted to identify the clustering of cytokines with the various infectious etiologies (fungi, Mycobacterium tuberculosis - MTB, and bacteria). Average age of patients was 35, of whom 77% were male, and the median CD4 count of 33cells/μl. Of the 57 HIV infected patients, in-hospital mortality was 12.3% and 33% died within a year of follow up. The PCA revealed increased IL-10, IL-12, IL-13, IL-17, Eotaxin, GCSF, MIP-1α, and MIP-1β concentrations to be associated with MTB infection. In patients with proven fungal infection, low concentrations of IL-1RA, IL-8, TNF-α and VEGF were identified. Bacterial infections displayed a distinct cytokine pattern and were not misclassified using the MTB or fungi cytokine patterns (p-value<0.0001). Our results indicate a unique pattern of pro-inflammatory cytokine/chemokine, allowing differentiation between bacterial and non-bacterial pathogens. Moreover, we found distinct, if imperfectly discriminatory, cytokine/chemokine patterns associated with MTB and fungal infections.

  17. Distinct genetic regions modify specific muscle groups in muscular dystrophy

    OpenAIRE

    2010-01-01

    Phenotypic expression in the muscular dystrophies is variable, even with the identical mutation, providing strong evidence that genetic modifiers influence outcome. To identify genetic modifier loci, we used quantitative trait locus mapping in two differentially affected mouse strains with muscular dystrophy. Using the Sgcg model of limb girdle muscular dystrophy that lacks the dystrophin-associated protein γ-sarcoglycan, we evaluated chromosomal regions that segregated with two distinct quan...

  18. Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets.

    Science.gov (United States)

    Furst, Daniel E; Emery, Paul

    2014-09-01

    Biologic therapies that target pathogenic cytokines such as TNF, IL-1β or IL-6 have greatly improved the treatment of RA. Unfortunately, not all RA patients respond to current biologic therapies and responses are not always maintained, suggesting that there are alternative drivers of RA pathogenesis that might serve as promising therapeutic targets. Discovery of the new Th17 subset of Th cells, and their role in autoimmune disease development, has implicated the proinflammatory IL-12 and IL-17 families of cytokines in RA disease pathogenesis. Members of these cytokine families are elevated in the blood and joints of RA patients and have been shown to remain elevated in patients who do not respond to current biologics. In addition, these cytokines have been shown to play roles in joint destruction and erosion. A new subclass of biologics that target the IL-12 and/or IL-17 signalling pathways are under development. Here we review evidence for a role of Th17 cells as well as IL-12 and IL-17 cytokines in RA pathogenesis as the rationale for a subsequent discussion of the ongoing and completed clinical trials of newly emerging biologic therapies directed at IL-12 or IL-17 pathway inhibition.

  19. Energy brands lack vitality; Energiemerken ontberen vitaliteit

    Energy Technology Data Exchange (ETDEWEB)

    Godri, S.; Wilders, E. [CONSULT Brand Strategy, Y and R Advertising, Amsterdam (Netherlands)

    2004-06-01

    The three Dutch energy companies (Nuon, Essent and Eneco Energie) have relatively little brand strength. The brands are not perceived to be sufficiently different from one another and are not valued by consumers. With liberalisation imminent, this is hardly a strong starting point. How can you win over consumers if it is not clear what is on offer? In the business market, decision-makers are better placed to distinguish between brands. However, the brands lack vitality in this sector of the market too. The only consolation is that the situation is by no means exclusive to the Netherlands. [Dutch] De merksterkte van de drie Nederlandse energiebedrijven Nuon, Essent en Eneco Energie, is gering. De energiemerken onderscheiden zich niet genoeg en missen waardering. Met het oog op de aanstaande liberalisering geen goede uitgangspositie. Hoe kun je consumenten voor je winnen als onduidelijk is waarvoor ze moeten kiezen? Op de zakelijk markt zijn de beslissers beter in staat om de merken te onderscheiden. Maar ook hier missen de energiemerken vitaliteit. Een troost: Nederlandse energiebedrijven zijn niet de enige met dit probleem.

  20. Autism with Intellectual Disability is Associated with Increased Levels of Maternal Cytokines and Chemokines During Gestation

    Science.gov (United States)

    Jones, Karen L.; Croen, Lisa A.; Yoshida, Cathleen K.; Heuer, Luke; Hansen, Robin; Zerbo, Ousseny; DeLorenze, Gerald N.; Kharrazi, Martin; Yolken, Robert; Ashwood, Paul; Van de Water, Judy

    2016-01-01

    Immune abnormalities have been described in some individuals with autism spectrum disorders (ASD) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay without ASD (DD) (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (DQ<70) (ASD+ID, N=184) and those without (DQ≥70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country, and weight, as well as infant gender, birth year, and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as GM-CSF, IFN-γ, IL-1α, and IL-6, compared to mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and MCP-1 compared to mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability (ID) associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to sub-phenotypes of ASD. PMID:27217154

  1. Cytokine-Like Factor 1, an Essential Facilitator of Cardiotrophin-Like Cytokine:Ciliary Neurotrophic Factor Receptor α Signaling and sorLA-Mediated Turnover.

    Science.gov (United States)

    Larsen, Jakob Vejby; Kristensen, Anders Mejer; Pallesen, Lone Tjener; Bauer, Johannes; Vægter, Christian Bjerggaard; Nielsen, Morten Schallburg; Madsen, Peder; Petersen, Claus Munck

    2016-04-01

    Cardiotrophin-like cytokine:cytokine-like factor-1 (CLC:CLF-1) is a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development. Mice lacking CLC:CLF-1 die soon after birth due to a suckling defect and show reduced numbers of motor neurons. Humans carrying mutations in CLC:CLF-1 develop similar disorders, known as Sohar-Crisponi or cold-induced sweating syndrome, and have a high risk of early death. It is well known that CLC binds the ciliary neurotrophic factor receptor α (CNTFRα) and is a prerequisite for signaling through the gp130/leukemia inhibitory factor receptor β (LIFRβ) heterodimer, whereas CLF-1 serves to promote the cellular release of CLC. However, the precise role of CLF-1 is unclear. Here, we report that CLF-1, based on its binding site for CLC and on two additional and independent sites for CNTFRα and sorLA, is a key player in CLC and CNTFRα signaling and turnover. The site for CNTFRα enables CLF-1 to promote CLC:CNTFRα complex formation and signaling. The second site establishes a link between the endocytic receptor sorLA and the tripartite CLC:CLF-1:CNTFRα complex and allows sorLA to downregulate the CNTFRα pool in stimulated cells. Finally, sorLA may bind and concentrate the tripartite soluble CLC:CLF-1:CNTFRα complex on cell membranes and thus facilitate its signaling through gp130/LIFRβ.

  2. Cytokines: The Good, the Bad, and the Deadly.

    Science.gov (United States)

    Ramani, Thulasi; Auletta, Carol S; Weinstock, Daniel; Mounho-Zamora, Barbara; Ryan, Patricia C; Salcedo, Theodora W; Bannish, Gregory

    2015-01-01

    Over the past 30 years, the world of pharmaceutical toxicology has seen an explosion in the area of cytokines. An overview of the many aspects of cytokine safety evaluation currently in progress and evolving strategies for evaluating these important entities was presented at this symposium. Cytokines play a broad role to help the immune system respond to diseases, and drugs which modulate their effect have led to some amazing therapies. Cytokines may be "good" when stimulating the immune system to fight a foreign pathogen or attack tumors. Other "good" cytokine effects include reduction of an immune response, for example interferon β reduction of neuron inflammation in patients with multiple sclerosis. They may be "bad" when their expression causes inflammatory diseases, such as the role of tumor necrosis factor α in rheumatoid arthritis or asthma and Crohn's disease. Therapeutic modulation of cytokine expression can help the "good" cytokines to generate or quench the immune system and block the "bad" cytokines to prevent damaging inflammatory events. However, care must be exercised, as some antibody therapeutics can cause "ugly" cytokine release which can be deadly. Well-designed toxicology studies should incorporate careful assessment of cytokine modulation that will allow effective therapies to treat unmet needs. This symposium discussed lessons learned in cytokine toxicology using case studies and suggested future directions.

  3. 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.

  4. How does Chinese medicine target cytokine imbalance in rheumatoid arthritis?

    Science.gov (United States)

    Liu, Jian; Sun, Yue

    2013-11-01

    Rheumatoid arthritis (RA) manifests as an imbalance between pro- and anti-inflammatory cytokines. Cytokine imbalance is suggested to play critical roles in the development of RA. Currently, various treatments for RA, including biological agents such as antibodies against inflammation mediators, or Chinese herbal medicines, intervene the disease by restoring the balance of cytokines. Chinese medicine (CM) can not only suppress the expression of pro-inflammatory cytokines, but also induce the expression of cytokines with anti-inflammatory and immunomodulatory effects. Thus, Chinese medicine can effectively reduce inflammatory cell infiltration into synovial tissue, pannus formation, and degradation of the extracellular matrix surrounding cartilage cells, thereby reducing subchondral bone damage. This paper reviews the changes of cytokine profiling during development of RA and discuss the mechanisms by which Chinese medicine restores the cytokine balance.

  5. Cytokines: Names and Numbers You Should Care About.

    Science.gov (United States)

    Holdsworth, Stephen R; Gan, Poh-Yi

    2015-12-07

    Cytokines play an important role in host defense against microorganisms. They orchestrate innate immunity by inducing protective local inflammation and systemic acute phase responses. Cytokines are important in initiating, amplifying, directing, mediating, and regulating adaptive immunity. Unfortunately, they may also direct tissue damage if excessive responses occur or if they are involved in directing and mediating autoimmunity. Under these circumstances, cytokines are potential therapeutic targets. Over the last 20 years, we have seen the successful development and clinical implementation of biologic strategies that target key cytokines in specific inflammatory diseases with efficacy, specificity, and toxicity profiles challenging conventional drug therapies. These therapies are finding new applications and many new agents show promise. Unfortunately, these new cytokine-based therapies have had little effect on renal disease. This review provides evidence that common renal diseases, including those causing AKI and the autoimmune proliferative and crescentic forms of GN, have cytokine mediation profiles that suggest they would be susceptible to cytokine-targeting therapeutic strategies.

  6. Plasma cytokine expression is associated with cardiac morbidity in chagas disease.

    Directory of Open Access Journals (Sweden)

    Giovane Rodrigo Sousa

    Full Text Available The expression of immune response appears to be associated with morbidity in Chagas disease. However, the studies in this field have usually employed small samples of patients and statistical analyses that do not consider the wide dispersion of cytokine production observed in these patients. The aim of this study was to evaluate the plasma cytokine levels in well-defined clinical polar groups of chagasic patients divided into categories that better reflect the wide cytokine profile and its relationship with morbidity. Patients infected with Trypanosoma cruzi (T. cruzi were grouped as indeterminate (IND and cardiac (CARD forms ranging from 23 to 69 years of age (mean of 45.6±11.25. The IND group included 82 individuals, ranging from 24 to 66 years of age (mean of 39.6±10.3. The CARD group included 94 patients ranging from 23 to 69 years of age (mean of 48±12.52 presenting dilated cardiomyopathy. None of the patients have undergone chemotherapeutic treatment, nor had been previously treated for T. cruzi infection. Healthy non-chagasic individuals, ranging from 29 to 55 years of age (mean of 42.6±8.8 were included as a control group (NI. IND patients have a higher intensity of interleukin 10 (IL-10 expression when compared with individuals in the other groups. By contrast, inflammatory cytokine expression, such as interferon gamma (IFN-γ, tumor necrosis factor alpha (TNF-α, interleukin 6 (IL-6, and interleukin 1 beta (IL-1β, proved to be the highest in the CARD group. Correlation analysis showed that higher IL-10 expression was associated with better cardiac function, as determined by left ventricular ejection fraction and left ventricular diastolic diameter values. Altogether, these findings reinforce the concept that a fine balance between regulatory and inflammatory cytokines represents a key element in the establishment of distinct forms of chronic Chagas disease.

  7. Cytokine profiles and hepatic injury in occult hepatitis C versus chronic hepatitis C virus infection.

    Science.gov (United States)

    Mousa, N; Eldars, W; Eldegla, H; Fouda, O; Gad, Y; Abousamra, N; Elmasry, E; Arafa, M

    2014-01-01

    Occult hepatitis C virus (HCV) infection is a new entity that should be considered when diagnosing patients with abnormal liver functions of unknown origin. This work was carried out to evaluate T-helper 1/T-helper 2 (Th1/Th2) cytokine profiles in patients with occult HCV infection versus chronic hepatitis C (CHC) infection, also to investigate any association between theses cytokines and liver histological features in both groups. Serum levels of Th1 cytokines (IL-2, IFN-gamma) and Th2 (IL-4 and IL-10) were measured in 35 patients with occult HCV infection compared to 50 patients with chronic hepatitis C infection and 30 healthy controls. We have found that Th1 cytokines were significantly increased in patients with CHC infection than in both occult HCV infection and control groups (p less than 0.001). On the other hand, serum IL-4 levels were higher in occult HCV infection than in CHC and control groups (p less than 0.001). Furthermore, serum IL-10 levels were higher in both patient groups vs control group (pless than 0.001), with no significant difference between CHC and occult HCV groups. Finally, only serum IL-10 levels were significantly higher among patients with high activity (A2-A3) than those with low activity (A0-A1) in both CHC and occult HCV groups (p=0.038, p=0.025, respectively). Patients with occult HCV infection exhibited a distinct immunoregulatory cytokine pattern that is shifted towards the Th2 arm.

  8. Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis.

    Science.gov (United States)

    Khaiboullina, Svetlana F; DeMeirleir, Kenny L; Rawat, Shanti; Berk, Grady S; Gaynor-Berk, Rory S; Mijatovic, Tatjana; Blatt, Natalia; Rizvanov, Albert A; Young, Sheila G; Lombardi, Vincent C

    2015-03-01

    Gulf War illness (GWI) is a chronic disease of unknown etiology characterized by persistent symptoms such as cognitive impairment, unexplained fatigue, pervasive pain, headaches, and gastrointestinal abnormalities. Current reports suggest that as many as 200,000 veterans who served in the 1990-1991 Persian Gulf War were afflicted. Several potential triggers of GWI have been proposed including chemical exposure, toxins, vaccines, and unknown infectious agents. However, a definitive cause of GWI has not been identified and a specific biological marker that can consistently delineate the disease has not been defined. Myalgic encephalomyelitis (ME) is a disease with similar and overlapping symptomology, and subjects diagnosed with GWI typically fit the diagnostic criteria for ME. For these reasons, GWI is often considered a subgroup of ME. To explore this possibility and identify immune parameters that may help to understand GWI pathophysiology, we measured 77 serum cytokines in subjects with GWI and compared these data to that of subjects with ME as well as healthy controls. Our analysis identified a group of cytokines that identified ME and GWI cases with sensitivities of 92.5% and 64.9%, respectively. The five most significant cytokines in decreasing order of importance were IL-7, IL-4, TNF-α, IL-13, and IL-17F. When delineating GWI and ME cases from healthy controls, the observed specificity was only 33.3%, suggesting that with respect to cytokine expression, GWI cases resemble control subjects to a greater extent than ME cases across a number of parameters. These results imply that serum cytokines are representative of ME pathology to a greater extent than GWI and further suggest that the two diseases have distinct immune profiles despite their overlapping symptomology.

  9. Soluble heparan sulfate fragments generated by heparanase trigger the release of pro-inflammatory cytokines through TLR-4.

    Directory of Open Access Journals (Sweden)

    Katharine J Goodall

    Full Text Available Heparanase is a β-D-endoglucuronidase that cleaves heparan sulfate (HS, facilitating degradation of the extracellular matrix (ECM and the release of HS-bound biomolecules including cytokines. The remodeling of the ECM by heparanase is important for various physiological and pathological processes, including inflammation, wound healing, tumour angiogenesis and metastasis. Although heparanase has been proposed to facilitate leukocyte migration through degradation of the ECM, its role in inflammation by regulating the expression and release of cytokines has not been fully defined. In this study, the role of heparanase in regulating the expression and release of cytokines from human and murine immune cells was examined. Human peripheral blood mononuclear cells treated ex vivo with heparanase resulted in the release of a range of pro-inflammatory cytokines including IL-1β, IL-6, IL-8, IL-10 and TNF. In addition, mouse splenocytes treated ex vivo with heparanase resulted in the release of IL-6, MCP-1 and TNF. A similar pattern of cytokine release was also observed when cells were treated with soluble HS. Furthermore, heparanase-induced cytokine release was abolished by enzymatic-inhibitors of heparanase, suggesting this process is mediated via the enzymatic release of cell surface HS fragments. As soluble HS can signal through the Toll-like receptor (TLR pathway, heparanase may promote the upregulation of cytokines through the generation of heparanase-cleaved fragments of HS. In support of this hypothesis, mouse spleen cells lacking the key TLR adaptor molecule MyD88 demonstrated an abolition of cytokine release after heparanase stimulation. Furthermore, TLR4-deficient spleen cells showed reduced cytokine release in response to heparanase treatment, suggesting that TLR4 is involved in this response. Consistent with these observations, the pathway involved in cytokine upregulation was identified as being NF-κB-dependent. These data identify a new

  10. Unusual Water-mediated Antigenic Recognition of the Proinflammatory Cytokine Interleukin-18

    Energy Technology Data Exchange (ETDEWEB)

    Argiriadi, Maria A.; Xiang, Tao; Wu, Chengbin; Ghayur, Tariq; Borhani, David W.; (Abbott)

    2009-10-21

    The unique cytokine interleukin-18 (IL-18) acts synergistically with IL-12 to regulate T-helper 1 and 2 lymphocytes and, as such, seems to underlie the pathogenesis of various autoimmune and allergic diseases. Several anti-IL-18 agents are in clinical development, including the recombinant human antibody ABT-325, which is entering trials for autoimmune diseases. Given competing cytokine/receptor and cytokine/receptor decoy interactions, understanding the structural basis for recognition is critical for effective development of anti-cytokine therapies. Here we report three crystal structures: the murine antibody 125-2H Fab fragment bound to human IL-18, at 1.5 {angstrom} resolution; the 125-2H Fab (2.3 {angstrom}); and the ABT-325 Fab (1.5 {angstrom}). These structures, along with human/mouse IL-18 chimera binding data, allow us to make three key observations relevant to the biology and antigenic recognition of IL-18 and related cytokines. First, several IL-18 residues shift dramatically (>10 {angstrom}) upon binding 125-2H, compared with unbound IL-18 (Kato, Z., Jee, J., Shikano, H., Mishima, M., Ohki, I., Ohnishi, H., Li, A., Hashimoto, K., Matsukuma, E., Omoya, K., Yamamoto, Y., Yoneda, T., Hara, T., Kondo, N., and Shirakawa, M. (2003) Nat. Struct. Biol. 10, 966-971). IL-18 thus exhibits plasticity that may be common to its interactions with other receptors. Related cytokines may exhibit similar plasticity. Second, ABT-325 and 125-2H differ significantly in combining site character and architecture, thus explaining their ability to bind IL-18 simultaneously at distinct epitopes. These data allow us to define the likely ABT-325 epitope and thereby explain the distinct neutralizing mechanisms of both antibodies. Third, given the high 125-2H potency, 10 well ordered water molecules are trapped upon complex formation in a cavity between two IL-18 loops and all six 125-2H complementarity-determining regions. Thus, counterintuitively, tight and specific antibody

  11. Cytokines, cytokine gene polymorphisms and Helicobacter pylori infection: friend or foe?

    Science.gov (United States)

    Figueiredo, Camila A; Marques, Cintia Rodrigues; Costa, Ryan dos Santos; da Silva, Hugo Bernardino F; Alcantara-Neves, Neuza M

    2014-05-14

    Helicobacter pylori (H. pylori) is a flagellated, spiral-shaped, microaerophilic Gram-negative bacillus that colonises the gastric mucosa of more than 50% of the human population. Infection is a risk factor for gastritis, ulcer disease and stomach cancer. Immunity against H. pylori is mainly related to Th1/Th17 skewing, and the activation of regulatory T cells is the main strategy used to limit inflammatory responses, which can result in the pathogen persistence and can lead to chronic gastrointestinal diseases, including cancer. Furthermore, host genetic factors that affect cytokines may determine differences in the susceptibility to many diseases. In this review, we present the cytokine profiles and the main cytokine gene polymorphisms associated with resistance/susceptibility to H. pylori and discuss how such polymorphisms may influence infection/disease outcomes.

  12. Herpesvirus saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor.

    Science.gov (United States)

    Yao, Zhengbin; Fanslow, William C; Seldin, Michael F; Rousseau, Anne-Marie; Painter, Sally L; Comeau, Michael R; Cohen, Jeffrey I; Spriggs, Melanie K

    2011-11-01

    Herpesvirus Saimiri gene 13 (HVS13) exhibits 57% identity with the predicted sequence of a T cell-derived molecule termed CTLA8. Recombinant HVS13 and CTLA8 stimulate transcriptional factor NF-kappaB activity and Interleukin-6 (IL-6) secretion in fibroblasts, and costimulate T cell proliferation. An HVS13.Fc fusion protein was used to isolate a cDNA encoding a novel receptor that also binds CTLA8. This receptor is unrelated to previously identified cytokine receptor families. A recombinant soluble receptor inhibited T cell proliferation and IL-2 production induced by PHA, concanavalin A (conA), and anti-TCR MAb. These results define CTLA8 and HVS13 as novel cytokines that bind to a novel cytokine receptor. We propose to call these molecules IL-17, vIL-17, and IL-17R, respectively.

  13. Lack of RNase L attenuates macrophage functions.

    Directory of Open Access Journals (Sweden)

    Xin Yi

    Full Text Available Macrophages are one of the major cell types in innate immunity against microbial infection. It is believed that the expression of proinflammatory genes such as tumor necrosis factor-α (TNF-α, interleukin (IL-1β, IL-6, and cyclooxygenase-2 (Cox-2 by macrophages is also crucial for activation of both innate and adaptive immunities. RNase L is an interferon (IFN inducible enzyme which is highly expressed in macrophages. It has been demonstrated that RNase L regulates the expression of certain inflammatory genes. However, its role in macrophage function is largely unknown.Bone marrow-derived macrophages (BMMs were generated from RNase L(+/+and (-/- mice. The migration of BMMs was analyzed by using Transwell migration assays. Endocytosis and phagocytosis of macrophages were assessed by using fluorescein isothiocyanate (FITC-Dextran 40,000 and FITC-E. coli bacteria, respectively. The expression of inflammatory genes was determined by Western Blot and ELISA. The promoter activity of Cox-2 was measured by luciferase reporter assays.Lack of RNase L significantly decreased the migration of BMMs induced by M-CSF, but at a less extent by GM-CSF and chemokine C-C motif ligand-2 (CCL2. Interestingly, RNase L deficient BMMs showed a significant reduction of endocytic activity to FITC-Dextran 40,000, but no any obvious effect on their phagocytic activity to FITC-bacteria under the same condition. RNase L impacts the expression of certain genes related to cell migration and inflammation such as transforming growth factor (TGF-β, IL-1β, IL-10, CCL2 and Cox-2. Furthermore, the functional analysis of the Cox-2 promoter revealed that RNase L regulated the expression of Cox-2 in macrophages at its transcriptional level. Taken together, our findings provide direct evidence showing that RNase L contributes to innate immunity through regulating macrophage functions.

  14. New constitutive latex osmotin-like proteins lacking antifungal activity.

    Science.gov (United States)

    Freitas, Cleverson D T; Silva, Maria Z R; Bruno-Moreno, Frederico; Monteiro-Moreira, Ana C O; Moreira, Renato A; Ramos, Márcio V

    2015-11-01

    Proteins that share similar primary sequences to the protein originally described in salt-stressed tobacco cells have been named osmotins. So far, only two osmotin-like proteins were purified and characterized of latex fluids. Osmotin from Carica papaya latex is an inducible protein lacking antifungal activity, whereas the Calotropis procera latex osmotin is a constitutive antifungal protein. To get additional insights into this subject, we investigated osmotins in latex fluids of five species. Two potential osmotin-like proteins in Cryptostegia grandiflora and Plumeria rubra latex were detected by immunological cross-reactivity with polyclonal antibodies produced against the C. procera latex osmotin (CpOsm) by ELISA, Dot Blot and Western Blot assays. Osmotin-like proteins were not detected in the latex of Thevetia peruviana, Himatanthus drasticus and healthy Carica papaya fruits. Later, the two new osmotin-like proteins were purified through immunoaffinity chromatography with anti-CpOsm immobilized antibodies. Worth noting the chromatographic efficiency allowed for the purification of the osmotin-like protein belonging to H. drasticus latex, which was not detectable by immunoassays. The identification of the purified proteins was confirmed after MS/MS analyses of their tryptic digests. It is concluded that the constitutive osmotin-like proteins reported here share structural similarities to CpOsm. However, unlike CpOsm, they did not exhibit antifungal activity against Fusarium solani and Colletotrichum gloeosporioides. These results suggest that osmotins of different latex sources may be involved in distinct physiological or defensive events.

  15. The Distinction Between English Synonyms

    Institute of Scientific and Technical Information of China (English)

    段佳

    2012-01-01

      A large number of new words and terms flock in the English vocabulary and English has a variety of expressive methods making it possible to express the same meaning by different words. Therefore English synonyms are so abundant that it is possible to describe the colorful world and to express the complicated, delicate human thought and emotions. But they bring people many problems such as the correct choice of words from synonyms. The reason for this problem is the insufficient knowledge of the distinction of English synonyms, which have differences in many aspects. This paper offers three main aspects in distinguishing English synonyms that include words’ meaning, coloring and usage.

  16. Solution assembly of cytokine receptor ectodomain complexes

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Zining; Ciardelli, T.L. [Dartmouth Medical School, Hanover, NH (United States). Dept. of Pharmacology and Toxicology; Johnson, K.W. [Chiron Corp., Emeryville, CA (United States)] [and others

    1995-09-01

    For the majority of single transmembrane-spanning cell surface receptors, signal transmission across the lipid bilayer barrier involves several discrete components of molecular recognition. The interaction between ligand and the extracellular segment of its cognate receptor (ectodomain) initiates either homomeric or heteromeric association of receptor subunits. Specific recognition among these subunits may then occur between ectodomain regions, within the membrane by interhelical contact or inside the cell between cytoplasmic domains. Any or all of these interactions may contribute to the stability of the signaling complex. It is the characteristics of ligand binding by the ectodomains of these receptors that controls the heteromeric or homomeric nature and the stoichiometry of the complex. Cytokines and their receptors belong to a growing family of macromolecular systems that exhibit these functional features and share many structural similarities as well. Interleukin-2 is a multifunctional cytokine that represents, perhaps, the most complex example to date of ligand recognition among the hematopoietin receptor family. It is the cooperative binding of IL-2 by all three proteins on the surface of activated T-lymphocytes, however, that ultimately results in crosslinking of the {beta}- and {gamma}-subunits and signaling via association of their cytoplasmic domains. Although the high-affinity IL-2R functions as a heterotrimer, heterodimers of the receptor subunits are also physiologically important. The {alpha}/{beta} heterodimer or {open_quotes}pseudo-high affinity{close_quotes} receptor captures IL-2 as a preformed cell surface complex while the {beta}/{gamma} intermediate affinity site exists, in the absence of the {alpha} subunit, on the majority of natural killer cells. We have begun to study stable complexes of cytokine receptor ectodomains of defined composition and that mimic the ligand binding characteristics of the equivalent cell surface receptor sites.

  17. Evidence of associations between cytokine genes and subjective reports of sleep disturbance in oncology patients and their family caregivers.

    Directory of Open Access Journals (Sweden)

    Christine Miaskowski

    Full Text Available The purposes of this study were to identify distinct latent classes of individuals based on subjective reports of sleep disturbance; to examine differences in demographic, clinical, and symptom characteristics between the latent classes; and to evaluate for variations in pro- and anti-inflammatory cytokine genes between the latent classes. Among 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their FCs, growth mixture modeling (GMM was used to identify latent classes of individuals based on General Sleep Disturbance Scale (GSDS obtained prior to, during, and for four months following completion of radiation therapy. Single nucleotide polymorphisms (SNPs and haplotypes in candidate cytokine genes were interrogated for differences between the two latent classes. Multiple logistic regression was used to assess the effect of phenotypic and genotypic characteristics on GSDS group membership. Two latent classes were identified: lower sleep disturbance (88.5% and higher sleep disturbance (11.5%. Participants who were younger and had a lower Karnofsky Performance status score were more likely to be in the higher sleep disturbance class. Variation in two cytokine genes (i.e., IL6, NFKB predicted latent class membership. Evidence was found for latent classes with distinct sleep disturbance trajectories. Unique genetic markers in cytokine genes may partially explain the interindividual heterogeneity characterizing these trajectories.

  18. Cytokines in the modulation of eosinophilia

    Directory of Open Access Journals (Sweden)

    Faccioli Lúcia H

    1997-01-01

    Full Text Available In this review we discuss our recently results showing interleukin 5 (IL-5 involvement in eosinophil migration and in the maintenance of eosinophilia in blood, bone marrow, lung and peritoneal cavity, in a visceral larva migrans syndrome model using guinea-pigs infected with Toxocara canis. We also describe the sequential release of TNF-alpha and IL-8 during the course of infection, and the interaction between these cytokines and IL-5 during infection. Finally we propose a new biological role for IL-5, at least in our model, as a modulator of IL-8 release and secretion.

  19. Chronic pain: cytokines, lymphocytes and chemokines.

    Science.gov (United States)

    de Miguel, Marcia; Kraychete, Durval Campos; Meyer Nascimento, Roberto Jose

    2014-01-01

    Chronic pain is a debilitating condition and, in most cases, difficult to treat. A prominent example of this is neuropathic pain. Understanding pathophysiological mechanisms of pain and, therefore, making this knowledge into an effective treatment is still a challenge to experts. Pain can now be considered as a neuro-immune disorder, since recent data indicate critical involvement of innate and adaptive immune responses following injury, and this interaction plays an important role in the onset and perpetuation of chronic pain. The aim of this article is to review the relationship between immune system and chronic pain, especially about neuropathic pain, and focusing on cytokines, chemokines and lymphocytes.

  20. AUTOPHAGY AND IL-1 FAMILY CYTOKINES

    Directory of Open Access Journals (Sweden)

    James Harris

    2013-01-01

    Full Text Available Autophagy is an important intracellular homeostatic mechanism for the targeting of cytosolic constituents, including organelles, for lysosomal degradation. Autophagy plays roles in numerous physiological processes, include immune cell responses to endogenous and exogenous pathogenic stimuli. Moreover, autophagy has a potentially pivotal role in the regulation of inflammatory responses. In particular, autophagy regulates endogenous inflammasome activators, as well as inflammasome components and pro-IL-1β. This review focuses specifically on the role autophagy plays in regulating the production, processing and secretion of IL-1 family cytokines.

  1. Standardization of cytokine flow cytometry assays

    Directory of Open Access Journals (Sweden)

    Cox Josephine

    2005-06-01

    Full Text Available Abstract Background Cytokine flow cytometry (CFC or intracellular cytokine staining (ICS can quantitate antigen-specific T cell responses in settings such as experimental vaccination. Standardization of ICS among laboratories performing vaccine studies would provide a common platform by which to compare the immunogenicity of different vaccine candidates across multiple international organizations conducting clinical trials. As such, a study was carried out among several laboratories involved in HIV clinical trials, to define the inter-lab precision of ICS using various sample types, and using a common protocol for each experiment (see additional files online. Results Three sample types (activated, fixed, and frozen whole blood; fresh whole blood; and cryopreserved PBMC were shipped to various sites, where ICS assays using cytomegalovirus (CMV pp65 peptide mix or control antigens were performed in parallel in 96-well plates. For one experiment, antigens and antibody cocktails were lyophilised into 96-well plates to simplify and standardize the assay setup. Results (CD4+cytokine+ cells and CD8+cytokine+ cells were determined by each site. Raw data were also sent to a central site for batch analysis with a dynamic gating template. Mean inter-laboratory coefficient of variation (C.V. ranged from 17–44% depending upon the sample type and analysis method. Cryopreserved peripheral blood mononuclear cells (PBMC yielded lower inter-lab C.V.'s than whole blood. Centralized analysis (using a dynamic gating template reduced the inter-lab C.V. by 5–20%, depending upon the experiment. The inter-lab C.V. was lowest (18–24% for samples with a mean of >0.5% IFNγ + T cells, and highest (57–82% for samples with a mean of Conclusion ICS assays can be performed by multiple laboratories using a common protocol with good inter-laboratory precision, which improves as the frequency of responding cells increases. Cryopreserved PBMC may yield slightly more

  2. Cytokines and Pancreatic β-Cell Apoptosis.

    Science.gov (United States)

    Berchtold, L A; Prause, M; Størling, J; Mandrup-Poulsen, T

    The discovery 30 years ago that inflammatory cytokines cause a concentration, activity, and time-dependent bimodal response in pancreatic β-cell function and viability has been a game-changer in the fields of research directed at understanding inflammatory regulation of β-cell function and survival and the causes of β-cell failure and destruction in diabetes. Having until then been confined to the use of pathophysiologically irrelevant β-cell toxic chemicals as a model of β-cell death, researchers could now mimic endocrine and paracrine effects of the cytokine response in vitro by titrating concentrations in the low to the high picomolar-femtomolar range and vary exposure time for up to 14-16h to reproduce the acute regulatory effects of systemic inflammation on β-cell secretory responses, with a shift to inhibition at high picomolar concentrations or more than 16h of exposure to illustrate adverse effects of local, chronic islet inflammation. Since then, numerous studies have clarified how these bimodal responses depend on discrete signaling pathways. Most interest has been devoted to the proapoptotic response dependent upon mainly nuclear factor κ B and mitogen-activated protein kinase activation, leading to gene expressional changes, endoplasmic reticulum stress, and triggering of mitochondrial dysfunction. Preclinical studies have shown preventive effects of cytokine antagonism in animal models of diabetes, and clinical trials demonstrating proof of concept are emerging. The full clinical potential of anticytokine therapies has yet to be shown by testing the incremental effects of appropriate dosing, timing, and combinations of treatments. Due to the considerable translational importance of enhancing the precision, specificity, and safety of antiinflammatory treatments of diabetes, we review here the cellular, preclinical, and clinical evidence of which of the death pathways recently proposed in the Nomenclature Committee on Cell Death 2012

  3. Lack of efficacy of ergocalciferol repletion

    Directory of Open Access Journals (Sweden)

    Thomas Wasser

    2012-04-01

    Full Text Available Introduction: Vitamin D has become an area of intensive scrutiny, both in medical and lay literature. However, there are limited data to suggest proper repletion regimens for those patients who have hypovitaminosis D. Consequently, various methods are used in clinical practice. The aim of this study was to assess the efficacy of various treatment strategies for hypovitaminosis D in an ambulatory internal medicine practice. Methods: A retrospective chart review between October 2005 and June 2010 of a suburban internal medicine practice was performed via query of the electronic medical record (Centricity, General Electric Healthcare, UK. Patients with a 25-hydroxyvitamin D concentration less than 32 mg/dl were identified and treated. Treatment success was defined as 25-hydroxyvitamin D concentrations greater than 32 mg/dl. Statistical analysis to assess changes in vitamin D level controlling for season, comorbidities, and demographics were used. Results: A total of 607 treatment episodes were identified, with 395 excluded due to lack of follow-up vitamin D level within 16 weeks, no treatment documented, topical treatment, doxercalciferol treatment, or non-compliance. Of the remaining patients, there were 212 treatment instances on 178 patients. Ergocalciferol 50,000 international units (IU was used most frequently (71.4% of the time.. A higher initial vitamin D level was positively associated with treatment success (adjusted odds ratio = 1.11, p=0.002. Increased doses of ergocalciferol increased the likelihood of treatment success (p=0.0011. Seasonal variation was related to posttreatment 25-hydroxyvitamin D concentration as was body mass index (BMI (p=0.003 and p=0.044. Conclusion: Pretreatment levels of 25-hydroxyvitamin D, BMI, season, and vitamin D dose are predictors of successful hypovitaminosis D treatment. Our data suggest that patients with initial 25-hydroxyvitamin D concentrations of <20 should be treated with a higher total dose of

  4. Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH17 cytokine interleukin-22

    Science.gov (United States)

    Hughes, Tiffany; Becknell, Brian; McClory, Susan; Briercheck, Edward; Freud, Aharon G.; Zhang, Xiaoli; Mao, Hsiaoyin; Nuovo, Gerard; Yu, Jianhua

    2009-01-01

    Considerable functional heterogeneity within human natural killer (NK) cells has been revealed through the characterization of distinct NK-cell subsets. Accordingly, a small subset of CD56+NKp44+NK cells, termed NK-22 cells, was recently described within secondary lymphoid tissue (SLT) as IL-22− when resting, with a minor fraction of this population becoming IL-22+ when activated. Here we discover that the vast majority of stage 3 immature NK (iNK) cells in SLT constitutively and selectively express IL-22, a TH17 cytokine important for mucosal immunity, whereas earlier and later stages of NK developmental intermediates do not express IL-22. These iNK cells have a surface phenotype of CD34−CD117+CD161+CD94−, largely lack expression of NKp44 and CD56, and do not produce IFN-γ or possess cytolytic activity. In summary, stage 3 iNK cells are highly enriched for IL-22 and IL-26 messenger RNA, and IL-22 protein production, but do not express IL-17A or IL-17F. PMID:19244159

  5. Altered energy balance and cytokine gene expression in a murine model of chronic infection with Toxoplasma gondii.

    Science.gov (United States)

    Arsenijevic, D; Girardier, L; Seydoux, J; Chang, H R; Dulloo, A G

    1997-05-01

    The temporal pattern of changes in energy balance and cytokine mRNA expression in spleen and brain were examined in a mouse model of infection with Toxoplasma gondii. During days 1-7 postinfection, food intake was unaltered, but energy expenditure was significantly increased, and this was associated with elevated tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-5, and interferon (IFN)-gamma. The hypermetabolic state persisted during subsequent anorexia, whose onset coincided with elevated IL-2, and at the end of the acute phase of cachexia, the dual anorexic and hypermetabolic states were associated with the cytokines examined: TNF-alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, and IFN-gamma. In the chronic phase of the infection, the mice showed either partial weight recovery (gainers) or no weight regain (nongainers). The infected gainers, though still hypophagic, were no longer hypermetabolic, and their cytokine mRNA was no longer elevated, except for TNF-alpha and IL-10. In contrast, the infected nongainers continued to show both anoroxia and hypermetabolism, which were associated with elevations in all cytokines examined and particularly those of the TH2 profile (IL-4 and IL-5) and IL-6. Taken together, these studies reveal a distinct pattern of cytokine mRNA expression underlying 1) hypermetabolism vs. anorexia, 2) acute vs. chronic cachexia, and 3) stable weight loss vs. partial weight recovery.

  6. HIV-1 imposes rigidity on blood and semen cytokine networks.

    Science.gov (United States)

    Lisco, Andrea; Introini, Andrea; Munawwar, Arshi; Vanpouille, Christophe; Grivel, Jean-Charles; Blank, Paul; Singh, Sarman; Margolis, Leonid

    2012-12-01

    Although it is established that the levels of individual cytokines are altered by HIV-1 infection, the changes in cytokine interrelations that organize them into networks have been poorly studied. Here, we evaluated these networks in HIV-infected and HIV-uninfected individuals in fluid compartments that are critical for HIV-1 pathogenesis and transmission, namely blood and semen. In samples collected from therapy-naïve HIV-1-infected and HIV-1-uninfected individuals, we measured HIV-1-load, CD4 cell count, and levels of 21 cytokines using a multiplex bead assay. Cytokine networks in blood and semen were different for HIV-1-infected and HIV-1-uninfected individuals. In both compartments of HIV-1-infected individuals, the cytokine networks were more interlocked than in controls: HIV-1 infection resulted in the establishment of new correlations and in the strengthening of pre-existing correlations between different cytokines. In blood and semen of HIV-infected patients, there were, respectively, 68 and 72 statistically significant correlations between cytokines, while in uninfected individuals, there were 18 and 21 such correlations. HIV-1 infection reorganizes the cytokine networks, establishing new strong correlations between various cytokines and thus imposes a high rigidity on the cytokine network. This rigidity may reflect the impairment of the ability of the immune system to respond to microbial challenges. © 2012 John Wiley & Sons A/S.

  7. Macrophage cytokines: Involvement in immunity and infectious diseases

    Directory of Open Access Journals (Sweden)

    Guillermo eArango Duque

    2014-10-01

    Full Text Available The evolution of macrophages has made them primordial for both development and immunity. Their functions range from the shaping of body plans to the ingestion and elimination of apoptotic cells and pathogens. Cytokines are small soluble proteins that confer instructions and mediate communication among immune and non-immune cells. A portfolio of cytokines is central to the role of macrophages as sentries of the innate immune system that mediate the transition from innate to adaptive immunity. In concert with other mediators, cytokines bias the fate of macrophages into a spectrum of inflammation-promoting ‘classically activated’, to anti-inflammatory or ‘alternatively activated’ macrophages. Deregulated cytokine secretion is implicated in several disease states ranging from chronic inflammation to allergy. Macrophages release cytokines via a series of beautifully orchestrated pathways that are spatiotemporally regulated. At the molecular level, these exocytic cytokine secretion pathways are coordinated by multi-protein complexes that guide cytokines from their point of synthesis to their ports of exit into the extracellular milieu. These trafficking proteins, many of which were discovered in yeast and commemorated in the 2013 Nobel Prize in Physiology or Medicine, coordinate the organelle fusion steps that are responsible for cytokine release. This review discusses the functions of cytokines secreted by macrophages, and summarizes what is known about their release mechanisms. This information will be used to delve into how selected pathogens subvert cytokine release for their own survival.

  8. Is fibromyalgia a distinct clinical syndrome?

    Science.gov (United States)

    Rau, C L; Russell, I J

    2000-01-01

    The validity of the fibromyalgia syndrome (FMS) as a distinct clinical entity has been challenged for several reasons. Many skeptics express concern about the subjective nature of chronic pain, the subjectivity of the tender point (TeP) examination, the lack of a gold standard laboratory test, and the absence of a clear pathogenic mechanism by which to define FMS. Another expressed concern has been the relative nature of the pain-distress relationship in the rheumatology clinic. The apparently continuous relationship between TePs and somatic distress across a variety of clinical disorders is said to argue against FMS as a separate clinical disorder. The most aggressive challenges of the FMS concept have been from legal defenses of insurance carriers motivated by economic concerns. Other forms of critique have presented as psychiatric dogma, uninformed posturing, suspicion of malingering, ignorance of nociceptive physiology, and occasionally have resulted from honest misunderstanding. It is not likely that a few paragraphs of data and logic will cause an unbeliever to change an ingrained opinion. Therefore, this review describes the clinical manifestations of FMS, responds to some of the theoretic arguments against it, and discusses some possible pathophysiologic mechanisms by which FMS may develop and persist as a unique syndrome.

  9. Phylogenetic autocorrelation under distinct evolutionary processes.

    Science.gov (United States)

    Diniz-Filho, J A

    2001-06-01

    I show how phylogenetic correlograms track distinct microevolutionary processes and can be used as empirical descriptors of the relationship between interspecific covariance (V(B)) and time since divergence (t). Data were simulated under models of gradual and speciational change, using increasing levels of stabilizing selection in a stochastic Ornstein-Uhlenbeck (O-U) process, on a phylogeny of 42 species. For each simulated dataset, correlograms were constructed using Moran's I coefficients estimated at five time slices, established at constant intervals. The correlograms generated under different evolutionary models differ significantly according to F-values derived from analysis of variance comparing Moran's I at each time slice and based on Wilks' lambda from multivariate analysis of variance comparing their overall profiles in a two-way design. Under Brownian motion or with small restraining forces in the O-U process, correlograms were better fit by a linear model. However, increasing restraining forces in the O-U process cause a lack of linear fit, and correlograms are better described by exponential models. These patterns are better fit for gradual than for speciational modes of change. Correlograms can be used as a diagnostic method and to describe the V(B)/t relationship before using methods to analyze correlated evolution that assume (or perform statistically better when) this relationship is linear.

  10. Cognitive impairment effects of early life stress in adolescents can be predicted with early biomarkers: Impacts of sex, experience, and cytokines.

    Science.gov (United States)

    Grassi-Oliveira, Rodrigo; Honeycutt, Jennifer A; Holland, Freedom H; Ganguly, Prabarna; Brenhouse, Heather C

    2016-09-01

    Childhood adversity increases vulnerability to psychiatric disorders that emerge in adolescence, in a sex-dependent manner. Early adversity modeled in rodents with maternal separation (MS) affects cognition and medial prefrontal cortex (mPFC) circuitry. Humans and animals exposed to early life adversity also display heightened circulating inflammatory cytokines, however the predictive relationship of these early measures with later behavioral deficits is unknown. Here, male and female rats were exposed to MS or control rearing during the postnatal period (P2-21). Blood samples were taken at distinct developmental time points for analysis of the pro-inflammatory cytokine IL-1β and the anti-inflammatory cytokines IL-4, and IL-10, followed by win-shift cognitive testing and analysis of mPFC parvalbumin (PVB) immunofluorescent interneurons in adolescence. Regression analyses were conducted to explore the relationship between early cytokines and adolescent behavioral measures. We observed sex- and age-dependent effects of MS on circulating cytokines. MS also yielded adolescent decreases in mPFC PVB and cognitive deficits, which were predicted by early cytokine expression in a sex- and experience-dependent manner. Taken together, the present data reveals that circulating cytokines and PVB levels are predictive of adolescent cognitive deficits, and therefore provide compelling evidence for a putative role of early biomarkers in mediating MS-induced behavioral dysfunction. Importantly, predictive relationships often depended on sex and on MS history, suggesting that early life experiences may yield individualistic mechanisms of vulnerability compared to the general population.

  11. Relationship of cytokines and cytokine signaling to immunodeficiency disorders in the mouse

    Directory of Open Access Journals (Sweden)

    Morawetz R.A.

    1998-01-01

    Full Text Available The contributions of cytokines to the development and progression of disease in a mouse model of retrovirus-induced immunodeficiency (MAIDS are controversial. Some studies have indicated an etiologic role for type 2 cytokines, while others have emphasized the importance of type 1 cytokines. We have used mice deficient in expression of IL-4, IL-10, IL-4 and IL-10, IFN-g, or ICSBP - a transcriptional protein involved in IFN signaling - to examine their contributions to this disorder. Our results demonstrate that expression of type 2 cytokines is an epiphenomenon of infection and that IFN-g is a driving force in disease progression. In addition, exogenously administered IL-12 prevents many manifestations of disease while blocking retrovirus expression. Interruption of the IFN signaling pathways in ICSBP-/- mice blocks induction of MAIDS. Predictably, ICSBP-deficient mice exhibit impaired responses to challenge with several other viruses. This immunodeficiency is associated with impaired production of IFN-g and IL-12. Unexpectedly, however, the ICSBP-/- mice also develop a syndrome with many similarities to chronic myelogenous leukemia in humans. The chronic phase of this disease is followed by a fatal blast crisis characterized by clonal expansions of undifferentiated cells. ICSBP is thus an important determinant of hematopoietic growth and differentiation as well as a prominent signaling molecule for IFNs

  12. Boswellia carterii extract inhibits TH1 cytokines and promotes TH2 cytokines in vitro.

    Science.gov (United States)

    Chevrier, Marc R; Ryan, Abigail E; Lee, David Y-W; Zhongze, Ma; Wu-Yan, Zhang; Via, Charles S

    2005-05-01

    Traditional herbal formulas used to treat inflammatory arthritis in China and India include Boswellia carterii or Boswellia serrata. They both contain boswellic acids (BAs) which have been shown to exhibit anti-inflammatory and antiarthritic properties. This study tests the hypothesis that mixtures of BAs derived from B. carterii have immunomodulatory properties. B. carterii plant resin obtained from China was prepared as an ethanol extract, and the presence of seven BAs was confirmed by column chromatography, high-performance liquid chromatography, and UV laser desorption/ionization tandem mass spectroscopy. The extract was then tested for its ability to alter in vitro production of TH1 cytokines (interleukin-2 [IL-2] and gamma interferon) and TH2 cytokines (IL-4 and IL-10) by murine splenocytes. Delivery of the resin extract using ethanol as a solvent resulted in significant cellular toxicity not seen with the addition of ethanol alone. By contrast, delivery of the resin extract using a sesame oil solvent resulted in a dose-dependent inhibition of TH1 cytokines coupled with a dose-dependent potentiation of TH2 cytokines. These results indicate that a purified mixture of BAs from B. carterii plant resin exhibits carrier-dependent immunomodulatory properties in vitro.

  13. Persistent foot-and-mouth disease virus infection in the nasopharynx of cattle: tissue-specific distribution and local cytokine expression

    Science.gov (United States)

    Tissues obtained post-mortem from cattle persistently infected with foot-and-mouth disease virus (FMDV) were analyzed to characterize the tissue-specific localization of FMDV and partial transcriptome profiles for selected immunoregulatory cytokines. Analysis of 28 distinct anatomic sites from 21 st...

  14. Salivary Immunosuppressive Cytokines IL-10 and IL-13 Are Significantly Elevated in Oral Squamous Cell Carcinoma Patients.

    Science.gov (United States)

    Aziz, Salman; Ahmed, Syed Shoaib; Ali, Asad; Khan, Faiza Akhter; Zulfiqar, Gulraiz; Iqbal, Javed; Khan, Ayyaz Ali; Shoaib, Muhammad

    2015-01-01

    Oral squamous cell carcinoma (OSCC) is considered to be one of the most fatal diseases worldwide, owing to its late diagnosis and lack of availability of established reliable biomarkers. The aim of this study was to highlight the significance of immunosuppressive cytokines as potential biomarkers in OSCC. Whole unstimulated saliva was collected from each individual (30 OSCC patients and 33 age- and gender-matched healthy controls). Immunosuppressive cytokines, including IL-4, IL-10, IL-13, and IL-1RA, were evaluated in each sample using Luminex multianalyte profiling (xMAP) technology on BioPlex instrument. Our results showed that all the studied salivary cytokines were raised in OSCC patients as compared to controls, where IL-10 and IL-13 salivary levels showed statistically significant difference (p = .004 and p = .010, respectively). Mean levels of salivary cytokines in three histologically defined OSCC categories, compared employing one-way ANOVA, showed that salivary levels of IL-1RA were highest in patients having poorly differentiated OSCC tumors as compared to those having moderately and well-differentiated tumors (p = .000 and p = .002, respectively). Among OSCC individuals, duration of smokeless tobacco correlated positively with IL-1RA (p = .036). We conclude that salivary levels of immunosuppressive cytokines, IL-4, IL-10, IL-13, and IL-1RA, could prove to be potential biomarkers of OSCC and can be further investigated as markers of early detection and disease progression.

  15. A role for IL-1 receptor antagonist or other cytokines in the acute therapeutic effects of IVIg?

    Science.gov (United States)

    Crow, Andrew R; Song, Seng; Semple, John W; Freedman, John; Lazarus, Alan H

    2007-01-01

    The exact mechanism of action of IVIg in the amelioration of immune thrombocytopenic purpura (ITP) is still unclear. Studies have suggested that IVIg may function through the regulation of cytokines, including interleukin-1 receptor antagonist (IL-1Ra), an inhibitor of phagocytosis. Using a mouse model relevant to ITP, we confirm an increase in mouse serum levels of IL-1Ra after exposure to IVIg, yet a recombinant IL-1Ra did not ameliorate thrombocytopenia. IVIg has also been shown to affect the expression of other regulatory cytokines. We have also recently established that IVIg specifically targets activating FcgammaRs on CD11c+ dendritic cells (DCs) as its primary mechanism of action in the amelioration of murine ITP. Herein, we show that IVIg functions therapeutically in mice lacking specific cytokines or their receptors that can potentially affect DC/macrophage function (IL-1 receptor, IL-4, IL-10, IL-12beta, TNF-alpha, IFN-gamma receptor, MIP-1alpha). This suggests that while IVIg may mediate the release of a variety of cytokines, the cytokines tested do not directly participate in the mechanism of IVIg action.

  16. Performance of multiplex commercial kits to quantify cytokine and chemokine responses in culture supernatants from Plasmodium falciparum stimulations.

    Directory of Open Access Journals (Sweden)

    Gemma Moncunill

    Full Text Available BACKGROUND: Cytokines and chemokines are relevant biomarkers of pathology and immunity to infectious diseases such as malaria. Several commercially available kits based on quantitative suspension array technologies allow the profiling of multiple cytokines and chemokines in small volumes of sample. However, kits are being continuously improved and information on their performance is lacking. METHODOLOGY/PRINCIPAL FINDINGS: Different cytokine/chemokine kits, two flow cytometry-based (eBioscience® FlowCytomix™ and BD™ Cytometric Bead Array Human Enhanced Sensitivity and four Luminex®-based (Invitrogen™ Human Cytokine 25-Plex Panel, Invitrogen™ Human Cytokine Magnetic 30-Plex Panel, Bio-Rad® Bio-Plex Pro™ Human Cytokine Plex Assay and Millipore™ MILLIPLEX® MAP Plex Kit were compared. Samples tested were supernatants of peripheral blood mononuclear cells of malaria-exposed children stimulated with Plasmodium falciparum parasite lysates. Number of responses in range that could be detected was determined and reproducibility of duplicates was evaluated by the Bland-Altman test. Luminex® kits performed better than flow cytometry kits in number of responses in range and reproducibility. Luminex® kits were more reproducible when magnetic beads were used. However, within each methodology overall performance depended on the analyte tested in each kit. Within the Luminex® kits, the Invitrogen™ with polystyrene beads had the poorer performance, whereas Invitrogen™ with magnetic beads had the higher percentage of cytokines/chemokines with both readings in range (40%, followed by Bio-Rad® with magnetic beads (35%. Regarding reproducibility, the Millipore™ kit had the highest percentage (60% of cytokines/chemokines with acceptable limits of agreement (<30%, followed by the Invitrogen™ with magnetic beads (40% that had tighter limits of agreement. CONCLUSIONS/SIGNIFICANCE: Currently available kits for cytokine and chemokine

  17. The Effect of Long-Term Exercise on the Production of Osteoclastogenic and Antiosteoclastogenic Cytokines by Peripheral Blood Mononuclear Cells and on Serum Markers of Bone Metabolism

    Directory of Open Access Journals (Sweden)

    J. Kelly Smith

    2016-01-01

    Full Text Available Although it is recognized that the mechanical stresses associated with physical activity augment bone mineral density and improve bone quality, our understanding of how exercise modulates bone homeostasis at the molecular level is lacking. In a before and after trial involving 43 healthy adults, we measured the effect of six months of supervised exercise training on the spontaneous and phytohemagglutinin-induced production of osteoclastogenic cytokines (interleukin-1α, tumor necrosis factor-α, antiosteoclastogenic cytokines (transforming growth factor-β1 and interleukins 4 and 10, pleiotropic cytokines with variable effects on osteoclastogenesis (interferon-γ, interleukin-6, and T cell growth and differentiation factors (interleukins 2 and 12 by peripheral blood mononuclear cells. We also measured lymphocyte phenotypes and serum markers of bone formation (osteocalcin, bone resorption (C-terminal telopeptides of Type I collagen, and bone homeostasis (25 (OH vitamin D, estradiol, testosterone, parathyroid hormone, and insulin-like growth factor 1. A combination of aerobic, resistance, and flexibility exercises done on average of 2.5 hours a week attenuated the production of osteoclastogenic cytokines and enhanced the production of antiosteoclastogenic cytokines. These changes were accompanied by a 16% reduction in collagen degradation products and a 9.8% increase in osteocalcin levels. We conclude that long-term moderate intensity exercise exerts a favorable effect on bone resorption by changing the balance between blood mononuclear cells producing osteoclastogenic cytokines and those producing antiosteoclastogenic cytokines. This trial is registered with Clinical Trials.gov Identifier: NCT02765945.

  18. Identification of a fourth ancient member of the IL-3/IL-5/GM-CSF cytokine family, KK34, in many mammals.

    Science.gov (United States)

    Yamaguchi, Takuya; Schares, Susann; Fischer, Uwe; Dijkstra, Johannes M

    2016-12-01

    The related cytokine genes IL-3, IL-5 and GM-CSF map to the (extended) TH2 cytokine locus of the mammalian genome. For chicken an additional related cytokine gene, KK34, was reported downstream of the IL-3 plus GM-CSF cluster, but hitherto it was believed that mammalian genomes lack this gene. However, the present study identifies an intact orthologue of chicken KK34 gene in many mammals like cattle and pig, while remnants of KK34 can be found in human and mouse. Bovine KK34 was found to be transcribed, and its recombinant protein could induce STAT5 phosphorylation and proliferation of lymphocytes upon incubation with bovine PBMCs. This concludes that KK34 is a fourth functional cytokine of the IL-3/IL-5/GM-CSF/KK34-family (alias IL-5 family) in mammals. While analyzing KK34, the present study also made new identifications of cytokine genes in the extended TH2 cytokine loci for reptiles, birds and marsupials. This includes a hitherto unknown cytokine gene in birds and reptiles which we designated "IL-5famE". Other newly identified genes are KK34, GM-CSF(-like), IL-5, and IL-13 in reptiles, and IL-3 in marsupials.

  19. Prerequisites for cytokine measurements in clinical trials with multiplex immunoassays

    Directory of Open Access Journals (Sweden)

    Rijkers Ger T

    2009-09-01

    Full Text Available Abstract Background Growing knowledge about cellular interactions in the immune system, including the central role of cytokine networks, has lead to new treatments using monoclonal antibodies that block specific components of the immune system. Systemic cytokine concentrations can serve as surrogate outcome parameters of these interventions to study inflammatory pathways operative in patients in vivo. This is now possible due to novel technologies such as multiplex immunoassays (MIA that allows detection of multiple cytokines in a single sample. However, apparently trivial underappreciated processes, (sample handling and storage, interference of endogenous plasma proteins can greatly impact the reliability and reproducibility of cytokine detection. Therefore we set out to investigate several processes that might impact cytokine profiles such as blood collecting tubes, duration of storage, and number of freeze thawing cycles. Results Since under physiological conditions cytokine concentrations normally are low or undetectable we spiked cytokines in the various plasma and serum samples. Overall recoveries ranged between 80-120%. Long time storage showed cytokines are stable for a period up to 2 years of storage at -80°C. After 4 years several cytokines (IL-1α, IL-1β, IL-10, IL-15 and CXCL8 degraded up to 75% or less of baseline values. Furthermore we show that only 2 out of 15 cytokines remained stable after several freeze-thawing cycles. We also demonstrate implementation of an internal control for multiplex cytokine immunoassays. Conclusion All together we show parameters which are essential for measurement of cytokines in the context of clinical trials.

  20. Proinflammatory cytokines oppose opioid induced acute and chronic analgesia

    OpenAIRE

    Hutchinson, Mark R.; Coats, Benjamen D; Lewis, Susannah S.; Zhang, Yingning; Sprunger, David B.; Rezvani, Niloofar; Baker, Eric M.; Jekich, Brian M.; Wieseler, Julie L.; Somogyi, Andrew A; Martin, David; Poole, Stephen; Judd, Charles M.; Steven F. Maier; Watkins, Linda R.

    2008-01-01

    Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morp...

  1. Role of inflammatory cytokines in peripheral nerve injury

    OpenAIRE

    Fregnan, Federica; Muratori, Luisa; Simões, Anabel Rodriguez; Giacobini-Robecchi, Maria Giuseppina; Raimondo, Stefania

    2012-01-01

    Inflammatory events occurring in the distal part of an injured peripheral nerve have, nowadays, a great resonance. Investigating the timing of action of the several cytokines in the important stages of Wallerian degeneration helps to understand the regenerative process and design pharmacologic intervention that promotes and expedites recovery. The complex and synergistic action of inflammatory cytokines finally promotes axonal regeneration. Cytokines can be divided into pro- and anti-inflamma...

  2. Quantitation of Rabbit Cytokine mRNA by Real-Time RT-PCR

    OpenAIRE

    Godornes, Charmie; Leader, Brandon Troy; Molini, Barbara J.; Centurion-Lara, Arturo; Lukehart, Sheila A.

    2007-01-01

    Fundamental understanding of rabbit immunology and the use of the rabbit as a disease model have long been hindered by the lack of immunological assays specific to this species. In the present study, we sought to develop a method to quantitate cytokine expression in rabbit cells and tissues. We report the development of a quantitative real-time RT-PCR method for measuring the relative levels of rabbit IFN-γ, IL-2, IL-4, IL-10 and TNF-α mRNA. Quantitation was accomplished by comparison to a st...

  3. Cytokine analysis of aqueous humor in HIV patients with cytomegalovirus retinitis.

    Science.gov (United States)

    Iyer, Jayant Venkatramani; Connolly, John; Agrawal, Rupesh; Yeo, Tun Kuan; Lee, Bernett; Au, Bijin; Teoh, Stephen C

    2013-11-01

    Cytomegalovirus retinitis (CMVR) is the most common opportunistic ocular infection in patients with AIDS. Comprehensive analysis of aqueous humor for immunologic factors has yet to be performed in patients with CMVR. This study aims to perform comprehensive immune factor analysis of aqueous humor in CMVR patients to determine the presence of any characteristic immunological profile in the aqueous humor. Comparative prospective analysis of aqueous humor was performed across three groups: (1) AIDS patients with CMVR (CMVR group) (n=20), (2) HIV-positive patients without CMVR (HIV group) (n=6) and (3) patients undergoing cataract surgery with no underlying ocular infection or inflammation (control group) (n=11). At least 100μl of aqueous humor was drawn from all subjects and fractionated prior to analysis for 41 cytokines, chemokines and growth factors with the FlexMAP 3D (Luminex®) platform using the Milliplex Human Cytokine® kit. Three distinct immunologic signatures were observed in the aqueous humor of the three groups. Statistically significant differences (phumor though clinically quiescent in CMVR revealed a unique immunologic signature consistent with a combined Th-1 and monocyte-macrophage mediated response. Subsequent longitudinal analysis of aqueous cytokine levels of CMVR through the course of treatment would allow better understanding of the immunopathogenetic mechanisms of CMVR. This may also be used to better prognosticate the disease, predict complications and allow better assessment of treatment response and individualization of treatment in the future. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Prevalence, hemodynamics, and cytokine profile of effusive-constrictive pericarditis in patients with tuberculous pericardial effusion.

    Directory of Open Access Journals (Sweden)

    Mpiko Ntsekhe

    Full Text Available BACKGROUND: Effusive constrictive pericarditis (ECP is visceral constriction in conjunction with compressive pericardial effusion. The prevalence of proven tuberculous ECP is unknown. Whilst ECP is distinguished from effusive disease on hemodynamic grounds, it is unknown whether effusive-constrictive physiology has a distinct cytokine profile. We conducted a prospective study of prevalence and cytokine profile of effusive-constrictive disease in patients with tuberculous pericardial effusion. METHODS: From July 2006 through July 2009, the prevalence of ECP and serum and pericardial levels of inflammatory cytokines were determined in adults with tuberculous pericardial effusion. The diagnosis of ECP was made by combined pericardiocentesis and cardiac catheterization. RESULTS: Of 91 patients evaluated, 68 had tuberculous pericarditis. The 36/68 patients (52.9%; 95% confidence interval [CI]: 41.2-65.4 with ECP were younger (29 versus 37 years, P=0.02, had a higher pre-pericardiocentesis right atrial pressure (17.0 versus 10.0 mmHg, P 15 mmHg (odds ratio [OR] = 48, 95%CI: 8.7-265; P 200 pg/ml (OR=10, 95%CI: 1.1, 93; P=0.04 were independently associated with ECP. CONCLUSION: Effusive-constrictive disease occurs in half of cases of tuberculous pericardial effusion, and is characterized by greater elevation in the pre-pericardiocentesis right atrial pressure and pericardial and serum IL-10 levels compared to patients with effusive non-constrictive tuberculous pericarditis.

  5. Extracellular IL-33 cytokine, but not endogenous nuclear IL-33, regulates protein expression in endothelial cells.

    Science.gov (United States)

    Gautier, Violette; Cayrol, Corinne; Farache, Dorian; Roga, Stéphane; Monsarrat, Bernard; Burlet-Schiltz, Odile; Gonzalez de Peredo, Anne; Girard, Jean-Philippe

    2016-10-03

    IL-33 is a nuclear cytokine from the IL-1 family that plays important roles in health and disease. Extracellular IL-33 activates a growing number of target cells, including group 2 innate lymphoid cells, mast cells and regulatory T cells, but it remains unclear whether intracellular nuclear IL-33 has additional functions in the nucleus. Here, we used a global proteomic approach based on high-resolution mass spectrometry to compare the extracellular and intracellular roles of IL-33 in primary human endothelial cells, a major source of IL-33 protein in human tissues. We found that exogenous extracellular IL-33 cytokine induced expression of a distinct set of proteins associated with inflammatory responses in endothelial cells. In contrast, knockdown of endogenous nuclear IL-33 expression using two independent RNA silencing strategies had no reproducible effect on the endothelial cell proteome. These results suggest that IL-33 acts as a cytokine but not as a nuclear factor regulating gene expression in endothelial cells.

  6. An Appropriate Modulation of Lymphoproliferative Response and Cytokine Release as Possible Contributors to Longevity

    Science.gov (United States)

    Martínez de Toda, Irene; Vida, Carmen; De la Fuente, Mónica

    2017-01-01

    The decrease in the proliferative response of lymphocytes is one of the most evident among the age-related changes of the immune system. This has been linked to a higher risk of mortality in both humans and experimental animals. However, long-lived individuals, in spite of optimally maintaining most of the functions of the immune system, also seem to show an impaired proliferative response. Thus, it was hypothesized that these individuals may have distinct evolution times in this proliferation and a different modulatory capacity through their cytokine release profiles. An individualized longitudinal study was performed on female ICR-CD1 mice, starting at the adult age (40 weeks old), analyzing the proliferation of peritoneal leukocytes at different ages in both basal conditions and in the presence of the mitogen Concanavalin A, for 4, 24 and 48 h of culture. The cytokine secretions (IL-2, IL-17, IL-1β, IL-6, TNF-α and IL-10) in the same cultures were also studied. Long-lived mice show a high proliferative capacity after short incubation times and, despite experiencing a functional decline when they are old, are able to compensate this decrease with an appropriate modulation of the lymphoproliferative response and cytokine release. This could explain their elevated resistance to infections and high longevity. PMID:28737707

  7. Cytokine ratios in chronic periodontitis and type 2 diabetes mellitus.

    Science.gov (United States)

    Acharya, Anirudh B; Thakur, Srinath; Muddapur, M V; Kulkarni, Raghavendra D

    Chronic periodontitis may influence systemic cytokines in type 2 diabetes. This study aimed to evaluate the cytokine ratios in type 2 diabetes with, and without chronic periodontitis. Gingival status, periodontal, glycemic parameters and serum cytokines were evaluated in participants grouped as healthy, chronic periodontitis, and type 2 diabetes with, and without chronic periodontitis. Cytokine ratios showed significant differences in type 2 diabetes and chronic periodontitis, were highest in participants having both type 2 diabetes and chronic periodontitis, with a statistically significant cut-off point and area under curve by receiver operating characteristic. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  8. Inflammatory cytokines in pediatric obstructive sleep apnea

    Science.gov (United States)

    Huang, Yu-Shu; Guilleminault, Christian; Hwang, Fang-Ming; Cheng, Chuan; Lin, Cheng-Hui; Li, Hsueh-Yu; Lee, Li-Ang

    2016-01-01

    Abstract Pediatric obstructive sleep apnea (OSA) is associated with chronic systemic inflammation and with cognitive impairments. This study aimed to investigate the status of proinflammatory cytokines, particularly interleukin 17 (IL-17) and interleukin 23 (IL-23) and cognition in pediatric OSA. Controls and OSA children participated in the study. Exclusion criteria were adenotonsillectomy, heart, neurological and severe psychiatric diseases, craniofacial syndromes, and obesity. Polysomnogram was followed by serum testing for inflammatory markers and neurocognitive tests such as continuous performance task (CPT) and Wisconsin card sorting test, questionnaires, analyses of plasma high-sensitivity C-reactive protein (HS-CRP), tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6), IL-17, and IL-23. Seventy-nine, 4 to 12-year-old subjects in 2 groups ended the study: 47 nonobese OSA children (mean age = 7.84 ± 0.56 years, body mass index [BMI] = 16.95 ± 0.47 kg/m2, BMI z-score = 0.15 ± 0.21, and mean apnea–hypopnea index [AHI] = 9.13 ± 1.67 events/h) and 32 healthy control children (mean age = 7.02 ± 0.65 years, with BMI = 16.55 ± 0.58 kg/m2, BMI z-score = −0.12 ± 0.27, and mean AHI = 0.41 ± 0.07 event/h) were enrolled. Serum cytokine analyses showed significantly higher levels of HS-CRP, IL-17, and IL-23 in OSA children (P = 0.002, P = 0.024, and P = 0.047). Regression test showed significant influence of HS-CRP, TNF-α, IL-6, IL-17, and specifically IL-23, with the continuous performance test and Wisconsin card sorting test. OSA children have abnormal levels of IL-17, an interleukin related to T helper 17 cells, a T helper cell involved in development of autoimmunity and inflammation. This high expression level may contribute to the complications of pediatric OSA; we also found a significant influence of inflammatory cytokines, particularly IL-23, on abnormal neurocognitive testing. PMID

  9. Leptin–cytokine crosstalk in breast cancer

    Science.gov (United States)

    Newman, Gale; Gonzalez-Perez, Ruben Rene

    2013-01-01

    Despite accumulating evidence suggesting a positive correlation between leptin levels, obesity, post-menopause and breast cancer incidence, our current knowledge on the mechanisms involved in these relationships is still incomplete. Since the cloning of leptin in 1994 and its receptor (OB-R) 1 year later by Friedman’s laboratory (Zhang et al., 1994) and Tartaglia et al. (Tartaglia et al., 1995), respectively, more than 22,000 papers related to leptin functions in several biological systems have been published (Pubmed, 2012). The ob gene product, leptin, is an important circulating signal for the regulation of body weight. Additionally, leptin plays critical roles in the regulation of glucose homeostasis, reproduction, growth and the immune response. Supporting evidence for leptin roles in cancer has been shown in more than 1000 published papers, with almost 300 papers related to breast cancer (Pubmed, 2012). Specific leptin-induced signaling pathways are involved in the increased levels of inflammatory, mitogenic and pro-angiogenic factors in breast cancer. In obesity, a mild inflammatory condition, deregulated secretion of proinflammatory cytokines and adipokines such as IL-1, IL-6, TNF-α and leptin from adipose tissue, inflammatory and cancer cells could contribute to the onset and progression of cancer. We used an in silico software program, Pathway Studio 9, and found 4587 references citing these various interactions. Functional crosstalk between leptin, IL-1 and Notch signaling (NILCO) found in breast cancer cells could represent the integration of developmental, proinflammatory and pro-angiogenic signals critical for leptin-induced breast cancer cell proliferation/migration, tumor angiogenesis and breast cancer stem cells (BCSCs). Remarkably, the inhibition of leptin signaling via leptin peptide receptor antagonists (LPrAs) significantly reduced the establishment and growth of syngeneic, xenograft and carcinogen-induced breast cancer and, simultaneously

  10. Lack of a Functioning P2X7 Receptor Leads to Increased Susceptibility to Toxoplasmic Ileitis.

    Directory of Open Access Journals (Sweden)

    Catherine M Miller

    Full Text Available Oral infection of C57BL/6J mice with the protozoan parasite Toxoplasma gondii leads to a lethal inflammatory ileitis.Mice lacking the purinergic receptor P2X7R are acutely susceptible to toxoplasmic ileitis, losing significantly more weight than C57BL/6J mice and exhibiting much greater intestinal inflammatory pathology in response to infection with only 10 cysts of T. gondii. This susceptibility is not dependent on the ability of P2X7R-deficient mice to control the parasite, which they accomplish just as efficiently as C57BL/6J mice. Rather, susceptibility is associated with elevated ileal concentrations of pro-inflammatory cytokines, reactive nitrogen intermediates and altered regulation of elements of NFκB activation in P2X7R-deficient mice.Our data support the thesis that P2X7R, a well-documented activator of pro-inflammatory cytokine production, also plays an important role in the regulation of intestinal inflammation.

  11. Polymorphisms in the selenoprotein S gene: lack of association with autoimmune inflammatory diseases

    Directory of Open Access Journals (Sweden)

    Díaz-Rubio Manuel

    2008-07-01

    Full Text Available Abstract Background Selenoprotein S (SelS protects the functional integrity of the endoplasmic reticulum against the deleterious effects of metabolic stress. SEPS1/SelS polymorphisms have been involved in the increased release of pro-inflammatory cytokines interleukin (IL-1β, tumor necrosis factor (TNF-α and IL-6 in macrophages. We aimed at investigating the role of the SEPS1 variants previously associated with higher plasma levels of these cytokines and of the SEPS1 haplotypes in the susceptibility to develop immune-mediated diseases characterized by an inflammatory component. Results Six polymorphisms distributed through the SEPS1 gene (rs11327127, rs28665122, rs4965814, rs12917258, rs4965373 and rs2101171 were genotyped in more than two thousand patients suffering from type 1 diabetes, rheumatoid arthritis or inflammatory bowel diseases and 550 healthy controls included in the case-control study. Conclusion Lack of association of SEPS1 polymorphisms or haplotypes precludes a major role of this gene increasing predisposition to these inflammatory diseases.

  12. Cytokine Gene Polymorphisms support diagnostic monitoring of Romanian Multiple Myeloma patients

    OpenAIRE

    2011-01-01

    Introduction: cytokines and their receptor genes are very polymorphic. SNPs in the promotor region of the gene may influence the rate of cytokine secretion and may affect the biological activity of the encoded cytokine. A number of cytokines and cytokine receptors have been directly linked to the development of human cancers. The aim of our study was to determine the cytokine gene polymorphism in Romanian multiple myeloma patients. Material and methods: cytokine genotyping was performed in 80...

  13. Penoscrotal porokeratosis: A distinct entity

    Directory of Open Access Journals (Sweden)

    Rajiv Joshi

    2015-01-01

    Full Text Available A 26-year-old man presented with five months history of redness associated with itching and burning over the scrotum and shaft of the penis with a persistent rash on those sites. There had been no response to topical steroid and antifungal creams. Clinical examination revealed a large well-circumscribed erythematous plaque with a thready raised border with a tiny groove at its summit that involved almost two-thirds of the ventral part of the shaft of the penis. Ill-defined erythema with a granular surface was seen over the anterior scrotal skin. A 4 mm punch biopsy of the plaque on the penile shaft revealed multiple cornoid lamellae located adjacent to one another. The patient was treated with topical emollients. Follow up after four months revealed almost complete resolution of the plaque on the penile shaft. Penoscrotal porokeratosis appears to be a distinct entity in the family of porokeratotic diseases, described only in young males in their twenties with involvement of the penile shaft and anterior scrotum with severe burning and itching and histologically associated with multiple cornoid lamellae. It may represent an unusual epidermal porokeratotic reaction pattern and may be a self-resolving condition.

  14. Elevated specific peripheral cytokines found in major depressive disorder patients with childhood trauma exposure: a cytokine antibody array analysis.

    Science.gov (United States)

    Lu, Shaojia; Peng, Hongjun; Wang, Lifeng; Vasish, Seewoobudul; Zhang, Yan; Gao, Weijia; Wu, Weiwei; Liao, Mei; Wang, Mi; Tang, Hao; Li, Wenping; Li, Weihui; Li, Zexuan; Zhou, Jiansong; Zhang, Zhijun; Li, Lingjiang

    2013-10-01

    Taking into consideration the previous evidence of revealing the relationship of early life adversity, major depressive disorder (MDD), and stress-linked immunological changes, we recruited 22 MDD patients with childhood trauma exposures (CTE), 21 MDD patients without CTE, and 22 healthy controls without CTE, and then utilized a novel cytokine antibody array methodology to detect potential biomarkers underlying MDD in 120 peripheral cytokines and to evaluate the effect of CTE on cytokine changes in MDD patients. Although 13 cytokines were identified with highly significant differences in expressions between MDD patients and normal controls, this relationship was significantly attenuated and no longer significant after consideration of the effect of CTE in MDD patients. Depressed individuals with CTE (TD patients) were more likely to have higher peripheral levels of those cytokines. Severity of depression was associated with plasma levels of certain increased cytokines; meanwhile, the increased cytokines led to a proper separation of TD patients from normal controls during clustering analyses. Our research outcomes add great strength to the relationship between depression and cytokine changes and suggest that childhood trauma may play a vital role in the co-appearance of cytokine changes and depression.

  15. Cytokine profiles of seventeen cytokines, growth factors and chemokines in cord blood and its relation to perinatal clinical findings.

    Science.gov (United States)

    Takahashi, Naoto; Uehara, Ritei; Kobayashi, Mami; Yada, Yukari; Koike, Yasunori; Kawamata, Ryou; Odaka, Jun; Honma, Yoko; Momoi, Mariko Y

    2010-03-01

    Few papers have investigated the cytokine profiles of multiple cytokines in cord blood. We obtained cord blood samples from 224 infants admitted to our neonatal intensive care unit. Cytokine profiles of 17 cytokines were investigated using cytometric bead array technology. We found a wide variety of cytokines of various levels which ranged from 0.59pg/ml (in Interleukin (IL)-4) to 222.0pg/ml (in macrophage inflammatory protein-1beta. Pro-inflammatory cytokines were highly correlated with each other and with granulocyte-colony stimulating factor and IL-8. On the contrary, IL-5, IL-13, and IL-17 did not show any significant correlation with other cytokines. Several maternal factors were strongly related to several cytokines in cord blood. IL-6, IL-8 and monocyte chemotactic protein-1 were closely related to certain neonatal diseases in preterm neonates. Some cytokines may be regulated independently of each other, while others appear to work as a network affecting physiological and pathological conditions in the fetus.

  16. 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.

  17. Mode of delivery and cord blood cytokines: a birth cohort study

    Directory of Open Access Journals (Sweden)

    DuBois Andrea M

    2006-09-01

    Full Text Available Abstract Background The mechanisms for the association between birth by cesarean section and atopy and asthma are largely unknown. Objective To examine whether cesarean section results in neonatal secretion of cytokines that are associated with increased risk of atopy and/or asthma in childhood. To examine whether the association between mode of delivery and neonatal immune responses is explained by exposure to the maternal gut flora (a marker of the vaginal flora. Methods CBMCs were isolated from 37 neonates at delivery, and secretion of IL-13, IFN-γ, and IL-10 (at baseline and after stimulation with antigens [dust mite and cat dander allergens, phytohemagglutinin, and lipopolysaccharide] was quantified by ELISA. Total and specific microbes were quantified in maternal stool. The relation between mode of delivery and cord blood cytokines was examined by linear regression. The relation between maternal stool microbes and cord blood cytokines was examined by Spearman's correlation coefficients. Results Cesarean section was associated with increased levels of IL-13 and IFN-γ. In multivariate analyses, cesarean section was associated with an increment of 79.4 pg/ml in secretion of IL-13 by CBMCs after stimulation with dust mite allergen (P Conclusion Cesarean section is associated with increased levels of IL-13 and IFN-γ, perhaps because of lack of labor and/or reduced exposure to specific microbes (e.g., gram-positive anaerobes at birth.

  18. Multiplex cytokine analysis of dermal interstitial blister fluid defines local disease mechanisms in systemic sclerosis.

    Science.gov (United States)

    Clark, Kristina En; Lopez, Henry; Abdi, Bahja Ahmed; Guerra, Sandra G; Shiwen, Xu; Khan, Korsa; Etomi, Oseme; Martin, George R; Abraham, David J; Denton, Christopher P; Stratton, Richard J

    2015-03-23

    Clinical diversity in systemic sclerosis (SSc) reflects multifaceted pathogenesis and the effect of key growth factors or cytokines operating within a disease-specific microenvironment. Dermal interstitial fluid sampling offers the potential to examine local mechanisms and identify proteins expressed within lesional tissue. We used multiplex cytokine analysis to profile the inflammatory and immune activity in the lesions of SSc patients. Dermal interstitial fluid sample from the involved forearm skin, and synchronous plasma samples were collected from SSc patients (n = 26, diffuse cutaneous SSc (DcSSc) n = 20, limited cutaneous SSc (LcSSc) n = 6), and healthy controls (HC) (n = 10) and profiled by Luminex® array for inflammatory cytokines, chemokines, and growth factors. Luminex® profiling of the dermal blister fluid showed increased inflammatory cytokines (median interleukin ( IL)-6 in SSc 39.78 pg/ml, HC 5.51 pg/ml, p = 0.01, median IL-15 in SSc 6.27 pg/ml, HC 4.38 pg/ml, p = 0.03), chemokines (monocyte chemotactic protein (MCP)-3 9.81 pg/ml in SSc, 7.18 pg/ml HC, p = 0.04), and profibrotic growth factors (platelet derived growth factor (PDGF)-AA 10.38 pg/ml versus 6.94 pg/ml in HC, p = 0.03). In general dermal fluid and plasma cytokine levels did not correlate, consistent with predominantly local production of these factors within the dermal lesions, rather than leakage from the serum. In hierarchical clustering and network analysis IL-6 emerged as a key central mediator. Our data confirm that an immuno-inflammatory environment and aberrant vascular repair are intimately linked to fibroblast activation in lesional skin in SSc. This non-invasive method could be used to profile disease activity in the clinic, and identifies key inflammatory or pro-fibrotic proteins that might be targeted therapeutically. Distinct subgroups of SSc may be defined that show innate or adaptive immune cytokine signatures.

  19. Differential T Cell Cytokine Receptivity and Not Signal Quality Distinguishes IL-6 and IL-10 Signaling during Th17 Differentiation.

    Science.gov (United States)

    Jones, Lindsay L; Alli, Rajshekhar; Li, Bofeng; Geiger, Terrence L

    2016-04-01

    How a large number of cytokines differentially signal through a small number of signal transduction pathways is not well resolved. This is particularly true for IL-6 and IL-10, which act primarily through STAT3 yet induce dissimilar transcriptional programs leading alternatively to pro- and anti-inflammatory effects. Kinetic differences in signaling, sustained to IL-10 and transient to IL-6, are critical to this in macrophages. T cells are also key targets of IL-6 and IL-10, yet how differential signaling in these cells leads to divergent cellular fates is unclear. We show that, unlike for macrophages, signal duration cannot explain the distinct effects of these cytokines in T cells. Rather, naive, activated, activated-rested, and memory CD4(+) T cells differentially express IL-6 and IL-10 receptors in an activation state-dependent manner, and this impacts downstream cytokine effects. We show a dominant role for STAT3 in IL-6-mediated Th17 subset maturation. IL-10 cannot support Th17 differentiation because of insufficient cytokine receptivity rather than signal quality. Enforced expression of IL-10Rα on naive T cells permits an IL-10-generated STAT3 signal equivalent to that of IL-6 and equally capable of promoting Th17 formation. Similarly, naive T cell IL-10Rα expression also allows IL-10 to mimic the effects of IL-6 on both Th1/Th2 skewing and Tfh cell differentiation. Our results demonstrate a key role for the regulation of receptor expression rather than signal quality or duration in differentiating the functional outcomes of IL-6 and IL-10 signaling, and identify distinct signaling properties of these cytokines in T cells compared with myeloid cells.

  20. Effects of dietary polyunsaturated fatty acids on in vivo splenic cytokine mRNA expression in layer chicks immunized with salmonella typhimurium lipopolysaccharide

    NARCIS (Netherlands)

    Sijben, J.W.C.; Schrama, J.W.; Parmentier, H.K.; Poel, van der J.J.; Klasing, K.C.

    2001-01-01

    Effects of dietary polyunsaturated fatty acids (PUFA) on immune responses in poultry have been reported. However, effects on the underlying mechanisms, such as the role of cytokines, have not been documented because the necessary tools were lacking. Recently, primer sets for chicken interleukin (IL)

  1. Lung-derived innate cytokines: new epigenetic targets of allergen-specific sublingual immunotherapy

    Directory of Open Access Journals (Sweden)

    Abbas Pishdadian

    2016-01-01

    Full Text Available Objective(s:Sublingual allergen-specific immunotherapy is a safe and effective method for treatment of IgE-mediated respiratory allergies; however, the underlying mechanisms are not fully understood. This study was planned to test whether sublingual immunotherapy (SLIT can exert epigenetic mechanisms through which the airway allergic responses can be extinguished. Materials and Methods:BALB/c mice were sensitized intraperitoneally and challenged intranasally. Then, they received sublingual treatment with recombinant Che a 2 (rChe a 2, a major allergen of Chenopodium album. After SLIT, allergen-specific antibodies in sera, cytokine profiles of spleen cell cultures, mRNA and protein expression of lung-derived IL-33, IL-25, and TSLP (thymic stromal lymphopoietin, and histone modifications of these three genes were assessed. Results:Following Immunotherapy, systemic immune responses shifted from Th2 to Th1 profile as demonstrated by significant decrease in IgE and IL-4 and substantial increase in IgG2a and IFN-γ. At local site, mRNA and protein levels of lung-derived pro-inflammatory cytokines IL-33 and TSLP were markedly down-regulated following SLIT that was associated with marked enrichment of trimethylated lysine 27 of histone H3 at promoter regions of these two cytokines. Conclusion:In our study, sublingual immunotherapy with recombinant allergen effectively attenuated allergic immune responses, at least partly, by induction of distinct histone modifications at specific loci. Additionally, the lung-derived pro-allergic cytokines IL-33 and TSLP could be promising mucosal candidates for either monitoring allergic conditions or therapeutic approaches.

  2. Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats.

    Science.gov (United States)

    Speisman, Rachel B; Kumar, Ashok; Rani, Asha; Foster, Thomas C; Ormerod, Brandi K

    2013-02-01

    We tested whether daily exercise modulates immune and neuroimmune cytokines, hippocampus-dependent behavior and hippocampal neurogenesis in aging male F344 rats (18mo upon arrival). Twelve weeks after conditioned running or control group assignment, the rats were trained and tested in a rapid water maze followed by an inhibitory avoidance task. The rats were BrdU-injected beginning 12days after behavioral testing and killed 3weeks later to quantify cytokines and neurogenesis. Daily exercise increased neurogenesis and improved immediate and 24h water maze discrimination index (DI) scores and 24h inhibitory avoidance retention latencies. Daily exercise decreased cortical VEGF, hippocampal IL-1β and serum MCP-1, GRO-KC and leptin levels but increased hippocampal GRO-KC and IL-18 concentrations. Serum leptin concentration correlated negatively with new neuron number and both DI scores while hippocampal IL-1β concentration correlated negatively with memory scores in both tasks. Cortical VEGF, serum GRO-KC and serum MCP-1 levels correlated negatively with immediate DI score and we found novel positive correlations between hippocampal IL-18 and GRO-KC levels and new neuron number. Pathway analyses revealed distinct serum, hippocampal and cortical compartment cytokine relationships. Our results suggest that daily exercise potentially improves cognition in aging rats by modulating hippocampal neurogenesis and immune and neuroimmune cytokine signaling. Our correlational data begin to provide a framework for systematically manipulating these immune and neuroimmune signaling molecules to test their effects on cognition and neurogenesis across lifespan in future experiments. Published by Elsevier Inc.

  3. Spatiotemporal phosphoprotein distribution and associated cytokine response of a traumatic injury.

    Science.gov (United States)

    Han, Alice A; Currie, Holly N; Loos, Matthew S; Vrana, Julie A; Fabyanic, Emily B; Prediger, Maren S; Boyd, Jonathan W

    2016-03-01

    Molecular mechanisms of wound healing have been extensively characterized, providing a better understanding of the processes involved in wound repair and offering advances in treatment methods. Both spatial and temporal investigations of injury biomarkers have helped to pinpoint significant time points and locations during the recovery process, which may be vital in managing the injury and making the appropriate diagnosis. This study addresses spatial and temporal differences of phosphoproteins found in skeletal muscle tissue following a traumatic femur fracture, which were further compared to co-localized cytokine responses. In particular, several proteins (Akt, ERK, c-Jun, CREB, JNK, MEK1, and p38) and post-translational phosphorylations (p-Akt, p-c-Jun, p-CREB, p-ERK1/2, p-MEK1, p-p38, p-GSK3α/β, p-HSP27, p-p70S6K, and p-STAT3) associated with inflammation, new tissue formation, and remodeling were found to exhibit significant spatial and temporal differences in response to the traumatic injury. Quadratic discriminant analysis of all measured responses, including cytokine concentrations from previously published findings, was used to classify temporal and spatial observations at high predictive rates, further confirming that distinct spatiotemporal distributions for total protein, phosphorylation signaling, and cytokine (IL-1α, IL-1ß, IL2, IL6, TNF-α, and MIP-1α) responses exist. Finally, phosphoprotein measurements were found to be significantly correlated to cytokine concentrations, suggesting coordinated intracellular and extracellular activity during crucial periods of repair. This study represents a first attempt to monitor and assess integrated changes in extracellular and intracellular signaling in response to a traumatic injury in muscle tissues, which may provide a framework for future research to improve both our understanding of wounds and their treatment options.

  4. The pro-inflammatory cytokine, interleukin-6, enhances the polarization of alternatively activated macrophages.

    Directory of Open Access Journals (Sweden)

    Maria Ruweka Fernando

    Full Text Available Macrophages are important innate immune cells that are associated with two distinct phenotypes: a pro-inflammatory (or classically activated subset with prototypic macrophage functions such as inflammatory cytokine production and bactericidal activity, and an anti-inflammatory (or alternatively activated (AAM subset linked with wound healing and tissue repair processes. In this study, we examined the effect of interlukein-6 on human and murine macrophage polarization. The results indicate that despite being commonly associated with pro-inflammatory functions and being implicated in the pathogenesis/pathophysiology of numerous inflammatory diseases, interleukin-6 can enhance the polarization of AAMs, based on increased expression of hallmark markers: arginase-1, Ym1 and CD206; this effect required the AAM differentiating cytokines, IL-4 and IL-13. Co-treatment of AAMs with IL-6 resulted in spontaneous release of IL-10, suppressed LPS-induced nitric oxide production and inhibited cytokine production by activated CD4+ T cells - immunoregulatory features not observed in the 'parent' IL-4+IL-13-induced AAM. The effect of IL-6 required signal transducer and activator of transcription (STAT-3, was partially dependent on up-regulation of the IL4Rα chain, and was independent of autocrine IL-10. In the presence of IFNγ, IL-6 promoted the production of IL-1β and TNFα suggesting that this cytokine can enhance the phenotype to which a macrophage has committed. This finding may explain the pleiotrophic nature of IL-6, where it is associated with the perpetuation and enhancement of disease in inflammatory situations, but is also necessary for resolution of inflammation and adequate wound healing to occur in others. Thus, the potential benefit of IL-6 in promoting an AAM, with its' anti-inflammatory and wound healing ability, may need to be considered in immunotherapies aimed at in vivo modulation or inhibition of IL-6.

  5. The pro-inflammatory cytokine, interleukin-6, enhances the polarization of alternatively activated macrophages.

    Science.gov (United States)

    Fernando, Maria Ruweka; Reyes, Jose Luis; Iannuzzi, Jordan; Leung, Gabriella; McKay, Derek Mark

    2014-01-01

    Macrophages are important innate immune cells that are associated with two distinct phenotypes: a pro-inflammatory (or classically activated) subset with prototypic macrophage functions such as inflammatory cytokine production and bactericidal activity, and an anti-inflammatory (or alternatively activated (AAM)) subset linked with wound healing and tissue repair processes. In this study, we examined the effect of interlukein-6 on human and murine macrophage polarization. The results indicate that despite being commonly associated with pro-inflammatory functions and being implicated in the pathogenesis/pathophysiology of numerous inflammatory diseases, interleukin-6 can enhance the polarization of AAMs, based on increased expression of hallmark markers: arginase-1, Ym1 and CD206; this effect required the AAM differentiating cytokines, IL-4 and IL-13. Co-treatment of AAMs with IL-6 resulted in spontaneous release of IL-10, suppressed LPS-induced nitric oxide production and inhibited cytokine production by activated CD4+ T cells - immunoregulatory features not observed in the 'parent' IL-4+IL-13-induced AAM. The effect of IL-6 required signal transducer and activator of transcription (STAT)-3, was partially dependent on up-regulation of the IL4Rα chain, and was independent of autocrine IL-10. In the presence of IFNγ, IL-6 promoted the production of IL-1β and TNFα suggesting that this cytokine can enhance the phenotype to which a macrophage has committed. This finding may explain the pleiotrophic nature of IL-6, where it is associated with the perpetuation and enhancement of disease in inflammatory situations, but is also necessary for resolution of inflammation and adequate wound healing to occur in others. Thus, the potential benefit of IL-6 in promoting an AAM, with its' anti-inflammatory and wound healing ability, may need to be considered in immunotherapies aimed at in vivo modulation or inhibition of IL-6.

  6. Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E_2 and cytokines

    Institute of Scientific and Technical Information of China (English)

    Mary Ann Cox; James Jackson; Michaela Stanton; Alberto Rojas-Triana; Loretta Bober; Maureen Laverty; Xiaoxin Yang; Feng Zhu; Jianjun Liu; Suke Wang; Frederick Monsma; Galya Vassileva; Maureen Maguire; Eric Gustafson; Marvin Bayne; Chuan-Chu Chou; Daniel Lundell; Chung-Her Jenh

    2009-01-01

    AIM: To investigate the effect of short-chain fatty acids(SCFAs) on production of prostaglandin E_2 (PGE_2),cytokines and chemokines in human monocytes.METHODS: Human neutrophils and monocytes were isolated from human whole blood by using 1-Step Polymorph and RosetteSep Human Monocyte Enrichment Cocktail, respectively. Human GPR41 and GPR43 mRNA expression was examined by quantitative realtimepolymerase chain reaction. The calcium flux assay was used to examine the biological activities of SCFAs in human neutrophils and monocytes. The effect of SCFAs on human monocytes and peripheral blood mononuclear cells (PBMC) was studied by measuring PGE_2, cytokines and chemokines in the supernatant.The effect of SCFAs in vivo was examined by intraplantar injection into rat paws.RESULTS: Human GPR43 is highly expressed in human neutrophils and monocytes. SCFAs induce robust calcium flux in human neutrophils, but not in human monocytes. In this study, we show that SCFAs can induce human monocyte release of PGE_2 and that this effect can be enhanced in the presence of lipopolysaccharide(LPS). In addition, we demonstrate that PGE_2 production induced by SCFA was inhibited by pertussis toxin, suggesting the involvement of a receptor-mediated mechanism. Furthermore, SCFAs can specifically inhibit constitutive monocyte chemotactic protein-1(MCP-1) production and LPS-induced interleukin-10(IL-10) production in human monocytes without affecting the secretion of other cytokines and chemokines examined. Similar activities were observed in human PBMC for the release of PGE_2, MCP-1 and IL-10 after SCFA treatment. In addition, SCFAs inhibit LPS-induced production of tumor necrosis factor-α and interferon-γ in human PBMC. Finally, we show that SCFAs and LPS can induce PGE_2 production in vivo by intraplantar injectioninto rat paws ( P < 0.01).CONCLUSION: SCFAs can have distinct antiinflammatory activities due to their regulation of PGE_2, cytokine and chemokine release from human immune

  7. Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium

    Energy Technology Data Exchange (ETDEWEB)

    Rennolds, Jessica; Malireddy, Smitha; Hassan, Fatemat; Tridandapani, Susheela; Parinandi, Narasimham [Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH 43210 (United States); Boyaka, Prosper N. [Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210 (United States); Cormet-Boyaka, Estelle, E-mail: Estelle.boyaka@osumc.edu [Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH 43210 (United States)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Cadmium induces secretion of IL-6 and IL-8 by two distinct pathways. Black-Right-Pointing-Pointer Cadmium increases NAPDH oxidase activity leading to Erk activation and IL-8 secretion. Black-Right-Pointing-Pointer Curcumin prevents cadmium-induced secretion of both IL-6 and IL-8 by airway cells. Black-Right-Pointing-Pointer Curcumin could be use to suppress lung inflammation due to cadmium inhalation. -- Abstract: Cadmium is a toxic metal present in the environment and its inhalation can lead to pulmonary disease such as lung cancer and chronic obstructive pulmonary disease. These lung diseases are characterized by chronic inflammation. Here we show that exposure of human airway epithelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL-8, two pivotal pro-inflammatory cytokines known to play an important role in pulmonary inflammation. We also determined that two distinct pathways controlled secretion of these proinflammatory cytokines by human airway epithelial cells as cadmium-induced IL-6 secretion occurs via an NF-{kappa}B dependent pathway, whereas IL-8 secretion involves the Erk1/2 signaling pathway. Interestingly, the natural antioxidant curcumin could prevent both cadmium-induced IL-6 and IL-8 secretion by human airway epithelial cells. In conclusion, curcumin could be used to prevent airway inflammation due to cadmium inhalation.

  8. Pivotal Advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation

    OpenAIRE

    Shao, Diane D.; Suresh, Rahul; Vakil, Varsha; Gomer, Richard H.; Pilling, Darrell

    2008-01-01

    CD14+ peripheral blood monocytes can differentiate into fibroblast-like cells called fibrocytes, which are associated with and are at least partially responsible for wound healing and fibrosis in multiple organ systems. Signals regulating fibrocyte differentiation are poorly understood. In this study, we find that when added to human PBMCs cultured in serum-free medium, the profibrotic cytokines IL-4 and IL-13 promote fibrocyte differentiation without inducing fibrocyte or fibrocyte precursor...

  9. Heavy metal mediated innate immune responses of the Indian green frog, Euphlyctis hexadactylus (Anura: Ranidae): Cellular profiles and associated Th1 skewed cytokine response.

    Science.gov (United States)

    Jayawardena, Uthpala A; Ratnasooriya, Wanigasekara D; Wickramasinghe, Deepthi D; Udagama, Preethi V

    2016-10-01

    Immune cell and cytokine profiles in relation to metal exposure though much studied in mammals has not been adequately investigated in amphibians, due mainly to lack of suitable reagents for cytokine profiling in non-model species. However, interspecies cross reactivity of cytokines permitted us to assay levels of IFNγ, TNFα, IL6 and IL10in a common anuran, the Indian green frog (Euphlyctis hexadactylus), exposed to heavy metals (Cd, Cr, Cu, Zn and Pb, at ~5ppm each) under field and laboratory settings in Sri Lanka. Enumeration of immune cells in blood and melanomacrophages in the liver, assay of serum and hepatic cytokines, and Th1/Th2 cytokine polarisation were investigated. Immune cell counts indicated overall immunosuppression with decreasing total WBC and splenocyte counts while neutrophil/lymphocyte ratio increased with metal exposure, indicating metal mediated stress. Serum IL6 levels of metal exposed frogs reported the highest (~9360pg/mL) of all cytokines tested. Significantly elevated IFNγ production (Pfrogs. Th1/Th2 cytokine ratio in both serum and liver tissue homogenates was Th1 skewed due to significantly higher production of pro-inflammatory cytokines, IFNγ in serum and TNFα in the liver (P<0.01).Metal mediated aggregations of melanomacrophages in the liver were positively and significantly (P<0.05) correlated with the hepatic expression of TNFα, IL6 and IL10 activity. Overall, Th1 skewed response may well be due to oxidative stress mediated nuclear factor κ-light chain enhancer of activated B cells (NFκB) which enhances the transcription of pro-inflammatory cytokines. Xenobiotic stress has recently imposed an unprecedented level of threat to wildlife, particularly to sensitive species such as amphibians. Therefore, understanding the interactions between physiological stress and related immune responses is fundamental to conserve these environmental sentinels in the face of emerging eco-challenges.

  10. Neonatal mycobacterial specific cytotoxic T‐lymphocyte and cytokine profiles in response to distinct BCG vaccination strategies

    National Research Council Canada - National Science Library

    Hussey, Gregory D; Watkins, Marcia L. V; Goddard, Elizabeth A; Gottschalk, Sean; Hughes, Elizabeth J; Iloni, Karen; Kibel, Maurice A; Ress, Stanley R

    2002-01-01

    This study evaluated whether different bacillus Calmette–Gue´rin (BCG) strains, routes of administration, vaccination age and percutaneous tools influenced immune responses to BCG vaccination in infants...

  11. Distinctiveness of Ugandapithecus from Proconsul

    Directory of Open Access Journals (Sweden)

    Gommery, D.

    2009-12-01

    Full Text Available The decision to create the genus Ugandapithecus by Senut et al., 2000 has been criticised, either directly and in detail by MacLatchy & Rossie (2005b who argued that it is a junior synonym of Proconsul, or indirectly without providing reasons, firstly by Harrison (2001 who wrote that he did not retain it as a genus distinct from Proconsul, and then by Suwa et al., (2007 who employed the name “Ugandapithecus” with inverted commas, implying some degree of doubt about its validity as a genus, but without providing details. More recently Harrison & Andrews (2009 have recognised the Meswa sample as a separate species but they argue that it should be maintained within Proconsul, despite the morphological differences that it has from other species of the genus. We here re-examine the question by comparing, on the one hand, the holotype maxilla of Proconsul africanus, the type species of the genus, with the upper dentition of Ugandapithecus major, and, on the other hand, the holotype mandible of Ugandapithecus major with the lower dentition and mandibles previously attributed to Proconsul africanus. We conclude that the differences between the known upper and lower dentitions of P. africanus and U. major are of such a degree that the two taxa warrant generic separation, and that the differences are not related to sexual dimorphism. Where Proconsul africanus differs from Ugandapithecus major, it approaches Proconsul nyanzae and Proconsul heseloni from Rusinga.Furthermore, the range of morphometric variation within the fossil samples previously attributed to Ugandapithecus major is so great that it far surpasses variation in any other hominoid, fossil or extant. Previously this great amount of variation was interpreted to mean that U. major was extremely dimorphic, with huge males and small females, but if this is true, then U. major would be unique among hominoids in having females in which the cheek teeth fall completely outside the range of

  12. Pivotal Advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation.

    Science.gov (United States)

    Shao, Diane D; Suresh, Rahul; Vakil, Varsha; Gomer, Richard H; Pilling, Darrell

    2008-06-01

    CD14+ peripheral blood monocytes can differentiate into fibroblast-like cells called fibrocytes, which are associated with and are at least partially responsible for wound healing and fibrosis in multiple organ systems. Signals regulating fibrocyte differentiation are poorly understood. In this study, we find that when added to human PBMCs cultured in serum-free medium, the profibrotic cytokines IL-4 and IL-13 promote fibrocyte differentiation without inducing fibrocyte or fibrocyte precursor proliferation. We also find that the potent, antifibrotic cytokines IFN-gamma and IL-12 inhibit fibrocyte differentiation. In our culture system, IL-1beta, IL-3, IL-6, IL-7, IL-16, GM-CSF, M-CSF, fetal liver tyrosine kinase 3, insulin growth factor 1, vascular endothelial growth factor, and TNF-alpha had no significant effect on fibrocyte differentiation. IL-4, IL-13, and IFN-gamma act directly on monocytes to regulate fibrocyte differentiation, and IL-12 acts indirectly, possibly through CD16-positive NK cells. We previously identified the plasma protein serum amyloid P (SAP) as a potent inhibitor of fibrocyte differentiation. When added together, the fibrocyte-inhibitory activity of SAP dominates the profibrocyte activities of IL-4 and IL-13. The profibrocyte activities of IL-4 and IL-13 and the fibrocyte-inhibitory activities of IFN-gamma and IL-12 counteract each other in a concentration-dependent manner. These results indicate that the complex mix of cytokines and plasma proteins present in inflammatory lesions, wounds, and fibrosis will influence fibrocyte differentiation.

  13. Mental quality of life is related to a cytokine genetic pathway.

    Directory of Open Access Journals (Sweden)

    Dounya Schoormans

    Full Text Available BACKGROUND: Quality of life (QoL in patients with chronic disease is impaired and cannot be solely explained by disease severity. We explored whether genetic variability and activity contributes to QoL in patients with Marfan syndrome (MFS, a genetic connective tissue disorder. METHODOLOGY/PRINCIPAL FINDINGS: In 121 MFS patients, patient characteristics (i.e. demographics and MFS-related symptoms were assessed. Patients completed the SF-36 to measure QoL. In addition, transcriptome wide gene expression and 484 Single Nucleotide Polymorphysms (SNPs in cytokine genes were available. QoL was first analyzed and associated with patient characteristics. Patients' physical QoL was impaired and weakly related with age and scoliosis, whereas mental quality of life (MCS was normal. To explain a largely lacking correlation between disease severity and QoL, we related genome wide gene expression to QoL. Patients with lower MCS scores had high expression levels of CXCL9 and CXCL11 cytokine-related genes (p=0.001; p=0.002; similarly, patients with low vitality scores had high expression levels of CXCL9, CXCL11 and IFNA6 cytokine-related genes (p=0.02; p=0.02; p=0.04, independent of patient characteristics. Subsequently, we associated cytokine related SNPs to mental QoL (MCS and vitality. SNP-cluster in the IL4R gene showed a weak association with MCS and vitality (strongest association p=0.0017. Although overall mental QoL was normal, >10% of patients had low scores for MCS and vitality. Post-hoc analysis of systemic inflammatory mediators showed that patients with lowest MCS and vitality scores had high levels of CCL11 cytokine (p=0.03; p=0.04. CONCLUSIONS/SIGNIFICANCE: Variation in the cytokine genetic pathway and its activation is related to mental QoL. These findings might allow us to identify and, ultimately, treat patients susceptible to poor QoL.

  14. Cytokine expression & TGF-beta signaling in cervical cancer

    NARCIS (Netherlands)

    Kloth, Judith Nathalie

    2009-01-01

    Immune surveillance is of utmost importance in preventing cervical carcinogenesis. Cytokines play a central role in directing and fine tuning the immune response. In cancer, cytokines can either be involved in stimulating the anti-tumor immune response or in tumor growth and progression. The studies

  15. Cytokines in crevicular fluid and orthodontic tooth movement

    NARCIS (Netherlands)

    Ren, Yijin; Vissink, Arjan

    2008-01-01

    This review aimed to evaluate studies on cytokines in the gingival crevicular fluid (GCF) during orthodontic treatment, summarizing the regulation patterns of the most commonly studied cytokines and exploring their clinical implications. To achieve this, a number of key databases were searched using

  16. Characterization and potential clinical applications of autoantibodies against cytokines

    DEFF Research Database (Denmark)

    de Lemos Rieper, Carina; Galle, Pia; Hansen, Morten Bagge

    2009-01-01

    Autoantibodies recognizing cytokines arise in certain patients during the course of therapy with recombinant cytokines, although they may arise spontaneously as well. They are typically high avidity and in vitro neutralizing IgG antibodies present in picomolar to nanomolar concentrations. Methodo...

  17. Cytokine Levels in the Serum of Healthy Subjects

    Directory of Open Access Journals (Sweden)

    Giulio Kleiner

    2013-01-01

    Full Text Available Growing knowledge about the cytokine network response has led to a better comprehension of mechanisms of pathologies and to the development of new treatments with biological drugs, able to block specific molecules of the immune response. Indeed, when the cytokine production is deregulated, diseases often occur. The understanding of the physiological mechanism of the cytokine network would be useful to better comprehend pathological conditions. Moreover, since the immune system and response change their properties with development, differences in patients' age should be taken into account, both in physiological and in pathological conditions. In this study, we analyzed the profile of 48 cytokines and chemokines in the serum of healthy subjects, comparing adults (≥18 years with young children and children (1–6 and 7–17 years. We found that a certain number of cytokines were not being produced in healthy subjects; others showed a constant serum level amongst the groups. Certain cytokines exhibited a downward or an upward trend with increasing age. The remaining cytokines were up- or downregulated in the group of the children with respect to the other groups. In conclusion, we drew some kinds of guidelines about the physiological production of cytokines and chemokines, underling the difference caused by aging.

  18. Cytokine levels in the serum of healthy subjects.

    Science.gov (United States)

    Kleiner, Giulio; Marcuzzi, Annalisa; Zanin, Valentina; Monasta, Lorenzo; Zauli, Giorgio

    2013-01-01

    Growing knowledge about the cytokine network response has led to a better comprehension of mechanisms of pathologies and to the development of new treatments with biological drugs, able to block specific molecules of the immune response. Indeed, when the cytokine production is deregulated, diseases often occur. The understanding of the physiological mechanism of the cytokine network would be useful to better comprehend pathological conditions. Moreover, since the immune system and response change their properties with development, differences in patients' age should be taken into account, both in physiological and in pathological conditions. In this study, we analyzed the profile of 48 cytokines and chemokines in the serum of healthy subjects, comparing adults (≥18 years) with young children and children (1-6 and 7-17 years). We found that a certain number of cytokines were not being produced in healthy subjects; others showed a constant serum level amongst the groups. Certain cytokines exhibited a downward or an upward trend with increasing age. The remaining cytokines were up- or downregulated in the group of the children with respect to the other groups. In conclusion, we drew some kinds of guidelines about the physiological production of cytokines and chemokines, underling the difference caused by aging.

  19. The role of cytokines in ultraviolet-B induced immunosuppression

    NARCIS (Netherlands)

    Boonstra, A.; Savelkoul, H.F.J.

    1997-01-01

    Summary : Cytokines play an important role in the mechanisms resulting in ultraviolet B-induced immunosuppression. They play a crucial role in the induction of local as well as systemic immunomodulatory events. Ultraviolet B irradiation directly induces the release of cytokines in the epidermis, res

  20. Cytokines in crevicular fluid and orthodontic tooth movement

    NARCIS (Netherlands)

    Ren, Yijin; Vissink, Arjan

    This review aimed to evaluate studies on cytokines in the gingival crevicular fluid (GCF) during orthodontic treatment, summarizing the regulation patterns of the most commonly studied cytokines and exploring their clinical implications. To achieve this, a number of key databases were searched using

  1. Inflammatory cytokines and risk of coronary heart disease

    DEFF Research Database (Denmark)

    Kaptoge, Stephen; Seshasai, Sreenivasa Rao Kondapally; Gao, Pei

    2014-01-01

    Because low-grade inflammation may play a role in the pathogenesis of coronary heart disease (CHD), and pro-inflammatory cytokines govern inflammatory cascades, this study aimed to assess the associations of several pro-inflammatory cytokines and CHD risk in a new prospective study, including meta...

  2. 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.

  3. Anti-cytokine therapies in T1D

    DEFF Research Database (Denmark)

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

    2013-01-01

    selective cytokine blockade as a component of preventative or interventional immunotherapy. The rationale and status of inhibitory therapy directed against IL-1, TNF, IL-12, IL-23, and IL-6 are discussed, towards a goal of using cytokine inhibition as a therapeutic platform to establish an in vivo milieu...

  4. Cytokines and the Risk of Preterm Delivery in Twin Pregnancies

    DEFF Research Database (Denmark)

    Rode, Line; Klein, Katharina; Larsen, Helle

    2012-01-01

    To estimate the association between cytokine levels in twin pregnancies and risk of spontaneous preterm delivery, including the effect of progesterone treatment.......To estimate the association between cytokine levels in twin pregnancies and risk of spontaneous preterm delivery, including the effect of progesterone treatment....

  5. Vitamin D and Inflammatory Cytokines in Healthy and Preeclamptic Pregnancies

    Directory of Open Access Journals (Sweden)

    David Barrera

    2015-08-01

    Full Text Available Preeclampsia is a pregnancy disease characterized by hypertension and proteinuria. Among several disorders, the imbalance of inflammatory cytokines and the alteration of vitamin D metabolism have been reported in preeclampsia. The effects of calcitriol upon inflammatory cytokines has been demonstrated. In healthy pregnant women there is a shift toward a Th2 cytokine profile, which is necessary for an adequate pregnancy outcome. As compared with normal pregnancy, high pro-inflammatory and low anti-inflammatory cytokine levels have been observed in preeclamptic women. Preeclampsia has been associated with low calcitriol levels and vitamin D deficiency is correlated with a higher risk of the development of this disease. It has been demonstrated that placenta is a source as well as the target of calcitriol and cytokines and placental dysfunction has been associated with preeclampsia. Therefore, the present manuscript includes a review about serum calcitriol levels in non-pregnant, pregnant, and preeclamptic women as well as a review on the fetoplacental vitamin D metabolism in healthy and preeclamptic pregnancies. In addition, circulating and fetoplacental inflammatory cytokines in healthy and preeclamptic pregnancies are reviewed. Finally, the effects of calcitriol upon placental pro-inflammatory cytokines are also explored. In conclusion, maternal and placental calcitriol levels are low in preeclampsia which may explain, at least in part, high pro-inflammatory cytokine levels in this disease.

  6. Class I Cytokine Receptors: Structure and function in the Membrane

    DEFF Research Database (Denmark)

    Bugge, Katrine Østergaard

    ample material of high quality for structural studies with NMR spectroscopy of several class I cytokine receptor TMDs. Furthermore, the structure of a class I cytokine receptor TMD in DHPC micelles was solved with solution-state NMR spectroscopy. Additionally, since structural studies of intact proteins...

  7. Autophagy modulates the Mycobacterium tuberculosis-induced cytokine response

    NARCIS (Netherlands)

    Kleinnijenhuis, J.; Oosting, M.; Plantinga, T.S.; Meer, J.W.M. van der; Joosten, L.A.B.; Crevel, R. van; Netea, M.G.

    2011-01-01

    Both autophagy and pro-inflammatory cytokines are involved in the host defence against mycobacteria, but little is known regarding the effect of autophagy on Mycobacterium tuberculosis (MTB)-induced cytokine production. In the present study, we assessed the effect of autophagy on production of monoc

  8. Cytokines in lethal graft-versus-host disease

    NARCIS (Netherlands)

    Knulst, A.C.; Bril-Bazuin, C.; Tibbe, G.J.M.; Oudenaren, van A.; Savelkoul, H.F.J.; Benner, R.

    1992-01-01

    Graft-versus-host disease (GVHD) is caused by donor T lymphocytes that recognize foreign antigens on host tissues. This leads to T cell activation, which involves a cascade of events including the transcription of genes for cytokines and their receptors and the production of cytokines. One of the fi

  9. Role of inflammatory cytokines in peripheral nerve injury

    Institute of Scientific and Technical Information of China (English)

    Federica Fregnan; Luisa Muratori; Anabel Rodriguez Sim(o)es; Maria Giuseppina Giacobini-Robecchi; Stefania Raimondo

    2012-01-01

    Inflammatory events occurring in the distal part of an injured peripheral nerve have,nowadays,a great resonance.Investigating the timing of action of the several cytokines in the important stages of Wallerian degeneration helps to understand the regenerative process and design pharmacologic intervention that promotes and expedites recovery.The complex and synergistic action of inflammatory cytokines finally promotes axonal regeneration.Cytokines can be divided into pro-and anti-inflammatory cytokines that upregutate and downregulate,respectively,the production of inflammatory mediators.While pro-inflammatory cytokines are expressed in the first phase of Wallerian degeneration and promote the recruitment of macrophages,anti-inflammatory cytokines are expressed after this recruitment and downregulate the production of all cytokines,thus determining the end of the process.In this review,we describe the major inflammatory cytokines involved in Wallerian degeneration and the early phases of nerve regeneration.In particular,we focus on interleukin-1,interleukin-2,interleukin-6,tumor necrosis factor-β,interleukin-10 and transforming growth factor-β.

  10. Vitamin D and Inflammatory Cytokines in Healthy and Preeclamptic Pregnancies.

    Science.gov (United States)

    Barrera, David; Díaz, Lorenza; Noyola-Martínez, Nancy; Halhali, Ali

    2015-08-04

    Preeclampsia is a pregnancy disease characterized by hypertension and proteinuria. Among several disorders, the imbalance of inflammatory cytokines and the alteration of vitamin D metabolism have been reported in preeclampsia. The effects of calcitriol upon inflammatory cytokines has been demonstrated. In healthy pregnant women there is a shift toward a Th2 cytokine profile, which is necessary for an adequate pregnancy outcome. As compared with normal pregnancy, high pro-inflammatory and low anti-inflammatory cytokine levels have been observed in preeclamptic women. Preeclampsia has been associated with low calcitriol levels and vitamin D deficiency is correlated with a higher risk of the development of this disease. It has been demonstrated that placenta is a source as well as the target of calcitriol and cytokines and placental dysfunction has been associated with preeclampsia. Therefore, the present manuscript includes a review about serum calcitriol levels in non-pregnant, pregnant, and preeclamptic women as well as a review on the fetoplacental vitamin D metabolism in healthy and preeclamptic pregnancies. In addition, circulating and fetoplacental inflammatory cytokines in healthy and preeclamptic pregnancies are reviewed. Finally, the effects of calcitriol upon placental pro-inflammatory cytokines are also explored. In conclusion, maternal and placental calcitriol levels are low in preeclampsia which may explain, at least in part, high pro-inflammatory cytokine levels in this disease.

  11. Spironolactone inhibits production of proinflammatory cytokines by human mononuclear cells

    DEFF Research Database (Denmark)

    Hansen, Peter Riis; Rieneck, Klaus; Bendtzen, Klaus

    2004-01-01

    The mineralocorticoid receptor antagonist spironolactone (SPIR) reduces the mortality and morbidity in patients with congestive heart failure (CHF). Overexpression of proinflammatory cytokines contribute to the development and progression of CHF.......The mineralocorticoid receptor antagonist spironolactone (SPIR) reduces the mortality and morbidity in patients with congestive heart failure (CHF). Overexpression of proinflammatory cytokines contribute to the development and progression of CHF....

  12. Peripheral blood neutrophil cytokine hyper-reactivity in chronic periodontitis.

    Science.gov (United States)

    Ling, Martin R; Chapple, Iain L C; Matthews, John B

    2015-10-01

    Pro-inflammatory cytokine release (IL-8, IL-6, TNF-α, IL-1β) by peripheral blood neutrophils, isolated from periodontitis patients (before/after therapy) and matched controls, was determined after 18 h culture in the presence/absence of Escherichia coli LPS, opsonised Staphylococcus aureus, heat-killed Fusobacterium nucleatum and Porphyromonas gingivalis. All cultures demonstrated differences in the amounts of each cytokine detected (P IL-6 > TNF-α = IL-1β). Median cytokine release from unstimulated patient neutrophils was consistently, but non-significantly, higher than from control cells. Stimulated cytokine release from untreated patient neutrophils was also consistently higher than from control cells. This hyper-reactivity was significant for all tested cytokines when data for all stimuli were combined (P TNF-α), opsonised S. aureus (IL-8, TNF-α, IL-1β) and P. gingivalis (IL-8, IL-1β). Cytokine production by patient neutrophils did not reduce following successful non-surgical periodontal therapy and, except for responses to F. nucleatum, the cytokine hyper-reactivity detected pre-therapy was retained. These data demonstrate that chronic periodontitis is characterised by neutrophils that constitutively exhibit cytokine hyper-reactivity, the effects of which could modulate local and systemic inflammatory-immune responses and influence the risk and severity of periodontitis-associated systemic inflammatory diseases.

  13. Carbohydrate Supplementation Influences Serum Cytokines after Exercise under Hypoxic Conditions

    Directory of Open Access Journals (Sweden)

    Aline Venticinque Caris

    2016-11-01

    Full Text Available Introduction: Exercise performed at the hypoxia equivalent of an altitude of 4200 m is associated with elevated inflammatory mediators and changes in the Th1/Th2 response. By contrast, supplementation with carbohydrates has an anti-inflammatory effect when exercise is performed under normoxic conditions. The objective of this study was to evaluate the effect of carbohydrate supplementation on cytokines and cellular damage markers after exercise under hypoxic conditions at a simulated altitude of 4200 m. Methods: Seven adult male volunteers who exercised for 60 min at an intensity of 50% VO2Peak were randomly evaluated under three distinct conditions; normoxia, hypoxia and hypoxia + carbohydrate supplementation. Blood samples were collected at rest, at the end of exercise and after 60 min of recovery. To evaluate hypoxia + carbohydrate supplementation, volunteers received a solution of 6% carbohydrate (maltodextrin or a placebo (strawberry-flavored Crystal Light®; Kraft Foods, Northfield, IL, USA every 20 min during exercise and recovery. Statistical analyses comprised analysis of variance, with a one-way ANOVA followed by the Tukey post hoc test with a significance level of p < 0.05. Results: Under normoxic and hypoxic conditions, there was a significant increase in the concentration of IL-6 after exercise and after recovery compared to at rest (p < 0.05, while in the hypoxia + carbohydrate group, there was a significant increase in the concentration of IL-6 and TNF-α after exercise compared to at rest (p < 0.05. Furthermore, under this condition, TNF-α, IL-2 and the balance of IL-2/IL-4 were increased after recovery compared to at rest (p < 0.05. Conclusion: We conclude that carbohydrate supplementation modified the IL-6 and TNF-α serum concentrations and shifted the IL-2/IL-4 balance towards Th1 in response without glycemic, glutaminemia and cell damage effects.

  14. Using cluster analysis of cytokines to identify patterns of inflammation in hospitalized patients with community-acquired pneumonia: a pilot study

    Science.gov (United States)

    Wiemken, Timothy L; Kelley, Robert R; Fernandez-Botran, Rafael; Mattingly, William A.; Arnold, Forest W.; Furmanek, Stephen P; Restrepo, Marcos I; Chalmers, James D; Peyrani, Paula; Cavallazzi, Rodrigo; Bordon, Jose; Aliberti, Stefano; Ramirez, Julio A.

    2017-01-01

    Introduction Patients with severe community-acquired pneumonia (CAP) are believed to have an exaggerated inflammatory response to bacterial infection. Therapies aiming to modulate the inflammatory response have been largely unsuccessful, perhaps reflecting that CAP is a heterogeneous disorder that cannot be modulated by a single anti-inflammatory approach. We hypothesize that the host inflammatory response to pneumonia may be characterized by distinct cytokine patterns, which can be harnessed for personalized therapies. Methods Here, we use hierarchical cluster analysis of cytokines to examine if patterns of inflammatory response in 13 hospitalized patients with CAP can be defined. This was a secondary data analysis of the Community-Acquired Pneumonia Inflammatory Study Group (CAPISG) database. The following cytokines were measured in plasma and sputum on the day of admission: interleukin (IL)-1β, IL-1 receptor antagonist (IL-1ra), IL-6, CXCL8 (IL-8), IL-10, IL-12p40, IL-17, interferon (IFN)γ, tumor necrosis factor (TNF)α, and CXCL10 (IP-10). Hierarchical agglomerative clustering algorithms were used to evaluate clusters of patients within plasma and sputum cytokine determinations. Results A total of thirteen patients were included in this pilot study. Cluster analysis identified distinct inflammatory response patterns of cytokines in the plasma, sputum, and the ratio of plasma to sputum. Conclusions Inflammatory response patterns in plasma and sputum can be identified in hospitalized patients with CAP. Characterization of the local and systemic inflammatory response may help to better discriminate patients for enrollment into clinical trials of immunomodulatory therapies.

  15. The cytokines cardiotrophin-like cytokine/cytokine-like factor-1 (CLC/CLF) and ciliary neurotrophic factor (CNTF) differ in their receptor specificities.

    Science.gov (United States)

    Tormo, Aurélie Jeanne; Letellier, Marie-Claude; Lissilaa, Rami; Batraville, Laurie-Anne; Sharma, Mukut; Ferlin, Walter; Elson, Greg; Crabé, Sandrine; Gauchat, Jean-François

    2012-12-01

    Ciliary neurotrophic factor (CNTF) and cardiotrophin-like cytokine (CLC) are two cytokines with neurotrophic and immunomodulatory activities. CNTF is a cytoplasmic factor believed to be released upon cellular damage, while CLC requires interaction with a soluble cytokine receptor, cytokine-like factor 1 (CLF), to be efficiently secreted. Both cytokines activate a receptor complex comprising the cytokine binding CNTF receptor α (CNTFRα) and two signaling chains namely, leukemia inhibitory factor receptor β (LIFRβ) and gp130. Human CNTF can recruit and activate an alternative receptor in which CNTFRα is substituted by IL-6Rα. As both CNTF and CLC have immune-regulatory activities in mice, we compared their ability to recruit mouse receptors comprising both gp130 and LIFRβ signaling chains and either IL-6Rα or IL-11Rα which, unlike CNTFRα, are expressed by immune cells. Our results indicate that 1) mouse CNTF, like its human homologue, can activate cells expressing gp130/LIFRβ with either CNTFRα or IL-6Rα and, 2) CLC/CLF is more restricted in its specificity in that it activates only the tripartite CNTFR. Several gp130 signaling cytokines influence T helper cell differentiation. We therefore investigated the effect of CNTF on CD4 T cell cytokine production. We observed that CNTF increased the number of IFN-γ producing CD4 T cells. As IFN-γ is considered a mediator of the therapeutic effect of IFN-β in multiple sclerosis, induction of IFN-γ by CNTF may contribute to the beneficial immunomodulatory effect of CNTF in mouse multiple sclerosis models. Together, our results indicate that CNTF activates the same tripartite receptors in mouse and human cells and further validate rodent models for pre-clinical investigation of CNTF and CNTF derivatives. Furthermore, CNTF and CLC/CLF differ in their receptor specificities. The receptor α chain involved in the immunomodulatory effects of CLC/CLF remains to be identified.

  16. Subfornical organ mediates sympathetic and hemodynamic responses to blood-borne proinflammatory cytokines.

    Science.gov (United States)

    Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Yu, Yang; Johnson, Alan Kim; Felder, Robert B

    2013-07-01

    Proinflammatory cytokines play an important role in regulating autonomic and cardiovascular function in hypertension and heart failure. Peripherally administered proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), act on the brain to increase blood pressure, heart rate, and sympathetic nerve activity. These molecules are too large to penetrate the blood-brain barrier, and so the mechanisms by which they elicit these responses remain unknown. We tested the hypothesis that the subfornical organ (SFO), a forebrain circumventricular organ that lacks a blood-brain barrier, plays a major role in mediating the sympathetic and hemodynamic responses to circulating proinflammatory cytokines. Intracarotid artery injection of TNF-α (200 ng) or IL-1β (200 ng) dramatically increased mean blood pressure, heart rate, and renal sympathetic nerve activity in rats with sham lesions of the SFO (SFO-s). These excitatory responses to intracarotid artery TNF-α and IL-1β were significantly attenuated in SFO-lesioned (SFO-x) rats. Similarly, the increases in mean blood pressure, heart rate, and renal sympathetic nerve activity in response to intravenous injections of TNF-α (500 ng) or IL-1β (500 ng) in SFO-s rats were significantly reduced in the SFO-x rats. Immunofluorescent staining revealed a dense distribution of the p55 TNF-α receptor and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, in the SFO. These data suggest that SFO is a predominant site in the brain at which circulating proinflammatory cytokines act to elicit cardiovascular and sympathetic responses.

  17. Lactic acid bacteria inhibit TH2 cytokine production by mononuclear cells from allergic patients.

    Science.gov (United States)

    Pochard, Pierre; Gosset, Philippe; Grangette, Corinne; Andre, Claude; Tonnel, André-Bernard; Pestel, Joël; Mercenier, Annick

    2002-10-01

    Among factors potentially involved in the increased prevalence of allergic diseases, modification of the intestinal bacteria flora or lack of bacterial stimulation during childhood has been proposed. Lactic acid bacteria (LAB) present in fermented foods or belonging to the natural intestinal microflora were shown to exert beneficial effects on human health. Recent reports have indicated their capacity to reduce allergic symptoms. The purpose of this investigation was to determine the effect of LAB on the production of type 2 cytokines, which characterize allergic diseases. PBMCs from patients allergic to house dust mite versus those from healthy donors were stimulated for 48 hours with the related Dermatophagoides pteronyssinus allergen or with a staphylococcal superantigen. The effect of LAB preincubation was assessed by measuring the type 2 cytokine production by means of specific ELISA. The tested gram-positive LAB were shown to inhibit the secretion of T(H)2 cytokines (IL-4 and IL-5). This effect was dose dependent and was observed irrespective of the LAB strain used. No significant inhibition was induced by the control, gram-negative Escherichia coli TG1. Interestingly, LAB reduced the T(H)2 cytokine production from allergic PBMCs specifically restimulated with the related allergen. The inhibition mechanism was shown to be dependent on antigen-presenting cells (ie, monocytes) and on the involvement of IL-12 and IFN-gamma. The tested LAB strains were demonstrated to exhibit an anti-T(H)2 activity, and thus different strains of this family might be useful in the prevention of allergic diseases.

  18. Cytokine therapy‐mediated neuroprotection in a Friedreich's ataxia mouse model

    Science.gov (United States)

    Cerminara, Nadia; Hares, Kelly; Redondo, Juliana; Cook, Amelia J.; Haynes, Harry R.; Burton, Bronwen R.; Pook, Mark; Apps, Richard; Scolding, Neil J.; Wilkins, Alastair

    2017-01-01

    Objectives Friedreich's ataxia is a devastating neurological disease currently lacking any proven treatment. We studied the neuroprotective effects of the cytokines, granulocyte‐colony stimulating factor (G‐CSF) and stem cell factor (SCF) in a humanized murine model of Friedreich's ataxia. Methods Mice received monthly subcutaneous infusions of cytokines while also being assessed at monthly time points using an extensive range of behavioral motor performance tests. After 6 months of treatment, neurophysiological evaluation of both sensory and motor nerve conduction was performed. Subsequently, mice were sacrificed for messenger RNA, protein, and histological analysis of the dorsal root ganglia, spinal cord, and cerebellum. Results Cytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological, and behavioural deficits associated with Friedreich's ataxia. Both G‐CSF and SCF had pronounced effects on frataxin levels (the primary molecular defect in the pathogenesis of the disease) and a regulators of frataxin expression. Sustained improvements in motor coordination and locomotor activity were observed, even after onset of neurological symptoms. Treatment also restored the duration of sensory nerve compound potentials. Improvements in peripheral nerve conduction positively correlated with cytokine‐induced increases in frataxin expression, providing a link between increases in frataxin and neurophysiological function. Abrogation of disease‐related pathology was also evident, with reductions in inflammation/gliosis and increased neural stem cell numbers in areas of tissue injury. Interpretation These experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease‐modifying, and neuroprotective treatment for Friedreich's ataxia. Ann Neurol 2017;81:212–226 PMID:28009062

  19. Toll-like receptors regulate B cell cytokine production in patients with diabetes

    Science.gov (United States)

    Jagannathan, M.; McDonnell, M.; Liang, Y.; Hasturk, H.; Hetzel, J.; Rubin, D.; Kantarci, A.; Van Dyke, T. E.; Ganley-Leal, L. M.

    2010-01-01

    Aims/hypothesis Understanding cellular and molecular events in diabetes mellitus will identify new approaches for therapy. Immune system cells are important modulators of chronic inflammation in diabetes mellitus, but the role of B cells is not adequately studied. The aim of this work was to define the function of B cells in diabetes mellitus patients through focus on B cell responses to pattern recognition receptors. Methods We measured expression and function of Toll-like receptors (TLRs) on peripheral blood B cells from diabetes mellitus patients by flow cytometry and multiplexed cytokine analysis. We similarly analysed B cells from non-diabetic donors and periodontal disease patients as comparative cohorts. Results B cells from diabetes mellitus patients secrete multiple pro-inflammatory cytokines, and IL-8 production is significantly elevated in B cells from diabetic patients compared with those from non-diabetic individuals. These data, plus modest elevation of TLR surface expression, suggest B cell IL-8 hyperproduction is a cytokine-specific outcome of altered TLR function in B cells from diabetes mellitus patients. Altered TLR function is further evidenced by demonstration of an unexpected, albeit modest ‘anti-inflammatory’ function for TLR4. Importantly, B cells from diabetes mellitus patients fail to secrete IL-10, an anti-inflammatory cytokine implicated in inflammatory disease resolution, under a variety of TLR-stimulating conditions. Comparative analyses of B cells from patients with a second chronic inflammatory disease, periodontal disease, indicated that some alterations in B cell TLR function associate specifically with diabetes mellitus. Conclusions/interpretation Altered TLR function in B cells from diabetes mellitus patients increases inflammation by two mechanisms: elevation of pro-inflammatory IL-8 and lack of anti-inflammatory/protective IL-10 production. PMID:20383694

  20. [Role of cytokines in the central nervous system].

    Science.gov (United States)

    Benavides, J; Toulmond, S

    1993-01-01

    Cytokines were first characterized as high-molecular weight modulators of the immune response. However they also play an important role in the CNS. Thus, some cytokines could influence the synaptic transmission or modulate the neuronal and glial growth during brain development or after brain injury. Activated glial cells appear to be the major cytokines producing cells. Some of these cytokines are glial cells mitogens, whilst others have a direct neurotrophic activity. These effects seem to be mediated by receptors similar to those of neurotrophic factors. Cytokines might be crucial factors in the evolution of different acute or chronic neuropathological processes such as ischemia, brain trauma, multiple sclerosis and Alzheimer's disease. Control of their effect on brain cells could allow prevention of brain damage observed in such pathologies.

  1. The inflammatory cytokines: molecular biomarkers for major depressive disorder?

    Science.gov (United States)

    Martin, Charlotte; Tansey, Katherine E; Schalkwyk, Leonard C; Powell, Timothy R

    2015-01-01

    Cytokines are pleotropic cell signaling proteins that, in addition to their role as inflammatory mediators, also affect neurotransmitter systems, brain functionality and mood. Here we explore the potential utility of cytokine biomarkers for major depressive disorder. Specifically, we explore how genetic, transcriptomic and proteomic information relating to the cytokines might act as biomarkers, aiding clinical diagnosis and treatment selection processes. We advise future studies to investigate whether cytokine biomarkers might differentiate major depressive disorder patients from other patient groups with overlapping clinical characteristics. Furthermore, we invite future pharmacogenetic studies to investigate whether early antidepressant-induced changes to cytokine mRNA or protein levels precede behavioral changes and act as longer-term predictors of clinical antidepressant response.

  2. 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.

  3. The role of cytokines in immunological tolerance: potential for therapy.

    Science.gov (United States)

    Harber, M; Sundstedt, A; Wraith, D

    2000-11-27

    Current immunosuppression protocols, although often effective, are nonspecific and therefore hazardous. Consequently, immunological tolerance that is antigen specific and does not globally depress the patient's immune system has become one of the Holy Grails of immunology. Since the discovery that cytokines have immunomodulatory effects, extensive research has investigated the potential of these molecules to induce and maintain specific immunological tolerance in the context of transplantation, allergy and autoimmunity. In this article, we review the possible mechanisms by which cytokines can modulate the immune response and the animal models that frequently confound the theory that a single cytokine, or group of cytokines, can induce tolerance in a predictable manner. Finally, we discuss the role of cytokines at a paracrine level, particularly in the context of inducing and maintaining antigen-specific, regulatory T cells with the clinical potential to suppress specific immune responses.

  4. The role of cytokines in immune changes induced by spaceflight

    Science.gov (United States)

    Sonnenfeld, G.; Miller, E. S.

    1993-01-01

    It has become apparent that spaceflight alters many immune responses. Among the regulatory components of the immune response that have been shown to be affected by spaceflight is the cytokine network. Spaceflight, as well as model systems of spaceflight, have been shown to affect the production and action of various cytokines including interferons, interleukins, colony stimulating factors, and tumor necrosis factors. These changes have been shown not to involve a general shutdown of the cytokine network but, rather, to involve selective alterations of specific cytokine functions by spaceflight. The full breadth of changes in cytokines induced by spaceflight, as well as mechanisms, duration, adaptation, reversibility, and significance to resistance to infection and neoplastic diseases, remains to be established.

  5. Distinctive Design A Practical Guide to a Useful, Beautiful Web

    CERN Document Server

    Dawson, Alexander

    2011-01-01

    Learn to produce a web site that stands out from the crowd One of the web designer's greatest challenges is to create a site distinctive enough to get noticed among the millions of sites already on the web. This book examines the bond between code, content and visuals to guide you through the factors that increase your design's visibility, usability and beauty. Using this practical advice, even web designers who lack strong artistic skills can develop super sites that strengthen the message and stand out from the crowd.Most books focus primarily on graphic design principles; this one shows you

  6. The distinctive biology of cancer in adolescents and young adults.

    Science.gov (United States)

    Bleyer, Archie; Barr, Ronald; Hayes-Lattin, Brandon; Thomas, David; Ellis, Chad; Anderson, Barry

    2008-04-01

    One explanation for the relative lack of progress in treating cancer in adolescents and young adults is that the biology of malignant diseases in this age group is different than in younger and older persons, not only in the spectrum of cancers but also within individual cancer types and within the patient (host). Molecular, epidemiological and therapeutic outcome comparisons offer clues to this distinctiveness in most of the common cancers of adolescents and young adults. Translational and clinical research should not assume that the biology of cancers and patients is the same as in other age groups, and treatment strategies should be tailored to the differences.

  7. Citoquinas en tuberculosis Cytokines in tuberculosis

    Directory of Open Access Journals (Sweden)

    Jaime I. Rodríguez

    1997-04-01

    Full Text Available La tuberculosis continúa siendo un modelo inmunológico para estudiar las infecciones intracelulares. Entenderlos complejos mecanismos de interacción de la micobacteria con el sistema inmune del hospedero permitirá un manejo más racional de los fenómenos clínicos que se presentan en la enfermedad. Las citoquinas desempeñan un papel fundamental tanto en el desarrollo de los mecanismos de inmunidad protectora como en el daño tisular presente en esta enfermedad. La estimulación in vitro de linfocitos de sujetos sanos tuberculino positivos con antígenos específicos induce preferencial mente un patrón de citoquinas tipo I (1'IL-2, 1'IFN-y, ~IL-4, ~IL-5, mientras que en la mayoría de los pacientes no se presenta este patrón. Las citoquinas tipo I conducen a la activación de los macrófagos que a su vez inhiben la replicación de las micobacterias. En el ratón, los macrófagos activados inhiben la micobacteria por medio del óxido nítrico; en los humanos la producción de óxido nítrico por los macrófagos no está plenamente demostrada. Recientemente se ha demostrado que la infección con M. tuberculosis puede inducir apoptosis en los macrófagos infectados. La apoptosis depende de la producción del Factor de Necrosis Tumoral a y de óxido nítrico. Paradójicamente, ellipoarabinomanán manosilado (ManLAM presente en la pared de las micobacterias inhibe la apoptosis. Estos hallazgos muestran un nuevo fenómeno en la interacción micobacteriamacrófago el cual debe estar finamente regulado tanto en el microorganismo como en el hospedero. Tuberculosis continues to be a model to study the immunological aspects of intracellular infections. A better understanding of the mycobacteria.host interaction would allow a more rational approach to the clinical problems of this disease. Cytokines playa key role in the development of protective immunity as well as in the tissue injury that occurs during the disease. In vitro stimulation with

  8. H pylori seropositivity and cytokine gene polymorphisms

    Institute of Scientific and Technical Information of China (English)

    Yasuaki Saijo; Eiji Yoshioka; Tomonori Fukui; Mariko Kawaharada; Fumihiro Sata; Hirokazu Sato; Reiko Kishi

    2007-01-01

    AIM: To investigate whether the pro- and antiinflammatory cytokine gene polymorphisms, IL1B-511C/T,IL1B-31C/T, IL6-634C/G, TNF-1031T/C, TNF-857C/T, and IL10-1082A/G, interact with smoking and drinking habits to influence infection with H pylori.METHODS: The subjects were 410 Japanese transit company employees. C-reactive protein and conventional cardiovascular risk factors were evaluated. Serum anti-H pylori antibodies were measured. The genotypes of IL1B-511C/T, IL1B-31C/T, IL6-634C/G, TNF-1031T/C,TNF-857C/T, and IL10-1082A/G polymorphisms were determined by allelic discrimination using fluorogenic probes and a 5'nuclease assay.RESULTS: In gender- and age-adjusted logistic analyses,the subjects with TNF-857T/T had a significantly lower odds ratio (OR) for H pylori seropositivity (reference -857C/C; OR = 0.15, 95% CI: 0.03-0.59, P = 0.007).After stratification according to smoking and drinking status, among never-smokers, the subjects with IL1B-511C/T had a significantly lower OR (reference -511C/C;OR = 0.30, 95% CI: 0.10-0.90, P = 0.032). Among drinkers in the 1-5 times/wk category, the subjects with IL1B-511T/T had a significantly lower OR (reference C/C; OR = 0.38, 95% CI: 0.16-0.95, P = 0.039), and the subjects with IL1B-31C/T and T/T had a significantly higher OR (reference C/C; C/T: OR = 2.59, 95% CI, P =0.042: 1.04-6.47; C/C: OR = 3.17, 95% CI: 1.23-8.14,P = 0.017). Among current smokers, the subjects with IL6-634C/G had a significantly higher OR (reference C/C;OR = 2.28, 95% CI: 1.13-4.58, P = 0.021). However,the interactions terms between the aforementioned genotypes and lifestyles were not statistically significant.CONCLUSION: Contrary to previous findings, the results herein suggest that the TNF-857T/T genotype may be protective against chronic infection with H pylori. Drinking and smoking habits may influence the effect of cytokine gene polymorphisms. Further studies are required to clarify the effects of the pro- and anti-inflammatory cytokine

  9. Distinct modulation of allergic T cell responses by subcutaneous vs. sublingual allergen-specific immunotherapy

    DEFF Research Database (Denmark)

    Schulten, V; Tripple, V; Aasbjerg, Kristian

    2016-01-01

    injections or SLIT tablets or neither. PBMCs were tested for Timothy grass (TG)-specific cytokine production by ELISPOT after in vitro expansion with TG-peptide pools. Phenotypic characterization of cytokine-producing cells was performed by FACS. RESULTS: In the SCIT group, decreased IL-5 production...... was observed starting 10 months after treatment commenced. At 24 months, T cell responses showed IL-5 levels significantly below the before-treatment baseline. No significant reduction of IL-5 was observed in the SLIT or untreated group. However, a significant transient increase in IL-10 production after 10......: The most dominant immunological changes on a cellular level were a decrease in IL-5 in the SCIT group and a significant, transient increase of IL-10 observed after 10 months of treatment in both treated groups. The distinct routes of AIT administration may induce different immunomodulatory mechanisms...

  10. Polyfunctional and IFN-γ monofunctional human CD4+ T cell populations are molecularly distinct

    Science.gov (United States)

    Burel, Julie G.; Apte, Simon H.; Groves, Penny L.; McCarthy, James S.; Doolan, Denise L.

    2017-01-01

    Pathogen-specific polyfunctional T cell responses have been associated with favorable clinical outcomes, but it is not known whether molecular differences exist between polyfunctional and monofunctional cytokine-producing T cells. Here, we report that polyfunctional CD4+ T cells induced during Plasmodium falciparum (P. falciparum) blood-stage infection in humans have a unique transcriptomic profile compared with IFN-γ monofunctional CD4+ T cells and, thus, are molecularly distinct. The 14-gene signature revealed in P. falciparum–reactive polyfunctional T cells is associated with cytokine signaling and lymphocyte chemotaxis, and systems biology analysis identified IL-27 as an upstream regulator of the polyfunctional gene signature. Importantly, the polyfunctional gene signature is largely conserved in Influenza-reactive polyfunctional CD4+ T cells, suggesting that polyfunctional T cells have core characteristics independent of pathogen specificity. This study provides the first evidence to our knowledge that consistent molecular differences exist between polyfunctional and monofunctional CD4+ T cells. PMID:28194431

  11. A genomic analysis of chicken cytokines and chemokines.

    Science.gov (United States)

    Kaiser, Pete; Poh, Tuang Yeow; Rothwell, Lisa; Avery, Stuart; Balu, Sucharitha; Pathania, Uday S; Hughes, Simon; Goodchild, Marianne; Morrell, Shaun; Watson, Michael; Bumstead, Nat; Kaufman, Jim; Young, John R

    2005-08-01

    As most mechanisms of adaptive immunity evolved during the divergence of vertebrates, the immune systems of extant vertebrates represent different successful variations on the themes initiated in their earliest common ancestors. The genes involved in elaborating these mechanisms have been subject to exceptional selective pressures in an arms race with highly adaptable pathogens, resulting in highly divergent sequences of orthologous genes and the gain and loss of members of gene families as different species find different solutions to the challenge of infection. Consequently, it has been difficult to transfer to the chicken detailed knowledge of the molecular mechanisms of the mammalian immune system and, thus, to enhance the already significant contribution of chickens toward understanding the evolution of immunity. The availability of the chicken genome sequence provides the opportunity to resolve outstanding questions concerning which molecular components of the immune system are shared between mammals and birds and which represent their unique evolutionary solutions. We have integrated genome data with existing knowledge to make a new comparative census of members of cytokine and chemokine gene families, distinguishing the core set of molecules likely to be common to all higher vertebrates from those particular to these 300 million-year-old lineages. Some differences can be explained by the different architectures of the mammalian and avian immune systems. Chickens lack lymph nodes and also the genes for the lymphotoxins and lymphotoxin receptors. The lack of functional eosinophils correlates with the absence of the eotaxin genes and our previously reported observation that interleukin- 5 (IL-5) is a pseudogene. To summarize, in the chicken genome, we can identify the genes for 23 ILs, 8 type I interferons (IFNs), IFN-gamma, 1 colony-stimulating factor (GM-CSF), 2 of the 3 known transforming growth factors (TGFs), 24 chemokines (1 XCL, 14 CCL, 8 CXCL, and 1 CX

  12. Signal 3 cytokines as modulators of primary immune responses during infections: the interplay of type I IFN and IL-12 in CD8 T cell responses.

    Directory of Open Access Journals (Sweden)

    Selina Jessica Keppler

    Full Text Available Signal 3 cytokines, such as IL-12 or type I IFN, support expansion and differentiation of CD8 T cells in vivo. If and how these two signal 3 cytokines compensate each other in T cell activation during different infections is so far unknown. Using CD8 T cells lacking receptors for IL-12, type I IFN or both, we show that the expansion of CD8 T cells depends on type I IFN (LCMV infection, type I IFN and IL-12 (Listeria and vesicular stomatitis virus infection or is largely independent of the two cytokines (vaccinia virus infection. Furthermore, we show that CD8 T cells lacking IL-12 and type I IFN signals are impaired in cytokine production and cytolytic activity in the context of VSV and Listeria infection. These effector CD8 T cells fail to express KLRG1, thereby exhibiting a memory-like phenotype which correlated with lower expression of the transcription factor T-bet and higher expression of Eomes. This indicates that the variable interplay of both signal 3 cytokines is mandatory for cell fate decision of CD8 T cells in the context of different infections. Furthermore our results demonstrate that the pathogen-induced overall inflammatory milieu and not the antigen load and/or the quality of antigen presentation critically determine the signal 3 dependence of CD8 T cells.

  13. Interleukin-6: a cytokine to forget.

    Science.gov (United States)

    Balschun, D; Wetzel, W; Del Rey, A; Pitossi, F; Schneider, H; Zuschratter, W; Besedovsky, H O

    2004-11-01

    It is known that proinflammatory cytokines such as interleukin-6 (IL-6) are expressed in the central nervous system (CNS) during disease conditions and affect several brain functions including memory and learning. In contrast to these effects observed during pathological conditions, here we describe a physiological function of IL-6 in the "healthy" brain in synaptic plasticity and memory consolidation. During long-term potentiation (LTP) in vitro and in freely moving rats, IL-6 gene expression in the hippocampus was substantially increased. This increase was long lasting, specific to potentiation, and was prevented by inhibition of N-methyl-D-aspartate receptors with (+/-)-2-amino-5-phosphonopentanoic acid (AP-5). Blockade of endogenous IL-6 by application of a neutralizing anti-IL-6 antibody 90 min after tetanus caused a remarkable prolongation of LTP. Consistently, blockade of endogenous IL-6, 90 min after hippocampus-dependent spatial alternation learning resulted in a significant improvement of long-term memory. In view of the suggested role of LTP in memory formation, these data implicate IL-6 in the mechanisms controlling the kinetics and amount of information storage.

  14. Involvement of IL-18 in the expansion of unique hepatic T cells with unconventional cytokine profiles during Schistosoma mansoni infection.

    Directory of Open Access Journals (Sweden)

    Keishi Adachi

    Full Text Available Infection with schistosomes invokes severe fibrotic granulomatous responses in the liver of the host. Schistosoma mansoni infection induces dramatic fluctuations in Th1 or Th2 cytokine responses systemically; Th1 reactions are provoked in the early phase, whilst Th2 responses become dominant after oviposition begins. In the liver, various unique immune cells distinct from those of conventional immune competent organs or tissues exist, resulting in a unique immunological environment. Recently, we demonstrated that S. mansoni infection induces unique CD4+ T cell populations exhibiting unconventional cytokine profiles in the liver of mice during the period between Th1- and Th2-phases, which we term the transition phase. They produce both IFN-γ and IL-4 or both IFN-γ and IL-13 simultaneously. Moreover, T cells secreting triple cytokines IFN-γ, IL-13 and IL-4 were also induced. We term these cells Multiple Cytokine Producing Hepatic T cells (MCPHT cells. During the transition phase, when MCPHT cells increase, IL-18 secretion was up-regulated in the liver and sera. In S. mansoni-infected IL-18-deficient mice, expansion of MCPHT cells was curtailed. Thus our data suggest that IL-18 produced during S. mansoni infection play a role in the expansion of MCPHT cells.

  15. Learning from the Messengers: Innate Sensing of Viruses and Cytokine Regulation of Immunity — Clues for Treatments and Vaccines

    Directory of Open Access Journals (Sweden)

    Jesper Melchjorsen

    2013-01-01

    Full Text Available Virus infections are a major global public health concern, and only via substantial knowledge of virus pathogenesis and antiviral immune responses can we develop and improve medical treatments, and preventive and therapeutic vaccines. Innate immunity and the shaping of efficient early immune responses are essential for control of viral infections. In order to trigger an efficient antiviral defense, the host senses the invading microbe via pattern recognition receptors (PRRs, recognizing distinct conserved pathogen-associated molecular patterns (PAMPs. The innate sensing of the invading virus results in intracellular signal transduction and subsequent production of interferons (IFNs and proinflammatory cytokines. Cytokines, including IFNs and chemokines, are vital molecules of antiviral defense regulating cell activation, differentiation of cells, and, not least, exerting direct antiviral effects. Cytokines shape and modulate the immune response and IFNs are principle antiviral mediators initiating antiviral response through induction of antiviral proteins. In the present review, I describe and discuss the current knowledge on early virus–host interactions, focusing on early recognition of virus infection and the resulting expression of type I and type III IFNs, proinflammatory cytokines, and intracellular antiviral mediators. In addition, the review elucidates how targeted stimulation of innate sensors, such as toll-like receptors (TLRs and intracellular RNA and DNA sensors, may be used therapeutically. Moreover, I present and discuss data showing how current antimicrobial therapies, including antibiotics and antiviral medication, may interfere with, or improve, immune response.

  16. Regulation of human cytokines by Cordyceps militaris

    OpenAIRE

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

    2014-01-01

    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 dos...

  17. Regulation of human cytokines by Cordyceps militaris

    OpenAIRE

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

    2014-01-01

    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 dos...

  18. Peripheral T cell cytokine responses for diagnosis of active tuberculosis.

    Directory of Open Access Journals (Sweden)

    Johannes Nemeth

    Full Text Available BACKGROUND: A test for diagnosis of active Tuberculosis (TB from peripheral blood could tremendously improve clinical management of patients. METHODS: Of 178 prospectively enrolled patients with possible TB, 60 patients were diagnosed with pulmonary and 27 patients with extrapulmonary TB. The frequencies of Mycobacterium tuberculosis (MTB specific CD4(+ T cells and CD8(+ T cells producing cytokines were assessed using overnight stimulation with purified protein derivate (PPD or early secretory antigenic target (ESAT-6, respectively. RESULTS: Among patients with active TB, an increased type 1 cytokine profile consisting of mainly CD4(+ T cell derived interferon (IFN-γ was detectable. Despite contributing to the cytokine profile as a whole, the independent diagnostic performance of one cytokine producing T cells as well as polyfunctional T cells was poor. IFN-γ/Interleukin(IL-2 cytokine ratios discriminated best between active TB and other diseases. CONCLUSION: T cells producing one cytokine and polyfunctional T cells have a limited role in diagnosis of active TB. The significant shift from a "memory type" to an "effector type" cytokine profile may be useful for further development of a rapid immune-diagnostic tool for active TB.

  19. Chronic fatigue syndrome and circulating cytokines: A systematic review.

    Science.gov (United States)

    Blundell, S; Ray, K K; Buckland, M; White, P D

    2015-11-01

    There has been much interest in the role of the immune system in the pathophysiology of chronic fatigue syndrome (CFS), as CFS may develop following an infection and cytokines are known to induce acute sickness behaviour, with similar symptoms to CFS. Using the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a search was conducted on PubMed, Web of Science, Embase and PsycINFO, for CFS related-terms in combination with cytokine-related terms. Cases had to meet established criteria for CFS and be compared with healthy controls. Papers retrieved were assessed for both inclusionary criteria and quality. 38 papers met the inclusionary criteria. The quality of the studies varied. 77 serum or plasma cytokines were measured without immune stimulation. Cases of CFS had significantly elevated concentrations of transforming growth factor-beta (TGF-β) in five out of eight (63%) studies. No other cytokines were present in abnormal concentrations in the majority of studies, although insufficient data were available for some cytokines. Following physical exercise there were no differences in circulating cytokine levels between cases and controls and exercise made no difference to already elevated TGF-β concentrations. The finding of elevated TGF-β concentration, at biologically relevant levels, needs further exploration, but circulating cytokines do not seem to explain the core characteristic of post-exertional fatigue.

  20. Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor

    OpenAIRE

    Yamada, Yasuhiro; Kirillova, Irina; Peschon, Jacques J.; Fausto, Nelson

    1997-01-01

    The mechanisms that initiate liver regeneration after resection of liver tissue are not known. To determine whether cytokines are involved in the initiation of liver growth, we studied the regeneration of the liver after partial hepatectomy (PH) in mice lacking type I tumor necrosis factor receptor (TNFR-I). DNA synthesis after PH was severely impaired in these animals, and the expected increases in the binding of the NF-κB and STAT3 transcription factors shortly after...

  1. Importance of IL-10 and IL-17 cytokines in human asthma as studied ...

    African Journals Online (AJOL)

    McRoy

    Importance of IL-10 and IL-17 cytokines in human asthma as studied by ELISPOT ... Detection of cytokines and other functional assays can be used to evaluate an immune ..... differentiate into memory cells with specific cytokine producing or ...

  2. Cytokine profiles in osteoporosis suggest a proresorptive bias.

    Science.gov (United States)

    Azizieh, Fawaz; Raghupathy, Raj; Shehab, Diaa; Al-Jarallah, Khaled; Gupta, Renu

    2017-09-01

    As the immune system is suggested to contribute to the pathophysiology of osteoporosis in menopause, we compared the levels of proresorptive and antiresorptive cytokines produced by peripheral blood mononuclear cells (PBMCs) from postmenopausal women with normal and low bone mineral density (BMD). Seventy-one postmenopausal women were studied; 25 had normal BMD and 46 had low BMD. Participants were categorized as normal (n = 25), osteopenic (n = 31), and osteoporotic (n = 15) based on T-scores. Levels of 10 cytokines produced by mitogen-stimulated PBMCs were measured by Multiplex ELISA. PBMCs from women with low BMD produced higher levels of the proresorptive cytokines tumor necrosis factor-alpha, interleukin (IL)-6, IL-12, and IL-17 (P = 0.014, 0.012, 0.011, and 0.049), and lower levels of the antiresorptive cytokines IL-4, IL-10, and IL-23 (P = 0.003, 0.018, and 0.025) compared with women with normal BMD. Proresorptive cytokines were similar in osteopenic and osteoporotic women, but both had higher levels than women with normal BMD. Osteoporotic women produced lower levels of the antiresorptive cytokines IL-4, IL-10, IL-13, and IL-23 compared with the normal BMD group (P = 0.001, 0.05, 0.05, and 0.026), and lower levels of IL-4 as compared with osteopenic women (P = 0.05). Osteopenic women produced lower levels of IL-4 and IL-10 compared with the normal BMD group (P = 0.025 and 0.038). Ratios of proresorptive to antiresorptive cytokines suggest a stronger proresorptive cytokine bias in women with low BMD. Most of the ratios are lowest in the normal BMD group, modest in osteopenic women, and highest in the osteoporotic group. Women with low BMD have a proresorptive cytokine bias.

  3. The IL-2 cytokine family in cancer immunotherapy.

    Science.gov (United States)

    Sim, Geok Choo; Radvanyi, Laszlo

    2014-08-01

    The use of cytokines from the IL-2 family (also called the common γ chain cytokine family) such as interleukin (IL)-2, IL-7, IL-15, and IL-21 to activate the immune system of cancer patients is one of the most important areas of current cancer immunotherapy research. The infusion of IL-2 at low or high doses for multiple cycles in patients with metastatic melanoma and renal cell carcinoma was the first successful immunotherapy for cancer proving that the immune system could completely eradicate tumor cells under certain conditions. The initial clinical success observed in some IL-2-treated patients encouraged further efforts focused on developing and improving the application of other IL-2 family cytokines (IL-4, IL-7, IL-9, IL-15, and IL-21) that have unique biological effects playing important roles in the development, proliferation, and function of specific subsets of lymphocytes at different stages of differentiation with some overlapping effects with IL-2. IL-7, IL-15, and IL-21, as well as mutant forms or variants of IL-2, are now also being actively pursued in the clinic with some measured early successes. In this review, we summarize the current knowledge on the biology of the IL-2 cytokine family focusing on IL-2, IL-15 and IL-21. We discuss the similarities and differences between the signaling pathways mediated by these cytokines and their immunomodulatory effects on different subsets of immune cells. Current clinical application of IL-2, IL-15 and IL-21 either as single agents or in combination with other biological agents and the limitation and potential drawbacks of these cytokines for cancer immunotherapy are also described. Lastly, we discuss the future direction of research on these cytokines, such as the development of new cytokine mutants and variants for improving cytokine-based immunotherapy through differential binding to specific receptor subunits.

  4. PGE2 Promotes Apoptosis Induced by Cytokine Deprivation through EP3 Receptor and Induces Bim in Mouse Mast Cells

    Science.gov (United States)

    Kovarova, Martina; Koller, Beverly H.

    2014-01-01

    Increased mast cell numbers are observed at sites of allergic inflammation and restoration of normal mast cell numbers is critical to the resolution of these responses. Early studies showed that cytokines protect mast cells from apoptosis, suggesting a simple model in which diminished cytokine levels during resolution leads to cell death. The report that prostaglandins can contribute both to recruitment and to the resolution of inflammation together with the demonstration that mast cells express all four PGE2 receptors raises the question of whether a single PGE2 receptor mediates the ability of PGE2 to regulate mast cell survival and apoptosis. We report here that PGE2 through the EP3 receptor promotes cell death of mast cells initiated by cytokine withdrawal. Furthermore, the ability of PGE2 to limit reconstitution of tissues with cultured mast cells is lost in cell lacking the EP3 receptor. Apoptosis is accompanied by higher dissipation of mitochondrial potential (ΔΨm), increased caspase-3 activation, chromatin condensation, and low molecular weight DNA cleavage. PGE2 augmented cell death is dependent on an increase in intracellular calcium release, calmodulin dependent kinase II and MAPK activation. Synergy between the EP3 pathway and the intrinsic mitochondrial apoptotic pathway results in increased Bim expression and higher sensitivity of mast cells to cytokine deprivation. This supports a model in which PGE2 can contribute to the resolution of inflammation in part by augmenting the removal of inflammatory cells in this case, mast cells. PMID:25054560

  5. Rheumatoid factor and its interference with cytokine measurements

    DEFF Research Database (Denmark)

    Bartels, Else Marie; Falbe Wätjen, Inger; Littrup Andersen, Eva;

    2011-01-01

    Use of cytokines as biomarkers for disease is getting more widespread. Cytokines are conveniently determined by immunoassay, but interference from present antibodies is known to cause problems. In rheumatoid arthritis (RA), interference of rheumatoid factor (RF) may be problematic. RF covers...... a group of autoantibodies from immunoglobulin subclasses and is present in 65-80% of RA patients. Partly removal of RF is possible by precipitation. This study aims at determining the effects of presence of RF in blood and synovial fluid on cytokine measurements in samples from RA patients and finding...

  6. Cytokine-producing T cell subsets in human leishmaniasis

    DEFF Research Database (Denmark)

    Kemp, Kåre

    2000-01-01

    Leishmania specific Th1/Th2 cells have been identified in humans as well as in mice. There is a correlation between the clinical outcome of the infection and the cytokine response profile. Generally, the production of Th2 cytokines leads to severe infection, whereas the production of Th1 cytokine...... cells mutually down-regulate each other. However, the presence of antigen specific regulatory T cell subsets may provide an environment that allows the presence of both Th1 and Th2 cells....

  7. [Mechanically gated cardiac ion channels and their regulation by cytokines].

    Science.gov (United States)

    Kamkin, A G; Makarenko, E Iu

    2012-01-01

    The publication presents discussion of the modern vision of mechanisms of mechanoelectric feedback in heart as well as most recent findings regarding possible regulation of cardiomyocyte mechanically gated ion channels by endogenous compounds of immune origin--cytokines. Special attention is devoted to description of cytokine action on cardiac cells, in particular to nitrogen oxide effects on ionic currents, which contribute to generation of the action potential of the cardiomyocyte. We hypothesize that cytokines can potentially trigger such mechano-dependent cardiac pathologies as arrhythmias and fibrillation.

  8. The cytokines (IFN-gamma, IL-2, IL-4, IL-10, IL-17) and Treg cytokine (TGF-beta1) levels in adults with immune thrombocytopenia.

    Science.gov (United States)

    Ma, Liangliang; Liang, Yan; Fang, Meiyun; Guan, Yanchun; Si, Yang; Jiang, Feng; Wang, Fangting

    2014-09-01

    Previous studies have indicated that autoimmune diseases might be caused by an imbalance of T helper cells (Th), cytokines, and regulatory T cells (Treg) cytokines. We measured the plasma concentrations of Th1-associated cytokines (IFN-gamma, IL-2), Th2 -associated cytokines (IL-4, IL-10), Th17-associated cytokine (IL-17) and Treg -associated cytokine (TGF-beta1) in adult patients with immune thrombocytopenia (ITP) and evaluated their clinical relevance. Plasma IFN-gamma, IL-2, IL-4, IL-10, IL-17 and TGF-beta1 concentrations of 52 ITP patients and 30 age- and sex-matched healthy controls were measured by enzyme-linked immunosorbent assay method (ELISA). Concentration of Th2 cytokines (IL-4 and IL-10) were significantly higher in ITP patients compared to controls (P cytokines (IFN-gamma, IL-2), Th17 cytokine (IL-17) and Treg cytokine (TGF-beta1) were lower in ITP patients (P cytokine concentration among the other subgroups in ITP patients was found. Among the ITP patients, concentration of IFN-gamma correlated positively and significantly with PAIgG (r = 0.48, P = 0.02). A significant correlation was neither found between other cytokine levels and platelet count, nor between cytokine levels and megakaryocytes number, nor between cytokines levels and PAIgG or GPIIb/IIIa and/or GPIb/IX autoantibodies. The present study demonstrates that an imbalance of Th and Treg cytokines may mediate the pathogenesis of ITP.

  9. Distinctiveness of Initial Preform Properties in Renovation

    Directory of Open Access Journals (Sweden)

    V. M. Yaroslavtsev

    2015-01-01

    Full Text Available Technologies of renovation form a special group of resource-and energy saving technological processes as they are, by definition, already aimed either at increasing resource of the objects satisfying needs of the society life support and practical activities in different spheres, or at extension of their life cycle including a reuse of material from which they are made. Renovation is used where there is a material object, which does not meet requirements of standard or technical documentation.A characteristic feature of the renovation technologies is lack of procedure for a choice of the preform as in all cases an initial preform is the renovation object itself. Thus each object, acting as an initial preform, has the exclusively individual properties, including technological ones.Distinctiveness of renovation object properties is correlated, first of all, with the personified conditions of formation and (or change of condition of their properties in time at all stages of life cycle (production – transportation – warehousing – operation starting with a preform material when manufacturing under all types of loadings (technological and operational. As a result each object forms its "history" of loading and damages and, therefore, its information base which has to consider the phenomenon of “heredity of life cycle”. The term "heredity of life cycle" characterizes information support of object at any moment under review, including both information of technological inheritance, and data of operational heredity.As a result at every moment of time we have a product with a set of new, uncertain properties caused by the phenomena of heredity of life cycle. These properties are individual for each object to be renovated, which changed its status for the status of initial preform for different types of renovation technologies. This is one of the most important distinctions of renovation technology from the technology used to manufacture a new

  10. Atopic dermatitis and cytokines: the immunoregulatory and therapeutic implications of cytokines in atopic dermatitis--part II: negative regulation and cytokine therapy in atopic dermatitis.

    Science.gov (United States)

    Noh, Geunwoong; Lee, Jaeho

    2012-09-01

    Atopic dermatitis is an immunologic disease that results in allergic inflammations of the skin. Cytokines are involved in the negative regulation of immunopathogenesis of atopic dermatitis. Negative immune regulation is also achieved by immune cells in addition to cytokines which are subsequently regulated by a counter-regulatory mechanism. Allergen tolerance is an important aspect of the treatment of atopic dermatitis. Recently, the IL-27, IL-21, and IL-10 cytokines were found to be important components of the counter regulatory mechanism that terminates immune response, and protects the host from excessive immune responses. IL-10 and TGF-β are well-known to be involved in the immune tolerance. IL-10 and IFN-γ are promising cytokines with respect to the prevention of allergen sensitization and the induction of allergen-specific tolerance. In particular, IFN-γ has unique tolerogenic effects with respect to pre-sensitized allergens, especially in atopic dermatitis. In this review, the role of cytokines in the immune tolerance and relevant patents are reviewed, and therapeutic strategies are presented based on the immunologic architecture of AD.

  11. Radiolabelled cytokines for imaging chronic inflammation

    Directory of Open Access Journals (Sweden)

    Alberto Signore

    2002-09-01

    Full Text Available Diagnosis and particularly follow-up of chronic inflammatory disorders could be often difficult in clinical practice. Indeed, traditional radiological techniques reveal only structural tissue alterations and are not able to monitor functional changes occurring in tissues affected by chronic inflammation. The continuous advances in the knowledge of the pathophysioloy of chronic disorders, combined with the progress of radiochemistry, led to the development of new specific radiolabelled agents for the imaging of chronic diseases. In this scenario, cytokines, due to their pivotal role in such diseases, represent good candidates as radiopharmaceuticals.O diagnóstico, e particularmente o acompanhamento das doenças inflamatórias crônicas, pode ser freqüentemente muito difícil na prática clínica. As técnicas radiológicas tradicionais revelam somente as alterações teciduais estruturas, não sendo capazes de monitorar as alterações funcionais que ocorrem nesses tecidos afetados pela inflamação crônica. O contínuo avanço no conhecimento da fisiopatologia dessas doenças, combinado com o progresso da radioquímica, levou ao desenvolvimento de novos agentes radiomarcados para a obtenção de imagens de doenças crônicas. Nesse cenário, as citocinas, devido ao papel primordial em tais doenças, apresentam-se como fortes candidatas a radiofármacos.

  12. IL-35 is a novel responsive anti-inflammatory cytokine--a new system of categorizing anti-inflammatory cytokines.

    Science.gov (United States)

    Li, Xinyuan; Mai, Jietang; Virtue, Anthony; Yin, Ying; Gong, Ren; Sha, Xiaojin; Gutchigian, Stefanie; Frisch, Andrew; Hodge, Imani; Jiang, Xiaohua; Wang, Hong; Yang, Xiao-Feng

    2012-01-01

    It remains unknown whether newly identified anti-inflammatory/immunosuppressive cytokine interleukin-35 (IL-35) is different from other anti-inflammatory cytokines such as IL-10 and transforming growth factor (TGF)-β in terms of inhibition of inflammation initiation and suppression of full-blown inflammation. Using experimental database mining and statistical analysis methods we developed, we examined the tissue expression profiles and regulatory mechanisms of IL-35 in comparison to other anti-inflammatory cytokines. Our results suggest that in contrast to TGF-β, IL-35 is not constitutively expressed in human tissues but it is inducible in response to inflammatory stimuli. We also provide structural evidence that AU-rich element (ARE) binding proteins and microRNAs target IL-35 subunit transcripts, by which IL-35 may achieve non-constitutive expression status. Furthermore, we propose a new system to categorize anti-inflammatory cytokines into two groups: (1) the house-keeping cytokines, such as TGF-β, inhibit the initiation of inflammation whereas (2) the responsive cytokines including IL-35 suppress inflammation in full-blown stage. Our in-depth analyses of molecular events that regulate the production of IL-35 as well as the new categorization system of anti-inflammatory cytokines are important for the design of new strategies of immune therapies.

  13. INVESTIGATION OF IMMUNE STATUS AND PRODUCTION CYTOKINE IN THE PATIENTS WITH ATOPIC AND MIXED-TYPE BRONCHIAL ASTHMA

    Directory of Open Access Journals (Sweden)

    A. V. Zurochka

    2009-01-01

    Full Text Available Abstract. We have performed immunophenotyping of lymphocytes, employing a flow cytometry approach, along with evaluation of spontaneous or mitogen-induced production of cytokines (IFNγ, IL-4, IL-1β, IL - 10, in the patients with atopic and bacterial (mixed-type bronchial asthma. We have detected mostly similar changes in lymphocyte parameters. However, among the patients with bacterial asthma, an imbalance of immune cells was more pronounced. Some common alterations of cytokine production were found, i.e., a decrease in IFNγ and IL-1β production, along with increased IL-4 and IL-10. These changes were more significant in the subjects being in acute phase of either atopic, or bacterial asthma. Moreover, IL-10 suppressed IFNγ to higher degree, than IL-4, thus favoring distinct predomination of Th2-type immune response.

  14. Cytokines and Cytokine Profiles in Human Autoimmune Diseases and Animal Models of Autoimmunity

    Directory of Open Access Journals (Sweden)

    Manfred Kunz

    2009-01-01

    Full Text Available The precise pathomechanisms of human autoimmune diseases are still poorly understood. However, a deepened understanding of these is urgently needed to improve disease prevention and early detection and guide more specific treatment approaches. In recent years, many new genes and signalling pathways involved in autoimmunity with often overlapping patterns between different disease entities have been detected. Major contributions were made by experiments using DNA microarray technology, which has been used for the analysis of gene expression patterns in chronic inflammatory and autoimmune diseases, among which were rheumatoid arthritis, systemic lupus erythematosus, psoriasis, systemic sclerosis, multiple sclerosis, and type-1 diabetes. In systemic lupus erythematosus, a so-called interferon signature has been identified. In psoriasis, researchers found a particular immune signalling cluster. Moreover the identification of a new subset of inflammatory T cells, so-called Th17 T cells, secreting interleukin (IL-17 as one of their major cytokines and the identification of the IL-23/IL-17 axis of inflammation regulation, have significantly improved our understanding of autoimmune diseases. Since a plethora of new treatment approaches using antibodies or small molecule inhibitors specifically targeting cytokines, cellular receptors, or signalling mechanisms has emerged in recent years, more individualized treatment for affected patients may be within reach in the future.

  15. Distinct Methylation of IFNG in the Gut

    OpenAIRE

    Gonsky, Rivkah; Deem, Richard L; Targan, Stephan R.

    2009-01-01

    Mucosal expression of proinflammatory cytokines plays a pivotal role in inflammatory bowel disease (IBD) pathogenesis. Epigenetic remodeling of chromatin via DNA methylation regulates gene expression. In this study, IFNG DNA methylation was analyzed within the mucosal compartment in both normal and IBD populations and compared to its peripheral counterparts. Overall IFNG methylation (across eight CpG sites) was significantly lower in lamina propria (LP) T cells compared to peripheral blood (P...

  16. Evidence for a Distinct Kind of Noun.

    Science.gov (United States)

    Soja, Nancy N.

    1994-01-01

    Examined the spontaneous speech of four children and their parents for use of determiners with NP-type nouns and count nouns. Found that the parents made a clear distinction between the two kinds of nouns, omitting determiners with the NP-type nouns but not with the count nouns. The children all made the same distinction by four years of age. (HTH)

  17. Killing and letting die: a defensible distinction.

    Science.gov (United States)

    Cartwright, W

    1996-04-01

    The distinction between killing and letting die is investigated and clarified. It is then argued that in most cases, though not in all, it is worse to kill than to let die. In euthanasia the significance of the distinction is diminished, but still important.

  18. House Dust Mites Confer a Distinct Immunological Feature among Dermatitis

    Directory of Open Access Journals (Sweden)

    Safa Baris

    2016-08-01

    Full Text Available Atopic dermatitis (AD is a heterogeneous disease with regard to clinical phenotype and natural history. We investigated T cell subtypes and cytokine responses in peripheral blood and skin lesions of AD patients with various sensitivities. Immunological studies were performed in 27 subjects: 9 house dust mite (HDM-sensitized; 6 subjects with sensitizations other than HDM; 7 non-allergic AD patients and 5 healthy controls. Among those, skin biopsy samples of 13 subjects were evaluated for immunohistochemical analyses, as well. The mean age was 8.93±5.17 years. HDM-allergic AD emerged as a distinct immunologic phenotype, with higher production of interleukin (IL-4, -5, -2 both at rest and when stimulated by Der p1 or SEB along with higher Th17. As for TH17 cell percentage, it was increased in all AD groups compared to healthy controls, while HDM-allergic group was distinguished with a significantly lower production of IL-17. Patients with sensitizations other than HDM were mostly similar to non-allergic AD, with increased Th17 and CD4+CD69+interferon-gamma (IFN-γ+ T cells percentage. The biopsy of lesional skin showed that HDM-allergic AD had lower IFN-γ and IFN-γ co-expressing CD8+ T cells compared to patients with other sensitizations (p=0.03 and p=0.04, respectively. Among the HDM allergic patients, pairwise comparison of lesional versus non-lesional skin revealed higher CD4+ T cells numbers, expression of forkhead box P3 (Foxp3 and T-cell-specific transcription factor (T-bet (p=0.018, p=0.018, p=0.018, respectively. HDM-allergic AD is a distinct subtype with a predominant skewing in Th2 and higher Th17 cell percentage along with a blunted Th1 response in the skin, all of which may have therapeutic implications.

  19. 29 CFR 18.602 - Lack of personal knowledge.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 1 2010-07-01 2010-07-01 true Lack of personal knowledge. 18.602 Section 18.602 Labor... OFFICE OF ADMINISTRATIVE LAW JUDGES Rules of Evidence Witnesses § 18.602 Lack of personal knowledge. A... witness has personal knowledge of the matter. Evidence to prove personal knowledge may, but need...

  20. Why Art Education Lacks Social Relevance: A Contextual Analysis.

    Science.gov (United States)

    Bersson, Robert

    1987-01-01

    This article examines why both the individual-centered and discipline-centered approaches to art education lack social relevance. Maintains that the lack of a social orientation in these two approaches is due to our social context and our capitalistic system. Proposes that democratic principles serve as the basis of a socially relevant,…

  1. Cytokines as Therapeutic Targets for the Gastrointestinal Manifestations of Scleroderma

    Directory of Open Access Journals (Sweden)

    Jennifer M Raoul

    2004-01-01

    Full Text Available Systemic sclerosis (SSc, or scleroderma, is a connective tissue disorder characterized by progressive fibrosis of the skin and internal organs. It has significance for gastroenterologists because the gastrointestinal tract is involved in 90% of SSc patients, who often present with esophageal dysfunction. Though the exact pathogenesis of SSc is unknown, there is increasing evidence supporting an immune mechanism. Cytokines are the soluble mediators of immune activation, altered fibroblast proliferation and extracellular matrix accumulation in SSc and thereby provide important therapeutic targets. In the present review, the involvement of cytokines in SSc is discussed with particular emphasis on cytokines and growth factors that have been implicated in the disease process and likely play an important role in the gastrointestinal manifestations of scleroderma. The role of cytokines as therapeutic targets in scleroderma forms the basis of this timely review

  2. Cytokine soluble receptors in perinatal and early neonatal life

    Directory of Open Access Journals (Sweden)

    Efthimia Protonotariou

    2003-01-01

    Full Text Available Background: In contrast to cellular receptors, soluble receptors do not enhance the cellular activation because they do not have transmembranic and cytoplasmic parts, acting thereby as endogenous regulatory mechanisms against systemic functions of cytokines.

  3. The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder.

    Science.gov (United States)

    Masi, Anne; Glozier, Nicholas; Dale, Russell; Guastella, Adam J

    2017-04-01

    Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental condition characterized by variable impairments in communication and social interaction as well as restricted interests and repetitive behaviors. Heterogeneity of presentation is a hallmark. Investigations of immune system problems in ASD, including aberrations in cytokine profiles and signaling, have been increasing in recent times and are the subject of ongoing interest. With the aim of establishing whether cytokines have utility as potential biomarkers that may define a subgroup of ASD, or function as an objective measure of response to treatment, this review summarizes the role of the immune system, discusses the relationship between the immune system, the brain, and behavior, and presents previously-identified immune system abnormalities in ASD, specifically addressing the role of cytokines in these aberrations. The roles and identification of biomarkers are also addressed, particularly with respect to cytokine profiles in ASD.

  4. High efficiency cell-specific targeting of cytokine activity

    Science.gov (United States)

    Garcin, Geneviève; Paul, Franciane; Staufenbiel, Markus; Bordat, Yann; van der Heyden, José; Wilmes, Stephan; Cartron, Guillaume; Apparailly, Florence; de Koker, Stefaan; Piehler, Jacob; Tavernier, Jan; Uzé, Gilles

    2014-01-01

    Systemic toxicity currently prevents exploiting the huge potential of many cytokines for medical applications. Here we present a novel strategy to engineer immunocytokines with very high targeting efficacies. The method lies in the use of mutants of toxic cytokines that markedly reduce their receptor-binding affinities, and that are thus rendered essentially inactive. Upon fusion to nanobodies specifically binding to marker proteins, activity of these cytokines is selectively restored for cell populations expressing this marker. This ‘activity-by-targeting’ concept was validated for type I interferons and leptin. In the case of interferon, activity can be directed to target cells in vitro and to selected cell populations in mice, with up to 1,000-fold increased specific activity. This targeting strategy holds promise to revitalize the clinical potential of many cytokines.

  5. [Interleukins network in rheumatoid arthritis pathophysiology: beyond proinflammatory cytokines].

    Science.gov (United States)

    Sánchez-Ramón, Silvia; López-Longo, Francisco Javier; Carreño, Luis

    2011-03-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovitis and progressive destruction of the joint cartilage and underlying bone, together with diverse extra-articular manifestations. Cytokines act as soluble effector mediators of the inflammatory process. Therapeutic neutralization with monoclonal antibodies against the pro-inflammatory cytokines TNF-alpha and interleukin 1 (IL-1) has shown a clear efficacy on inflammation and clinical manifestations of RA, although a percentage of patients do not respond. This review covers new relevant cytokines in the RA physiopathology and potential biomarkers of inflammation. The current challenge is to develop biomarkers that enable an earlier diagnosis, as well as prognostic markers and new therapeutic candidates. Combined administration of several of these cytokines could eventually address a personalized treatment approach for each patient.

  6. Cytokines in bipolar disorder vs. healthy control subjects

    DEFF Research Database (Denmark)

    Munkholm, Klaus; Braüner, Julie Vestergaard; Kessing, Lars Vedel

    2013-01-01

    Bipolar disorder may be associated with peripheral immune system dysfunction; however, results in individual studies are conflicting. Our aim was to systematically review evidence of peripheral cytokine alterations in bipolar disorder integrating findings from various affective states....

  7. The Problem of Anti-Cytokine Therapy in Psoriasis Patients

    Directory of Open Access Journals (Sweden)

    Ramina K. Keshileva, PhD

    2012-09-01

    Full Text Available All forms of psoriasis show an increase in the presence of certain cytokines, including, IL-2, IL-6, IL-8 and TNF-alpha, with the last one revealing direct participation in the pathogenesis of dermatosis as modern biological therapeutic agents act directly on the activation of this cytokine. A study of the cytokine profile shows Th1-type immune response in the psoriasis patients, the severity of which depends upon the clinical form of the dermatosis. In this study, 104 patients with psoriasis were treated using the immunomodulating preparation, polyoxidonium, in a complex therapy. In these patients, the regress of the PASI index was noted, which concurred with the normalization of the known parameters of the cytokines, and primarily, with a reduction in the TNF-alpha level, which clearly demonstrated the therapeutic efficacy of polyoxidonium, the preparation used.

  8. Social conformity despite individual preferences for distinctiveness.

    Science.gov (United States)

    Smaldino, Paul E; Epstein, Joshua M

    2015-03-01

    We demonstrate that individual behaviours directed at the attainment of distinctiveness can in fact produce complete social conformity. We thus offer an unexpected generative mechanism for this central social phenomenon. Specifically, we establish that agents who have fixed needs to be distinct and adapt their positions to achieve distinctiveness goals, can nevertheless self-organize to a limiting state of absolute conformity. This seemingly paradoxical result is deduced formally from a small number of natural assumptions and is then explored at length computationally. Interesting departures from this conformity equilibrium are also possible, including divergence in positions. The effect of extremist minorities on these dynamics is discussed. A simple extension is then introduced, which allows the model to generate and maintain social diversity, including multimodal distinctiveness distributions. The paper contributes formal definitions, analytical deductions and counterintuitive findings to the literature on individual distinctiveness and social conformity.

  9. Morphine reduces local cytokine expression and neutrophil infiltration after incision

    Directory of Open Access Journals (Sweden)

    Li Xiangqi

    2007-10-01

    Full Text Available Abstract Background Inflammation and nociceptive sensitization are hallmarks of tissue surrounding surgical incisions. Recent studies demonstrate that several cytokines may participate in the enhancement of nociception near these wounds. Since opioids like morphine interact with neutrophils and other immunocytes, it is possible that morphine exerts some of its antinociceptive action after surgical incision by altering the vigor of the inflammatory response. On the other hand, keratinocytes also express opioid receptors and have the capacity to produce cytokines after injury. Our studies were directed towards determining if opioids alter cytokine production near incisions and to identify cell populations responsible for producing these cytokines. Results A murine incisional model was used to measure the effects of acute morphine administration (0.1–10 mg/kg on nociceptive thresholds, neutrophil infiltration and cytokine production in hind paw skin 30 minutes and 2 hours after incision. Incised hind paws displayed profound allodynia which was reduced by morphine (0.1–10 mg/kg in the 2 hours following incision. Skin samples harvested from these mice showed enhanced levels of 5 cytokines: IL-1β, IL-6, tumor necrosis factor alpha (TNFα, granulocyte colony stimulating factor (G-CSF and keratinocyte-derived cytokine (KC. Morphine reduced these incision-stimulated levels. Separate analyses measuring myeloperoxidase (MPO and using immunohistochemistry demonstrated that morphine dose-dependently reduced the infiltration of neutrophils into the peri-incisional tissue. The dose of morphine required for reduction of cytokine accumulation, however, was below that required for inhibition of peri-incisional neutrophil infiltration. Additional immunohistochemical studies revealed wound edge keratinocytes as being an important source of cytokines in the acute phase after incision. Conclusion Acute morphine administration of doses as low as 0.1 mg/kg reduces

  10. Nonsteroidal anti-inflammatory drugs may affect cytokine response and benefit healing of combat-related extremity wounds.

    Science.gov (United States)

    Lisboa, Felipe A; Bradley, Matthew J; Hueman, Matthew T; Schobel, Seth A; Gaucher, Beverly J; Styrmisdottir, Edda L; Potter, Benjamin K; Forsberg, Jonathan A; Elster, Eric A

    2017-04-01

    After adequate operative debridement and antimicrobial therapies, combat-related extremity wounds that either heal or fail are both associated with a distinct inflammatory response. Short-term use of nonsteroidal anti-inflammatory drugs in postoperative pain management may affect this response and, by consequence, the healing potential of these wounds. We investigated whether patients treated with nonsteroidal anti-inflammatory drugs had a distinct inflammatory response; different rates of critical colonization, defined as >10(5) colony forming units on quantitative bacteriology; and healing potential. We retrospectively reviewed the records of 73 patients with combat-related extremity wounds. Patients were separated into 2 groups: those who received nonsteroidal anti-inflammatory drugs during the debridement period (nonsteroidal anti-inflammatory drugs group, N = 17) and those who did not (control group; N = 56). Serum and wound tissue samples collected during each operative debridement were measured for 32 known cytokines and tested for quantitative bacteriology, respectively. We compared cytokine concentrations between groups and then designed a logistic regression model to identify variables associated with successful wound healing, while controlling for known confounders. Despite similar demographics and wound characteristics, the nonsteroidal anti-inflammatory drugs group had significant lesser concentrations of inflammatory cytokines, interleukin-2, interleukin-6, interleukin-8, and monocyte chemoattractant protein-1. On multivariate analysis, nonsteroidal anti-inflammatory drug treatment emerged as a predictor of successful wound healing after controlling for known confounders such as wound size, tobacco use, Acute Physiology and Chronic Health Evaluation II score, and critical colonization. Treatment with nonsteroidal anti-inflammatory drugs for postoperative pain management after major combat-related extremity trauma is associated with lesser

  11. Relationship between cytokines and running economy in marathon runners

    Directory of Open Access Journals (Sweden)

    Luna Junior Luiz Antonio

    2016-01-01

    Full Text Available Running economy (RE, expresses the relationship between the energy cost of running (Cr and the work performed by a runner and is an predictor of performance. Given the intense effort of marathon runners during training and competition and the dearth of studies that address performance and cytokines in this population, the objective of the current study was to investigate the relationship between RE and cytokines in marathon runners.

  12. Neuroinflammatory Cytokines-The Common Thread in Alzheimer's Pathogenesis.

    Science.gov (United States)

    Griffin, W Sue T; Barger, Steven W

    2010-01-01

    This article discusses the potential role of the cytokine cycle and its corollary as drivers of the relentless progression of Alzheimer's neuropathologies, whether they are the result of gene mutations, gene polymorphisms, and/or environmental and comorbid conditions. Based on the discovery of cytokine overexpression as an accompaniment to the dementia-related glial activation, the cytokine hypothesis was proposed. This states that in response to the negative impact on neurons of known and unknown risk factors-which include genetic inheritance, comorbid and environmental factors-microglia and astrocytes become activated and produce excess amounts of the immune-modulating cytokine interleukin-1 (IL-1) and the neuritogenic cytokine S100B, respectively. Finding that these glial events occur in fetuses and neonates with Down syndrome provided the first evidence that productive immune responses by activated glia precede rather than follow overt AD-related pathology. This finding can be added to the demonstration of IL-1 induction of amyloid β (Aβ) precursor protein and astrocyte activation with excess production of neuritogenic factor S100B. This combination suggests that IL-1 and S100B overexpression would favor the Aβ production and dystrophic neurite growth necessary for laying down neuritic Aβ plaques. This, together with demonstration of IL-1 induction of excessive production of the precursors of other features common in AD prompted a corollary to the cytokine hypothesis. The corollary states that regardless of the primary cause of the neuronal insult, the result will be chronic glial activation, which in turn will result in further neuronal injury, still more glial activation with excess cytokine expression and so on. This article discusses known causes, genetic and environmental risk factors, and comorbid conditions, and the potential contribution of glial activation with excessive cytokine expression to each.

  13. Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity

    Directory of Open Access Journals (Sweden)

    Bozza Patricia T

    2008-06-01

    Full Text Available Abstract Background Dengue virus pathogenesis is not yet fully understood and the identification of patients at high risk for developing severe disease forms is still a great challenge in dengue patient care. During the present study, we evaluated prospectively the potential of cytokines present in plasma from patients with dengue in stratifying disease severity. Methods Seventeen-cytokine multiplex fluorescent microbead immunoassay was used for the simultaneous detection in 59 dengue patients. GLM models using bimodal or Gaussian family were determined in order to associate cytokines with clinical manifestations and laboratory diagnosis. Results IL-1β, IFN-γ, IL-4, IL-6, IL-13, IL-7 and GM-CSF were significantly increased in patients with severe clinical manifestations (severe dengue when compared to mild disease forms (mild dengue. In contrast, increased MIP-1β levels were observed in patients with mild dengue. MIP-1β was also associated with CD56+NK cell circulating rates. IL-1β, IL-8, TNF-α and MCP-1 were associated with marked thrombocytopenia. Increased MCP-1 and GM-CSF levels correlated with hypotension. Moreover, MIP-1β and IFN-γ were independently associated with both dengue severity and disease outcome. Conclusion Our data demonstrated that the use of a multiple cytokine assay platform was suitable for identifying distinct cytokine profiles associated with the dengue clinical manifestations and severity. MIP-β is indicated for the first time as a good prognostic marker in contrast to IFN-γ that was associated with disease severity.

  14. INVESTIGATION OF CYTOKINE PROFILE IN PATIENTS WITH REACTIVE ARTHRITIS

    Directory of Open Access Journals (Sweden)

    T. V. Gaponova

    2008-01-01

    Full Text Available Abstract. Pathogenesis of reactive arthritis (ReA is not clear yet. Several trials suggest that increased production of proinflammatory cytokines is responsible for development of arthritis in ReA, while other studies report that Th1 cytokine response in ReA is impaired in favor of Th2 response. The aim of our study was to investigate serum levels of cytokines IL-1β, IL-4, IL-6, TNFα, IFNγ and IL-1Ra in the patients with ReA of different etiology, as compared with infection-related arthritis. The results of our study had demonstrated that serum levels of IL-1β and TNFα in the patients with ReA were significantly higher, whereas IL-1Ra, IL-4, IL-6 proved to be significantly lower than in healthy controls. Serum levels of IL-6 were significantly higher in patients with chronic ReA, as compared to the cases of acute and recurrent ReA. No significant differences in cytokine profiles were found between the patients with ReA, and the persons with infection-related arthritis. The data obtained are, generally, suggestive for proinflammatory Th1 cytokine profile in ReA patients studied, this confirming the mostly assumed pathogenetic hypothesis for reactive arthritis where an underlying cytokine imbalance is suggested. (Med. Immunol., 2008, vol. 10, N 2-3, pp 167-172.

  15. Cytokine and Immuno-Gene Therapy for Solid Tumors

    Institute of Scientific and Technical Information of China (English)

    Chuan-Yuan Li; Qian Huang; Hsiang-Fu Kung

    2005-01-01

    Despite recent progress in our understanding of cancer biology and in many areas of cancer treatment, the success rate for cancer therapy remains dismal. Immunotherapy for cancer has long been an exciting field for many cancer researchers due to the possibility to mobilize the body's own immune system to eradicate cancer not only locally but also systemically. Since its initial discovery, cytokine-based immunotherapy has been vigorously and extensively investigated for cancer treatment due to the perception of it as a relatively easily purifiable, injectable form of cancer treatment agent. However, so far most cytokine-based therapy trials have fallen short of expectations. One of main obstacles is the difficulty to achieve therapeutically relevant dosage in patients without generating excessive normal tissue toxicity. The emergence of novel gene therapy approach to deliver therapeutic cytokine to tumors locally generated great excitement since it has the potential of generating sustained high local concentration of immunostimulatory cytokine without raising the systemic levels of the cytokines, which is responsible for most of the observed toxicity. In this review, we will attempt to provide an overview of the field and discuss some of the problems associated with cytokine-based immuno-gene therapy and potential solutions.Cellular & Molecular Immunology. 2005;2(2):81-91.

  16. Cytokine and Immuno-Gene Therapy for Solid Tumors

    Institute of Scientific and Technical Information of China (English)

    Chuan-YuanLi; QianHuang; Hsiang-FuKung

    2005-01-01

    Despite recent progress in our understanding of cancer biology and in many areas of cancer treatment, the success rate for cancer therapy remains dismal. Immunotherapy for cancer has long been an exciting field for many cancer researchers due to the possibility to mobilize the body's own immune system to eradicate cancer not only locally but also systemically. Since its initial discovery, cytokine-based immunotherapy has been vigorously and extensively investigated for cancer treatment due to the perception of it as a relatively easily purifiable, injectable form of cancer treatment agent. However, so far most cytokine-based therapy trials have fallen short ofexpectations. One of main obstacles is the difficulty to achieve therapeutically relevant dosage in patients without generating excessive normal tissue toxicity. The emergence of novel gene therapy approach to deliver therapeutic cytokine to tumors locally generated great excitement since it has the potential of generating sustained high local concentration of immunostimulatory cytokine without raising the systemic levels of the cytokines, which is responsible for most of the observed toxicity. In this review, we will attempt to provide an overview of the field and discuss some of the problems associated with cytokine-based immuno-gene therapy and potential solutions. Cellular & Molecular Immunology. 2005;2(2):81-91.

  17. Cytokines as biomarkers in depressive disorder: current standing and prospects.

    Science.gov (United States)

    Lichtblau, Nicole; Schmidt, Frank M; Schumann, Robert; Kirkby, Kenneth C; Himmerich, Hubertus

    2013-10-01

    The frequently observed co-occurrence of depressive disorders and inflammatory diseases suggests a close connection between the nervous and the immune systems. Increased pro-inflammatory and type 1 cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-α and interferon (IFN)-γ, appear to be an important link. Cytokines are synthesized by immune cells in the blood and peripheral tissues and by glial cells in the central nervous system (CNS). Evidence suggests that the blood-brain barrier (BBB) is permeable to cytokines and immune cells, and that afferent nerves, e.g. the vagus nerve, mediate the communication between peripheral inflammatory processes and CNS. Cytokines such as IL-1ß, TNF-α and IFN-γ seem to contribute to the pathophysiology of depression by activating monoamine reuptake, stimulating the hypothalamic-pituitary-adrenocortical (HPA) axis and decreasing production of serotonin due to increased activity of indolamine-2,3-dioxygenase (IDO). However, critical appraisal of these hypotheses is required, because cytokine elevation is not specific to depression. Moreover, several effective antidepressants such as amitriptyline and mirtazapine have been shown to increase cytokine production. When applying immunomodulatory therapies, these drugs may increase the risk of specific side effects such as infections or interact with antidepressant drugs on important functions of the body such as the coagulation system.

  18. Cytokines in autoimmunity: role in induction, regulation, and treatment.

    Science.gov (United States)

    Moudgil, Kamal D; Choubey, Divaker

    2011-10-01

    Cytokines play a pivotal role in the pathogenesis of autoimmune diseases. The precise triggers for the breakdown of self-tolerance and the subsequent events leading to the induction of pathogenic autoimmune responses remain to be defined for most of the naturally occurring autoimmune diseases. Studies conducted in experimental models of human autoimmune diseases and observations in patients have revealed a general scheme in which proinflammatory cytokines contribute to the initiation and propagation of autoimmune inflammation, whereas anti-inflammatory cytokines facilitate the regression of inflammation and recovery from acute phase of the disease. This idea is embodied in the T helper (Th) 1/Th2 paradigm, which over the past two decades has had a major influence on our thinking about the role of cytokines in autoimmunity. Interestingly, over the past decade, the interleukin (IL)-17/IL-23 axis has rapidly emerged as the new paradigm that has compelled us to critically re-examine the cytokine-driven immune events in the pathogenesis and treatment of autoimmunity. In this 2-volume special issue of the journal, leading experts have presented their research findings and viewpoints on the role of cytokines in the context of specific autoimmune diseases.

  19. Glial cytokines in Alzheimer's disease: review and pathogenic implications.

    Science.gov (United States)

    Mrak, R E; Sheng, J G; Griffin, W S

    1995-08-01

    The roles of activated glia and of glial cytokines in the pathogenesis of Alzheimer's disease are reviewed. Interleukin-1 (IL-1), a microglia-derived acute phase cytokine, activates astrocytes and induces expression of the astrocyte-derived cytokine, S100 beta, which stimulates neurite growth (and thus has been implicated in neuritic plaque formation) and increases intracellular free calcium levels. Interleukin-1 also upregulates expression and processing of beta-amyloid precursor proteins (beta-APPs) (thus favoring beta-amyloid deposition) and induces expression of alpha 1-antichymotrypsin, thromboplastin, the complement protein C3, and apolipoprotein E, all of which are present in neuritic plaques. These cytokines, and the molecular and cellular events that they engender, form a complex of interactions that may be capable of self-propagation, leading to chronic overexpression of glial cytokines with neurodegenerative consequences. Self-propagation may be facilitated by means of several reinforcing feedback loops. beta-Amyloid, for instance, directly activates microglia, thus inducing further IL-1 production, and activates the complement system, which also leads to microglial activation with IL-1 expression. Self-propagation also could result when S100 beta-induced increases in intraneuronal free calcium levels lead to neuronal injury and death with consequent microglial activation. Such chronic, self-propagating, cytokine-mediated molecular and cellular reactions would explain the progressive neurodegeneration and dementia of Alzheimer's disease.

  20. Circulating cytokines and cytokine receptors in infliximab treatment failure due to TNF-α independent Crohn disease

    DEFF Research Database (Denmark)

    Steenholdt, Casper; Coskun, Mehmet; Buhl, Sine;

    2016-01-01

    -IFX antibodies. Circulating cytokines and cytokine receptors were assessed by enzyme-linked immunosorbent assay: granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1α, IL-1β, IL-1Ra, IL-6, IL-10, IL-12p70, soluble TNF receptor (sTNF-R) 1, sTNF-R2, IL-17A, and monocyte chemotactic...... to predominantly TNF-α-independent signaling pathways in their disease. Cytokine and cytokine receptor levels were comparable between patients with nonimmune PK failure and PD failure at time of manifestation of IFX failure, but with higher IL-6 and sTNF-R2 levels among IFX treatment failures as compared...

  1. Role of cytokines in thymus- versus peripherally derived- regulatory T cell differentiation and function

    Directory of Open Access Journals (Sweden)

    jérémie david Goldstein

    2013-06-01

    Full Text Available CD4+CD25+Foxp3+ regulatory T cells (Tregs are essential players in the control of immune responses. Recently, accordingly to their origin, two main subsets of Tregs have been described: thymus-derived Tregs (tTregs and peripherally derived Tregs (pTregs. Numerous signaling pathways including the IL-2/STAT5 or the TGF-β/Smad3 pathways play a crucial role in segregating the two lineages. Here, we review some of the information existing on the distinct requirements of IL-2, TGF-β and TNF-α three major cytokines involved in tTreg and pTreg generation, homeostasis and function. Today it is clear that signaling via the IL-2Rβ chain (CD122 common to IL-2 and IL-15 is required for proper differentiation of tTregs and for tTreg and pTreg survival in the periphery. This notion has led to the development of promising therapeutic strategies based on low-dose IL-2 administration to boost the patients' own Treg compartment and dampen autoimmunity and inflammation. Also, solid evidence points to TGF-β as the master regulator of pTreg differentiation and homeostasis. However, therapeutic administration of TGF-β is difficult to implement due to toxicity and safety issues. Knowledge on the role of TNF-α on the biology of Tregs is fragmentary and inconsistent between mice and humans. Moreover, emerging results from the clinical use of TNF-α inhibitors indicate that part of their anti-inflammatory effect may be dependent on their action on Tregs. Given the profusion of clinical trials testing cytokine administration or blocking to modulate inflammatory diseases, a better knowledge of the effects of cytokines on tTregs and pTregs biology is necessary to improve the efficiency of these immunotherapies.

  2. Sequencing and Gene Expression Analysis of Leishmania tropica LACK Gene.

    Directory of Open Access Journals (Sweden)

    Nour Hammoudeh

    2014-12-01

    Full Text Available Leishmania Homologue of receptors for Activated C Kinase (LACK antigen is a 36-kDa protein, which provokes a very early immune response against Leishmania infection. There are several reports on the expression of LACK through different life-cycle stages of genus Leishmania, but only a few of them have focused on L.tropica.The present study provides details of the cloning, DNA sequencing and gene expression of LACK in this parasite species. First, several local isolates of Leishmania parasites were typed in our laboratory using PCR technique to verify of Leishmania parasite species. After that, LACK gene was amplified and cloned into a vector for sequencing. Finally, the expression of this molecule in logarithmic and stationary growth phase promastigotes, as well as in amastigotes, was evaluated by Reverse Transcription-PCR (RT-PCR technique.The typing result confirmed that all our local isolates belong to L.tropica. LACK gene sequence was determined and high similarity was observed with the sequences of other Leishmania species. Furthermore, the expression of LACK gene in both promastigotes and amastigotes forms was confirmed.Overall, the data set the stage for future studies of the properties and immune role of LACK gene products.

  3. Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis.

    Science.gov (United States)

    Neitzke, Daniel J; Bowers, Jacob S; Andrijauskaite, Kristina; O'Connell, Nathaniel S; Garrett-Mayer, Elizabeth; Wrangle, John; Li, Zihai; Paulos, Chrystal M; Cole, David J; Rubinstein, Mark P

    2017-03-09

    Adoptive cellular therapy (ACT) with the Th17 subset of CD4(+) T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that these cytokines are important for Th17 cells. We found that Th17 cells proliferated in response to IL-2, IL-7, and IL-15 in vitro. However, in contrast to many other T cell subsets, including conventionally activated CD8(+) T cells, we found that Th17 cells were resistant to apoptosis in the absence of IL2Rγ-chain cytokines. To determine whether Th17 cells utilize IL2Rγ-chain cytokines in vivo, we tracked Th17 cell engraftment after adoptive transfer with or without cytokine depletion. Depletion of IL-7 and/or IL-2 decreased initial engraftment, while depletion of IL-15 did not. Supplementation of IL-2 increased initial Th17 engraftment. To assess the clinical relevance of these findings, we treated melanoma-bearing mice with Th17 cell adoptive transfer and concurrent cytokine depletion or supplementation. We found that simultaneous depletion of IL-2 and IL-7 decreased therapeutic efficacy, depletion of IL-15 had no effect, and IL-2 supplementation increased therapeutic efficacy. Our results show that Th17 cells are responsive to IL2Rγ-chain cytokines, and provide insight into the application of these cytokines for Th17-based therapeutic strategies.

  4. Multiparameter fluorescence imaging for quantification of TH-1 and TH-2 cytokines at the single-cell level

    Science.gov (United States)

    Fekkar, Hakim; Benbernou, N.; Esnault, S.; Shin, H. C.; Guenounou, Moncef

    1998-04-01

    Immune responses are strongly influenced by the cytokines following antigenic stimulation. Distinct cytokine-producing T cell subsets are well known to play a major role in immune responses and to be differentially regulated during immunological disorders, although the characterization and quantification of the TH-1/TH-2 cytokine pattern in T cells remained not clearly defined. Expression of cytokines by T lymphocytes is a highly balanced process, involving stimulatory and inhibitory intracellular signaling pathways. The aim of this study was (1) to quantify the cytokine expression in T cells at the single cell level using optical imaging, (2) and to analyze the influence of cyclic AMP- dependent signal transduction pathway in the balance between the TH-1 and TH-2 cytokine profile. We attempted to study several cytokines (IL-2, IFN-(gamma) , IL-4, IL-10 and IL-13) in peripheral blood mononuclear cells. Cells were prestimulated in vitro using phytohemagglutinin and phorbol ester for 36h, and then further cultured for 8h in the presence of monensin. Cells were permeabilized and then simple-, double- or triple-labeled with the corresponding specific fluorescent monoclonal antibodies. The cell phenotype was also determined by analyzing the expression of each of CD4, CD8, CD45RO and CD45RA with the cytokine expression. Conventional images of cells were recorded with a Peltier- cooled CCD camera (B/W C5985, Hamamatsu photonics) through an inverted microscope equipped with epi-fluorescence (Diaphot 300, Nikon). Images were digitalized using an acquisition video interface (Oculus TCX Coreco) in 762 by 570 pixels coded in 8 bits (256 gray levels), and analyzed thereafter in an IBM PC computer based on an intel pentium processor with an adequate software (Visilog 4, Noesis). The first image processing step is the extraction of cell areas using an edge detection and a binary thresholding method. In order to reduce the background noise of fluorescence, we performed an opening

  5. Monoacylglycerol lipase promotes Fcγ receptor-mediated phagocytosis in microglia but does not regulate LPS-induced upregulation of inflammatory cytokines.

    Science.gov (United States)

    Kouchi, Zen

    2015-08-21

    Monoacylglycerol lipase (MAGL) is important for neuroinflammation. However, the regulatory mechanisms underlying its expression and function remain unknown. Lipopolysaccharide (LPS) treatment post-translationally upregulated MAGL expression, whereas it downregulated MAGL transcription through a Stat6-mediated mechanism in microglia. Neither MAGL knockdown nor JZL-184, a selective MAGL inhibitor, suppressed LPS-induced upregulation of inflammatory cytokines in microglia. Moreover, exogenous expression of MAGL in BV-2 microglial cell line, which lacks endogenous MAGL, did not promote the induction of inflammatory cytokines by LPS treatment. Interestingly, MAGL knockdown reduced Fcγ receptor-mediated phagocytosis in primary microglia, and introduction of MAGL into the BV-2 cells increased Fcγ receptor-mediated phagocytosis. Collectively, these results suggest that MAGL regulates phagocytosis, but not LPS-mediated cytokine induction in microglia.

  6. Uncaria tomentosa aqueous-ethanol extract triggers an immunomodulation toward a Th2 cytokine profile.

    Science.gov (United States)

    Domingues, Alexandre; Sartori, Alexandrina; Valente, Ligia Maria Marino; Golim, Marjorie Assis; Siani, Antonio Carlos; Viero, Rosa Marlene

    2011-08-01

    Uncaria tomentosa (Willd.) DC (Rubiaceae) is a large woody vine that is native to the Amazon and Central American rainforests and is used widely in traditional medicine for its immunomodulatory and antiinflammatory activities. The present work used in vivo immunotoxic and in vitro immunomodulatory experiments to investigate the effects of a pentacyclic oxindole alkaloid extract from U. tomentosa bark on lymphocyte phenotype, Th1/Th2 cytokine production, cellular proliferation and cytotoxicity. For the in vivo immunotoxicity testing, BALB/c male mice were treated once a day with 125, 500 or 1250 mg/kg of U. tomentosa extract for 28 days. For the in vitro protocol, lymphocytes were cultured with 10-500 μg/mg of the extract for 48 h. The extract increased the cellularity of splenic white pulp and the thymic medulla and increased the number of T helper lymphocytes and B lymphocytes. Also, a large stimulatory effect on lymphocyte viability was observed. However, mitogen-induced T lymphocyte proliferation was significantly inhibited at higher concentrations of U. tomentosa extract. Furthermore, an immunological polarization toward a Th2 cytokine profile was observed. These results suggest that the U. tomentosa aqueous-ethanol extract was not immunotoxic to mice and was able to modulate distinct patterns of the immune system in a dose-dependent manner. Copyright © 2011 John Wiley & Sons, Ltd.

  7. Actual concepts in rhinosinusitis: a review of clinical presentations, inflammatory pathways, cytokine profiles, remodeling, and management.

    Science.gov (United States)

    Eloy, Philippe; Poirrier, Anne Lise; De Dorlodot, Clotilde; Van Zele, Thibaut; Watelet, Jean Baptiste; Bertrand, Bernard

    2011-04-01

    Rhinosinusitis (RS) is a heterogeneous group of diseases. It is a significant and increasing health problem that affects about 15% of the population in Western countries. It has a substantial impact on patients' health-related quality of life and daily functioning and represents a huge financial burden to society and the health care system as a result of the direct and indirect costs. In addition, RS is not well-understood, and little is known about the etiology and pathophysiology. In the past decade, many papers have been published that have changed our understanding of RS. RS is commonly classified into acute and chronic RS based on symptom duration. In acute RS, an inflammatory reaction initiated by a viral infection characterizes most uncomplicated, mild to moderate cases. Therefore, the first line of treatment for these cases are intranasal steroids and not antibiotics. In severe and complicated cases, antibiotics combined with topical steroids remain the treatment of choice. On the other hand, chronic RS is actually subdivided into two distinct entities (chronic rhinosinusitis with and without polyps), as growing evidence indicates that these entities have specific inflammatory pathways and cytokine profiles. The authors review recent data regarding the clinical presentations, cytokine profiles, tissue remodeling, and modalities of treatment for each form of RS.

  8. Hierarchical effects of pro-inflammatory cytokines on the post-influenza susceptibility to pneumococcal coinfection

    Science.gov (United States)

    Duvigneau, Stefanie; Sharma-Chawla, Niharika; Boianelli, Alessandro; Stegemann-Koniszewski, Sabine; Nguyen, Van Kinh; Bruder, Dunja; Hernandez-Vargas, Esteban A.

    2016-11-01

    In the course of influenza A virus (IAV) infections, a secondary bacterial infection frequently leads to serious respiratory conditions provoking high hospitalization and death tolls. Although abundant pro-inflammatory responses have been reported as key contributing factors for these severe dual infections, the relative contributions of cytokines remain largely unclear. In the current study, mathematical modelling based on murine experimental data dissects IFN-γ as a cytokine candidate responsible for impaired bacterial clearance, thereby promoting bacterial growth and systemic dissemination during acute IAV infection. We also found a time-dependent detrimental role of IL-6 in curtailing bacterial outgrowth which was not as distinct as for IFN-γ. Our numerical simulations suggested a detrimental effect of IFN-γ alone and in synergism with IL-6 but no conclusive pathogenic effect of IL-6 and TNF-α alone. This work provides a rationale to understand the potential impact of how to manipulate temporal immune components, facilitating the formulation of hypotheses about potential therapeutic strategies to treat coinfections.

  9. Characterization of Membrane-shed Microvesicles from Cytokine-stimulated β-Cells Using Proteomics Strategies*

    Science.gov (United States)

    Palmisano, Giuseppe; Jensen, Søren Skov; Le Bihan, Marie-Catherine; Lainé, Jeanne; McGuire, James N.; Pociot, Flemming; Larsen, Martin Røssel

    2012-01-01

    Microparticles and exosomes are two of the most well characterized membrane-derived microvesicles released either directly from the plasma membrane or released through the fusion of intracellular multivesicular bodies with the plasma membrane, respectively. They are thought to be involved in many significant biological processes such as cell to cell communication, rescue from apoptosis, and immunological responses. Here we report for the first time a quantitative study of proteins from β-cell-derived microvesicles generated after cytokine induced apoptosis using stable isotope labeled amino acids in cell culture combined with mass spectrometry. We identified and quantified a large number of β-cell-specific proteins and proteins previously described in microvesicles from other cell types in addition to new proteins located to these vesicles. In addition, we quantified specific sites of protein phosphorylation and N-linked sialylation in proteins associated with microvesicles from β-cells. Using pathway analysis software, we were able to map the most distinctive changes between microvesicles generated during growth and after cytokine stimulation to several cell death and cell signaling molecules including tumor necrosis factor receptor superfamily member 1A, tumor necrosis factor, α-induced protein 3, tumor necrosis factor-interacting kinase receptor-interacting serine-threonine kinase 1, and intercellular adhesion molecule 1. PMID:22345510

  10. Continuous infusion of proinflammatory cytokines into the brain to study brain cytokine induced local and systemic immune effects.

    Science.gov (United States)

    Schöning, B; Elepfandt, P; Lanksch, W R; Volk, H D; Woiciechowsky, C

    1999-07-01

    Proinflammatory cytokines are produced in the brain after various kinds of insult (ischemia, trauma, infection). In this process interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha are most important. These cytokines are key mediators of inflammation. Furthermore, these cytokines can act as neurotransmitters and develop direct effects on the central nervous system (CNS) including fever, sleep and stimulation of the neuroendocrine as well as sympathetic nervous system. Moreover, IL-1beta and TNF-alpha may also be involved in brain repair and regenerating processes. However, most of the data about the role of cytokines in the brain have been obtained from either in vitro studies or bolus injections into the brain parenchyma or cerebroventricular system. On the other hand, it is known that cytokines are released continuously into the brain after a cerebral insult over a period of 24 to 48 h. In order to further complete the knowledge about the interactions between neural and immune cells to overcome the primary insult and initiate repair and regeneration in the CNS, a new animal model of local inflammation reaction was established using chronic intracerebral infusion of rat recombinant cytokines.

  11. Colonic lesions, cytokine profiles, and gut microbiota in plasminogen-deficient mice

    DEFF Research Database (Denmark)

    Vestergaard, Bill; Krych, Lukasz; Lund, Leif R.

    2015-01-01

    Plasminogen-deficient (FVB/NPan-plg(tm1Jld), plg(tm1Jld)) mice, which are widely used as a wound-healing model, are prone to spontaneous rectal prolapses. The aims of this study were 1) to evaluate the fecal microbiome of plg(tm1Jld) mice for features that might contribute to the development...... of rectal prolapses and colonic inflammation and 2) to assess the relevance of the inflammatory phenotype to the variability in wound healing in this model. The (plgtm1Jld) mice exhibited delayed wound healing, and they could be divided into 3 distinct groups that differed according to the time until wound...... closure. Colonic lesions in plg(tm1Jld) mice, which were characterized by necrotizing ulcerations and cystically dilated glands, were restricted to the intermediate and distal parts of the colon. The cytokine profile was indicative of chronic tissue damage, but the genetic modification did not change...

  12. Differentiating the Influences of Aging and Adiposity on Brain Weights, Levels of Serum and Brain Cytokines, Gastrointestinal Hormones, and Amyloid Precursor Protein.

    Science.gov (United States)

    Banks, William A; Abrass, Christine K; Hansen, Kim M

    2016-01-01

    Aging and obesity exert important effects on disease. Differentiating these effects is difficult, however, because weight gain often accompanies aging. Here, we used a nested design of aged, calorically restricted, and refed rats to measure changes in brain and blood levels of cytokines and gastrointestinal hormones, brain amyloid precursor protein levels, and brain and body weights. By comparing groups and using path analysis, we found divergent influences of chronological aging versus body weight, our main findings being (i) changes in whole brain weight and serum macrophage colony-stimulating factor levels correlated better with body weight than with chronological aging, (ii) a decrease in brain cytokines and brain plasminogen activator inhibitor levels correlated better with chronological aging than with body weight, (iii) serum erythropoietin levels were influenced by both body weight and aging, (iv) serum plasminogen activator inhibitor, serum cytokines, and brain tumor necrosis factor were not influenced by aging or body weight, and (v) brain amyloid precursor protein more closely related to body weight and serum levels of gastrointestinal hormones than to brain weight, chronological aging, or cytokines. These findings show that although aging and body weight interact, their influences are distinct not only among various cytokines and hormones but also between the central nervous system and the peripheral tissue compartments.

  13. 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.

  14. Therapeutic modulation of growth factors and cytokines in regenerative medicine.

    Science.gov (United States)

    Ioannidou, Effie

    2006-01-01

    Regeneration that takes place in the human body is limited throughout life. Therefore, when organs are irreparably damaged, they are usually replaced with an artificial device or donor organ. The term "regenerative medicine" covers the restoration or replacement of cells, tissues, and organs. Stem cells play a major role in regenerative medicine by providing the way to repopulate organs damaged by disease. Stem cells have the ability to self renew and to regenerate cells of diverse lineages within the tissue in which they reside. Stem cells could originate from embryos or adult tissues. Growth factors are proteins that may act locally or systemically to affect the growth of cells in several ways. Various cell activities, including division, are influenced by growth factors. Cytokines are a family of low-molecular-weight proteins that are produced by numerous cell types and are responsible for regulating the immune response, inflammation, tissue remodeling and cellular differentiation. Target cells of growth factors and cytokines are mesenchymal, epithelial and endothelial cells. These molecules frequently have overlapping activities and can act in an autocrine or paracrine fashion. A complex network of growth factors and cytokines guides cellular differentiation and regeneration in all organs and tissues. The aim of this paper is to review the role of growth factors and cytokines in different organs or systems and explore their therapeutic application in regenerative medicine. The role of stem cells combined with growth factors and cytokines in the regeneration of vascular and hematopoietic, neural, skeletal, pancreatic, periodontal, and mucosal tissue is reviewed. There is evidence that supports the use of growth factors and cytokines in the treatment of neurological diseases, diabetes, cardiovascular disease, periodontal disease, cancer and its complication, oral mucositis. After solving the ethical issues and establishing clear and reasonable regulations

  15. The influence of traditional herbal formulas on cytokine activity.

    Science.gov (United States)

    Burns, J J; Zhao, Lijun; Taylor, Ethan Will; Spelman, Kevin

    2010-11-28

    Many of the botanical "immunomodulators", a class of herbal medicines widely recognized in traditional medical systems such as Chinese Medicine (TCM) and Ayurvedic Medicine, alter immune function and may offer clinically relevant therapeutics or leads to therapeutics. Many of these traditional remedies are prepared from combinations of medicinal plants which may influence numerous molecular pathways. These effects may differ from the sum of effects from the individual plants and therefore, research demonstrating the effects of the formula is crucial for insights into the effects of traditional remedies. In this review we surveyed the primary literature for research that focused on combinations of medicinal plants and effects on cytokine activity. The results demonstrate that many extracts of herb mixtures have effects on at least one cytokine. The most commonly studies cytokines were IL-4, IL-6, IL-10, TNF and IFN-γ. The majority of the formulas researched derived from TCM. The following formulas had activity on at least three cytokines; Chizukit N, CKBM, Daeganghwal-tang, Food Allergy Formula, Gamcho-Sasim-Tang, Hachimi-jio-gan, Herbkines, Hochuekki, Immune System Formula, Jeo-Dang-Tang, Juzen-taiho-to, Kakkon-to, Kan jang, Mao-Bushi-Saishin-to, MSSM-002, Ninjin-youei-to, PG201, Protec, Qing-huo-bai-du-yin, Qingfu Guanjieshu, Sambucol Active Defense, Seng-fu-tang, Shin-Xiao-Xiang, Tien Hsien, Thuja formula, Unkei-to, Vigconic, Wheeze-relief-formula, Xia-Bai-San, Yangyuk-Sanhwa-Tang, Yi-fey Ruenn-hou, and Yuldahansotang. Of the western based combinations, formulas with Echinacea spp. were common and showed multiple activities. Numerous formulas demonstrated activity on both gene and protein expression. The research demonstrates that the reviewed botanical formulas modulate cytokine activity, although the bulk of the research is in vitro. Therapeutic success using these formulas may be partially due to their effects on cytokines. Further study of phytotherapy on

  16. Plasma Cytokine Levels in Astronauts Before and after Spaceflight

    Science.gov (United States)

    Mehta, Satish K.; Aggarwal, Barat B.; Feiveson, Alan H.; Hammond, Dinne K.; Castro, Victoria A.; Stowe, Raymond; Pierson Duane L.

    2008-01-01

    Space flight is a unique experience and results in adverse effects on human physiology. Changes have been reported in various physiological systems, including musculoskeletal, neurovestibular, cardiovascular, endocrine, immunity and increased latent viral reactivation as well as others. The potential mechanisms behind these changes are not fully understood. Various cytokines such as IL-1, IL-6, TNF and chemokines have been linked to several of these changes, like muscle loss, bone loss, fatigue, sleep deprivation and viral reactivation. Eighteen astronauts (15 M and 3 F) from 8 spaceflights and 10 healthy age-matched adults (6 M, 4 F) were included in the present study. A panel of 21 plasma cytokines was analyzed with the Luminex 100 to measure the cytokines in these subjects 10 days before the flight (L-10), 2-3 hour after landing (R+0), 3 days after landing (R+3), and at their annual medical exam (AME). IL-10, IL-1, IFN-alpha, MCP-1 and IP-10 increased significantly at L-10 as compared with AME levels. IL-6 and IFN-alpha showed significant increases at R + 0 (P less than .05) over their baseline levels (AME). Cytokine levels at R+3 were not significantly different from R+0. IL-10 and IL-6 have been reported to increase in during viral reactivation. These data show that there was a shift from TH1 to TH2 cytokines L-10 and R+0. We also studied viral reactivation in 10 of the 18 subjects included in the present study before, during, and after space flight. Increased salivary varicella zoster virus (VZV) shedding in these subjects was found either during or after the mission. VZV shedding correlated with the increased levels of cytokines especially IL-10 and IL-6. Overall, our data suggests that cytokines may play an important role in regulating adverse changes in astronauts, and further studies are needed to fully understand the mechanism.

  17. The distinctive features for standard Chinese (Putonghua)

    Institute of Scientific and Technical Information of China (English)

    ZHANG Jialu

    2006-01-01

    The distinctive features, which are one of the important research subjects in Phonetics and Phonology and in speech technology also, are the ultimate units of speech. Firstly a phoneme system of the standard Chinese-Putonghua was determined based on the results of cluster analysis of perceptual confusion of speech sounds of Putonghua. Then according to the principle of choice between the two opposites proposed by Jakobson, Fant and Halle, considering the characteristics of Putonghua the distinctive feature values for Initials, Finals and Tones were determined in this paper. And the features have been formulated at both acoustic level and genetic level. The distinctive feature trees of Chinese initials and finals were drawn in addition to the feature tables, in order to understand the distinctive features for individual phoneme easily.

  18. Validity of Sensory Systems as Distinct Constructs

    OpenAIRE

    2014-01-01

    Confirmatory factor analysis testing whether sensory questionnaire items represented distinct sensory system constructs found, using data from two age groups, that such constructs can be measured validly using questionnaire data.

  19. Comparison of microglia and infiltrating CD11c+ cells as antigen presenting cells for T cell proliferation and cytokine response

    DEFF Research Database (Denmark)

    Wlodarczyk, Agnieszka; Løbner, Morten; Cédile, Oriane

    2014-01-01

    BACKGROUND: Tissue-resident antigen-presenting cells (APC) exert a major influence on the local immune environment. Microglia are resident myeloid cells in the central nervous system (CNS), deriving from early post-embryonic precursors, distinct from adult hematopoietic lineages. Dendritic cells...... but detectable levels of all these cytokines. Transforming growth factor beta expression was similar in all three populations. Although CNS-resident and blood-derived CD11c+ cells showed equivalent ability to induce proliferation of myelin oligodendrocyte glycoprotein-immunised CD4+ T cells, CD11c+ microglia...

  20. Chemo-enzymatic synthesis and in vitro cytokine profiling of tailor-made oligofructosides

    Directory of Open Access Journals (Sweden)

    Homann Arne

    2012-11-01

    Full Text Available Abstract Background It is well known that carbohydrates play fundamental roles in cell signaling and infection processes as well as tumor formation and progression. However, the interaction pathways and cellular receptors targeted by carbohydrates and glycoconjugates remain poorly examined and understood. This lack of research stems, at least to a major part, from accessibility problems of large, branched oligosaccharides. Results To test glycan - cell interactions in vitro, a variety of tailored oligosaccharides was synthesized chemo-enzymatically. Glycosyltransferases from the GRAS organisms Bacillus megaterium (SacB and Aspergillus niger (Suc1 were used in this study. Substrate engineering of these glycosyltransferases generally acting on sucrose leads to the controlled formation of novel tailored di-, tri- and tetrasaccharides. Already industrially used as prebiotics in functional food, the immunogenic potential of novel oligosaccharides was characterized in this study. A differential secretion of CXCL8 and CCL2 was observed upon oligosaccharide co-cultivation with colorectal epithelial Caco-2 cells. Conclusion Pure carbohydrates are able to stimulate a cytokine response in human endothelial cells in vitro. The type and amount of cytokine secretion depends on the type of co-cultivated oligosaccharide.

  1. Brain metabolic markers reflect susceptibility status in cytokine gene knockout mice with murine cerebral malaria.

    Science.gov (United States)

    Parekh, Sapan B; Bubb, William A; Hunt, Nicholas H; Rae, Caroline

    2006-11-01

    Treatment of cerebral malaria, a complication of the world's most significant parasitic disease, remains problematic due to lack of understanding of its pathogenesis. Metabolic changes, along with cytokine expression alterations and blood cell sequestration in the brain, have previously been reported during severe disease in human infection and mouse models leading to the "cytopathic hypoxia" and "sequestration" theories of pathogenesis. Here, to determine the robustness of the metabolic changes and their relationship to disease development, we investigated changes in cerebral metabolic markers in a mouse model of cerebral malaria (CM) in wildtype (C57BL/6) and cytokine knockout (TNF(-/-), IFNgamma(-/-) and LTalpha(-/-)) mice using multinuclear magnetic resonance spectroscopy. Mice susceptible to CM (wildtype, TNF(-/-)) showed decreased cerebral glucose use, decreased Krebs cycle metabolism and decreased high-energy phosphates. Conversely, mice resistant to CM (IFNgamma(-/-), LTalpha(-/-)) showed little sign of these effects, despite identical levels of parasitemia. Previously reported changes in lactate were shown to be strain dependent. Elevated glutamine and decreased phosphorylation potential emerged as robust metabolic markers of susceptibility, further implicating the trytophan/NAD(+) pathway in disease development. Thus these metabolic changes are firmly linked both to the immune system response to malaria and to the occurrence of pathogenic changes in experimental CM.

  2. Preferential Th1 cytokine profile of phosphoantigen-stimulated human Vγ9Vδ2 T cells.

    LENUS (Irish Health Repository)

    Dunne, Margaret R

    2010-01-01

    Human Vγ9Vδ2 T cells recognise pyrophosphate-based antigens (phosphoantigens) and have multiple functions in innate and adaptive immunity, including a unique ability to activate other cells of the immune system. We used flow cytometry and ELISA to define the early cytokine profiles of Vγ9Vδ2 T cells stimulated in vitro with isopentenyl pyrophosphate (IPP) and (E)-4-hydroxy-3-methyl-but-2 enyl pyrophosphate (HMB-PP) in the absence and presence of IL-2 and IL-15. We show that fresh Vγ9Vδ2 T cells produce interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) within 4 hours of stimulation with phosphoantigen, but neither IL-10, IL-13, nor IL-17 was detectable up to 72 hours under these conditions. Cytokine production was not influenced by expression or lack, thereof, of CD4 or CD8. Addition of IL-2 or IL-15 caused expansion of IFN-γ-producing Vγ9Vδ2 T cells, but did not enhance IFN-γ secretion after 24-72 hours. Thus, phosphoantigen-stimulated Vγ9Vδ2 T cells have potential as Th1-biasing adjuvants for immunotherapy.

  3. T-Helper Cytokine Profiles in Patients with Kawasaki Disease.

    Science.gov (United States)

    Lee, Sang Bum; Kim, Young Hyun; Hyun, Myung Chul; Kim, Yeo Hyang; Kim, Hee Sun; Lee, Young Hwan

    2015-11-01

    Kawasaki disease is an acute systemic vasculitis of which pathogenesis suspected is caused by immune dysregulation. The goal of this study is to evaluate the activation pattern of T helper cell type 1 (Th1) and T helper cell type 2 (Th2) in patients with Kawasaki disease. Prospective study of 60 patients (male 36, female 24) with diagnosis of Kawasaki disease were enrolled. One hundred and eighty blood samples from these patients were collected according to the different clinical stages {before initial intravenous immunoglobulin (IVIG), 5 days after initial IVIG, 2 months after initial IVIG}. The plasma level of Th1 cytokines; interferon-gamma (IFN-γ) & interleukin (IL)-2 and Th2 cytokines; IL-4 & IL-10 were measured by enzyme-liked immunosorbent assay. In all patients, the plasma level of Th1 cytokines (IFN-γ, IL-2) and Th2 cytokines (IL-4 and IL-10) were markedly elevated during the acute stage of Kawasaki disease. Since then, the plasma level of all these cytokines decreased significantly along with the process of clinical stages. Regardless of the existence of coronary artery lesion or no response to initial IVIG treatment, there were no significant differences between them. These data suggest that both Th1 and Th2 cells may be activated simultaneously during the acute stage of Kawasaki disease. Further studies are therefore required to establish the difference of activation pattern of T helper cells between Kawasaki disease and other inflammatory diseases.

  4. Changes of the cytokine profile in inflammatory bowel diseases

    Institute of Scientific and Technical Information of China (English)

    Gy(o)rgyi Müzes; Béla Molnár; Zsolt Tulassay; Ferenc Sipos

    2012-01-01

    Cytokines are indispensable signals of the mucosaassociated immune system for maintaining normal gut homeostasis.An imbalance of their profile in favour of inflammation initiation may lead to disease states,such as that is observed in inflammatory bowel diseases (IBD).Although Crohn's disease (CD) is often described as a prototype of T-helper 1-type diseases,and ulcerative colitis (UC) is traditionally viewed as a T-helper 2-mediated condition,the classic paradigm,which categorises cytokines into pro-and anti-inflammatory groups,has recently been changed.The inflammation regulatory pathways may not be mutually exclusive as individual cytokines can have diverse and even opposing functions in various clinical and immunological settings.None the less there are many common immunological responses in IBD that are mediated by cytokines.Although they regulate and influence the development,course and recurrence of the inflammatory process,the concrete pathogenic role of these small signaling molecules is sometimes not unambiguous in the subtypes of the disease.Our aim is to review the current information about pro-and anti-inflammatory effects of traditionally studied and recently discovered cytokines in the pathogenesis of UC and CD.The better understanding of their production and functional activity may lead to the development of new therapeutic modalities.

  5. A Review: Inflammatory Process in Alzheimer's Disease, Role of Cytokines

    Directory of Open Access Journals (Sweden)

    Jose Miguel Rubio-Perez

    2012-01-01

    Full Text Available Alzheimer's disease (AD is the most common neurodegenerative disorder to date. Neuropathological hallmarks are β-amyloid (Aβ plaques and neurofibrillary tangles, but the inflammatory process has a fundamental role in the pathogenesis of AD. Inflammatory components related to AD neuroinflammation include brain cells such as microglia and astrocytes, the complement system, as well as cytokines and chemokines. Cytokines play a key role in inflammatory and anti-inflammatory processes in AD. An important factor in the onset of inflammatory process is the overexpression of interleukin (IL-1, which produces many reactions in a vicious circle that cause dysfunction and neuronal death. Other important cytokines in neuroinflammation are IL-6 and tumor necrosis factor (TNF-α. By contrast, other cytokines such as IL-1 receptor antagonist (IL-1ra, IL-4, IL-10, and transforming growth factor (TGF-β can suppress both proinflammatory cytokine production and their action, subsequently protecting the brain. It has been observed in epidemiological studies that treatment with nonsteroidal anti-inflammatory drugs (NSAIDs decreases the risk for developing AD. Unfortunately, clinical trials of NSAIDs in AD patients have not been very fruitful. Proinflammatory responses may be countered through polyphenols. Supplementation of these natural compounds may provide a new therapeutic line of approach to this brain disorder.

  6. Zinc and Regulation of Inflammatory Cytokines: Implications for Cardiometabolic Disease

    Directory of Open Access Journals (Sweden)

    Samir Samman

    2012-07-01

    Full Text Available In atherosclerosis and diabetes mellitus, the concomitant presence of low-grade systemic inflammation and mild zinc deficiency highlights a role for zinc nutrition in the management of chronic disease. This review aims to evaluate the literature that reports on the interactions of zinc and cytokines. In humans, inflammatory cytokines have been shown both to up- and down-regulate the expression of specific cellular zinc transporters in response to an increased demand for zinc in inflammatory conditions. The acute phase response includes a rapid decline in the plasma zinc concentration as a result of the redistribution of zinc into cellular compartments. Zinc deficiency influences the generation of cytokines, including IL-1β, IL-2, IL-6, and TNF-α, and in response to zinc supplementation plasma cytokines exhibit a dose-dependent response. The mechanism of action may reflect the ability of zinc to either induce or inhibit the activation of NF-κB. Confounders in understanding the zinc-cytokine relationship on the basis of in vitro experimentation include methodological issues such as the cell type and the means of activating cells in culture. Impaired zinc homeostasis and chronic inflammation feature prominently in a number of cardiometabolic diseases. Given the high prevalence of zinc deficiency and chronic disease globally, the interplay of zinc and inflammation warrants further examination.

  7. The Common γc-Cytokines and Transplantation Tolerance

    Institute of Scientific and Technical Information of China (English)

    XianchangLi

    2004-01-01

    Transplant rejection, like tolerance, is a T cell-dependent event.There is compelling evidence to suggest that induction of transplant tolerance is an actively learned process in which T cells need to engage with the alloantigens in order to learn to tolerate the allograft. A family of cytokines whose receptors use the same IL-2 receptor γc chain (also called the common γc) plays an important role in regulating multiple aspects of the allograft response (i.e. rejection vs. tolerance). It is undeniable that γc cytokines can drive clonal expansion and effector maturation of alloreactive T cells, and therefore, targeting such cytokines or their receptor components remains an attractive way of blocking transplant rejection. However, we just started to appreciate that γc cytokines also regulate the acquisition of transplant tolerance via programming activated T cells for apoptotic cell death and via guiding the evolution of regulatory T cells. Thus, understanding precisely the role of γc cytokines in regulating T cell homeostasis and T cell regulation is critically important in the induction of transplant tolerance.

  8. The Common γc-Cytokines and Transplantation Tolerance

    Institute of Scientific and Technical Information of China (English)

    Xianchang Li

    2004-01-01

    Transplant rejection, like tolerance, is a T cell-dependent event. There is compelling evidence to suggest that induction of transplant tolerance is an actively learned process in which T cells need to engage with the alloantigens in order to learn to tolerate the allograft. A family of cytokines whose receptors use the same IL-2 receptor γc chain (also called the common γc) plays an important role in regulating multiple aspects of the allograft response (I.e. Rejection vs. Tolerance). It is undeniable that γc cytokines can drive clonal expansion and effector maturation of alloreactive T cells, and therefore, targeting such cytokines or their receptor components remains an attractive way of blocking transplant rejection. However, we just started to appreciate that γc cytokines also regulate the acquisition of transplant tolerance via programming activated T cells for apoptotic cell death and via guiding the evolution of regulatory T cells. Thus, understanding precisely the role of γc cytokines in regulating T cell homeostasis and T cell regulation is critically important in the induction of transplant tolerance.

  9. Serum levels of melatonin and cytokines in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Naser Farhadi

    2014-04-01

    Full Text Available Cytokines are important factors of the immune system in autoimmune diseases such as multiple sclerosis (MS in which damage caused by oxidants plays a major role in the pathology. Melatonin secreted by the pineal gland has recently been considered as an antioxidant. The purpose of this study was to determine the relationship between melatonin and cytokines in patients with MS. Thirty patients with MS and 30 healthy controls were selected. Serum levels of melatonin and cytokines, including interleukin-4, interferon-γ, and tumor necrosis factor alpha (TNF-α, were detected in all participants by the enzyme-linked immunosorbent assay (ELISA method. There was a significant difference between patient and control groups in the levels of melatonin and TNF-α. Also, no significant correlation between the serum levels of melatonin and cytokines in both patient and control groups was seen. We concluded that decrease of melatonin and subsequent increase of pro-inflammatory cytokine, TNF-α, could be a factor in the inflammatory reactions in the pathologic process of MS.

  10. Plasma inflammatory cytokines correlate to the ovarian hyperstimulation syndrome.

    Science.gov (United States)

    Abramov, Y; Schenker, J G; Lewin, A; Friedler, S; Nisman, B; Barak, V

    1996-07-01

    The objective of this study was to follow the kinetics of four inflammatory cytokines in the plasma and ascitic fluid of seven patients who developed severe ovarian hyperstimulation syndrome (OHSS) after induction of ovulation for in-vitro fertilization. Blood samples were obtained from these patients at three different times: upon hospitalization; when significant clinical improvement was evident; and after complete resolution. Samples were analysed for interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor alpha (TNF-alpha). Ascitic fluid was obtained by therapeutic paracentesis from all study patients during the active phase and analysed for these cytokines. Two control groups were available: the first included 15 women undergoing controlled ovarian stimulation for in-vitro fertilization without developing OHSS, while the second consisted of 25 healthy women not undergoing ovulation induction or any other medical treatment. High concentrations of IL-1, IL-6 and TNF-alpha were detected in all individuals upon admission for severe OHSS. Concentrations dropped significantly along with clinical improvement, reaching normal values after complete resolution. A statistically significant correlation was found between plasma cytokine concentrations and certain biological characteristics of the syndrome such as leukocytosis, increased haematocrit, and elevated plasma 17-beta-oestradiol concentrations. Ascitic fluid obtained from the study patients contained high IL-6 and IL-8 concentrations, while other cytokines were unaltered. These results suggest close association between inflammatory cytokines and the pathophysiology of the ovarian hyperstimulation syndrome.

  11. Relationships among prenatal depression, plasma cortisol, and inflammatory cytokines.

    Science.gov (United States)

    Shelton, Melissa M; Schminkey, Donna L; Groer, Maureen W

    2015-05-01

    A secondary pilot study was carried out as part of a larger parent study of thyroid function in pregnancy and postpartum. All women in the parent study (N = 631) had blood samples, demographic data, and measures of perceived stress and dysphoric moods collected between 16 and 26 weeks' gestation. The current study was completed with a subset of 105 pregnant women to examine the relationships among perceived stress, depression, plasma cortisol, and cytokines during the second trimester of pregnancy. Stress was measured using Cohen's Perceived Stress Scale and dysphoric moods using the Profile of Mood States Depression/Dejection Scale. Cytokines were measured by a 12-plex analysis on a Luminex-200, and cortisol was measured by enzyme-linked immunosorbent assay on stored plasma samples. Stress and depression scores were highly correlated, and depressive symptoms were inversely correlated with 3 of the 12 cytokines: interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-7. Cortisol was inversely correlated with proinflammatory cytokines (IL-1β and TNF-α) and anti-inflammatory cytokines (IL-4, IL-5, IL-10, and IL-13). These data support the new conceptualizations of normal pregnancy as an inflammatory state that is carefully regulated, as both excessive and inadequate inflammation are potentially hazardous to the health of the pregnancy and fetus.

  12. Correlation of restenosis after rabbit carotid endarterectomy and inflammatory cytokines

    Institute of Scientific and Technical Information of China (English)

    Jun-Jun Liang; Wei Xue; Li-Zhi Lou; Cheng Liu; Zhao-Fen Wang; Qing-Guo Li; Shao-Hua Huang

    2014-01-01

    Objective:To establish rabbit model of restenosis after carotid endarterectomy surgery, and to study tissue inflammatory cytokines(TNF-α,IL-6) involved in restenosis.Methods:A total of32 rabbits were randomly divided into two groups: model group and control group.The right common carotid artery in rabbits was damaged by carotid endar terectomy in model group.The tissues were harvested at different time points respectively, the pathological changes of the vascular wall after operation were observed at different time points.The changes of expression of tissue vascular wall inflammatory cytokines(TNF-α,IL-6) at different time points after the surgery was observed byRT-PCR, and the changes of serum inflammatory cytokines(TNF-α, IL -6) were detected byELISA.Results:The new intima appeared after7 daysof the injury and reached the peak on28 d which is uneven and significantly thicker than the control group (P<0.01).The tissue inflammatory cytokines(TNF-α,IL-6) were significantly increased after the rabbit common carotid artery injury, which was significant difference compared with normal control group(P<0.05).Conclusions:The tissue inflammatory factors significantly increase after the rabbit carotid artery injury, which suggests the mutual concurrent effects of inflammatory cytokines can result in the proliferation of vascular restenosis.

  13. BASIC AND LABORATORY SCIENCES MURINE CYTOKINE PATTERNS FOLLOWING RUBELLA VACCINATION

    Directory of Open Access Journals (Sweden)

    Piirvanch Farzaneli

    2003-06-01

    Full Text Available Although thorough studies on the immune reponse to rubella have been per¬formed, less attention has been given to the cellular mechanism and mediators that shape the process. Specifically, information concerning the nature of cytokine patterns involved in the immune response to Rubella vaccination is not available. This study deals with cytokine production patterns of spleen cells from Balb/c mice following vaccination with the Takahashi strain of Rubella vaccine. Mice were injected intraperitonealy with Rubella virus and PBS and 7. 10 or 14 days later, spleen cells were separated and cultured with varying doses of virus, con A or only the medium. ELISA assays were performed on supernatants for measure¬ment of IL-4. INF-y and IL-5. LTT (Lymphocyte Transformation Test was also performed. The data indicate variation in cytokine patterns during the time peri¬ods after vaccination. On day 7 a type 1 pattern was observed. The LTT response was also indicative of CMI (Cell Mediated Immunity response on the 7lh and 14"' days while a transient suppression on day 10 was observed. These results indicate a time dependent cytokine response with variation ultimately leading to a domi¬nant type 1 (Tl cytokine response.

  14. Prostaglandin E2 in tick saliva regulates macrophage cell migration and cytokine profile

    Science.gov (United States)

    2013-01-01

    Background Ticks are obligate hematophagous ectoparasites that suppress the host’s immune and inflammatory responses by secreting immuno-modulatory and anti-inflammatory molecules in their saliva. In previous studies we have shown that tick salivary gland extract (SGE) and saliva from Dermacentor variabilis have distinct effects on platelet-derived growth factor (PDGF)-stimulated IC-21 macrophage and NIH3T3-L1 fibroblast migration. Since tick saliva contains a high concentration of prostaglandin E2 (PGE2), a potent modulator of inflammation, we used a PGE2 receptor antagonist to evaluate the role of PGE2 in the different migratory responses induced by saliva and its impact on macrophage cytokine profile. Methods Adult ticks were fed on female New Zealand white rabbits for 5-8 days. Female ticks were stimulated with dopamine/theophylline to induce salivation and saliva was pooled. Competitive enzyme immunoassays (EIA) were used to measure saliva PGE2 content and the changes in macrophage intracellular cyclic adenosine monophosphate (cAMP) levels. The effects of tick saliva on macrophage and fibroblast migration were assessed in the absence and presence of the PGE2 receptor antagonist, AH 6809, using blind well chamber assays. A cytokine antibody array was used to examine the effects of tick saliva on macrophage cytokine secretion. Statistical significance was determined by one-way ANOVA; Student Newman-Kuels post-test was used for multiple comparisons. Results The saliva-induced increase in PDGF-stimulated macrophage migration was reversed by AH 6809. The inhibition of PDGF-stimulated fibroblast migration by saliva was also antagonist-sensitive. Tick saliva induced macrophages to secrete copious amounts of PGE2, and conditioned medium from these cells caused an AH 6809-sensitive inhibition of stimulated fibroblast migration, showing that macrophages can regulate fibroblast activity. We show that tick saliva decreased the secretion of the pro

  15. 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

    encountered TG in vivo, using their responses to classic primary and secondary antigens, keyhole limpet haemocyanin (KLH) and tetanus toxoid (TT), respectively, for comparison. While TG elicited T-cell proliferation kinetics typical of a secondary response, the cytokine profile was distinct from that for TT...

  16. Serum Cytokine Profile by ELISA in Patients with Echinococcal Cysts of the Liver: A Stage-Specific Approach to Assess Their Biological Activity

    Directory of Open Access Journals (Sweden)

    Luca Piccoli

    2012-01-01

    Full Text Available To investigate the usefulness of serum cytokine dosage in the clinical management of cystic echinococcosis (CE, we analyzed serum levels of Th1 and Th2 cytokines in patients with hepatic CE in different cyst stages, CE1-2 (active, CE3a-3b (transitional, and CE4-5 (inactive. Ex vivo assessment of Th1 (IFN-γ and Th2 (IL-4, IL-13, and IL-10 cytokines in sera was carried out using ELISA. IL-10 was undetectable in all serum samples of patients and controls, while a few sera contained measurable amounts of IFN-γ, IL-4, and IL-13. No statistically significant difference was found between the percentages of positive samples for each cytokine and the different groups analyzed (patients/controls, stage, number, location, and size of the cyst, serology, and sex of patients, with the exception of the association of IL-4 and IL-13 with the cyst stage. Overall, this investigation showed many limits of serum cytokine dosage as a marker of biological activity of echinococcal cysts. Because of low sensitivity and lack of specificity of this test, we believe that other ways to evaluate ex vivo biological activity of the cysts should be explored.

  17. Heavy metal mediated innate immune responses of the Indian green frog, Euphlyctis hexadactylus (Anura: Ranidae): Cellular profiles and associated Th1 skewed cytokine response

    Energy Technology Data Exchange (ETDEWEB)

    Jayawardena, Uthpala A.; Ratnasooriya, Wanigasekara D.; Wickramasinghe, Deepthi D.; Udagama, Preethi V., E-mail: dappvr@yahoo.com

    2016-10-01

    Immune cell and cytokine profiles in relation to metal exposure though much studied in mammals has not been adequately investigated in amphibians, due mainly to lack of suitable reagents for cytokine profiling in non-model species. However, interspecies cross reactivity of cytokines permitted us to assay levels of IFNγ, TNFα, IL6 and IL10in a common anuran, the Indian green frog (Euphlyctis hexadactylus), exposed to heavy metals (Cd, Cr, Cu, Zn and Pb, at ~ 5 ppm each) under field and laboratory settings in Sri Lanka. Enumeration of immune cells in blood and melanomacrophages in the liver, assay of serum and hepatic cytokines, and Th1/Th2 cytokine polarisation were investigated. Immune cell counts indicated overall immunosuppression with decreasing total WBC and splenocyte counts while neutrophil/lymphocyte ratio increased with metal exposure, indicating metal mediated stress. Serum IL6 levels of metal exposed frogs reported the highest (~ 9360 pg/mL) of all cytokines tested. Significantly elevated IFNγ production (P < 0.05) was evident in heavy metal exposed frogs. Th1/Th2 cytokine ratio in both serum and liver tissue homogenates was Th1 skewed due to significantly higher production of pro-inflammatory cytokines, IFNγ in serum and TNFα in the liver (P < 0.01).Metal mediated aggregations of melanomacrophages in the liver were positively and significantly (P < 0.05) correlated with the hepatic expression of TNFα, IL6 and IL10 activity. Overall, Th1 skewed response may well be due to oxidative stress mediated nuclear factor κ-light chain enhancer of activated B cells (NFκB) which enhances the transcription of pro-inflammatory cytokines. Xenobiotic stress has recently imposed an unprecedented level of threat to wildlife, particularly to sensitive species such as amphibians. Therefore, understanding the interactions between physiological stress and related immune responses is fundamental to conserve these environmental sentinels in the face of emerging eco

  18. The Asthma Phenotype in the Obese: Distinct or Otherwise?

    Directory of Open Access Journals (Sweden)

    Sherry Farzan

    2013-01-01

    Full Text Available Asthma is a heterogenous disorder that can be classified into several different phenotypes. Recent cluster analyses have identified an “obese-asthma” phenotype which is characterized by late onset, female predominance and lack of atopy. In addition, obesity among early-onset asthmatics clearly exists and heightens the clinical presentation. Observational studies have demonstrated that asthma among the obese has a clinical presentation that is more severe, harder to control, and is not as responsive to standard controller therapies. While weight loss studies have demonstrated improvement in asthma outcomes, further studies need to be performed. The current knowledge of the existence of two obesity-asthma phenotypes (early- versus late-onset asthma should encourage investigators to study these entities separately since just as they have distinct presentations, their course, response to therapies, and weight loss strategies may be different as well.

  19. Distinction of gem spinels from the himalayan mountain belt.

    Science.gov (United States)

    Malsy, Anna; Klemmb, Leonhard

    2010-01-01

    Gem spinel deposits in Myanmar, Vietnam and Tajikistan have their formation in association with Himalayan orogenesis. Gem-quality orange, pink, red and purple spinels from deposits at Mogok (Myanmar), Luc Yen (Vietnam), and Kuh-i-Lal (Tajikistan) have been investigated by 'standard' gemological testing and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). Microscopic examination yielded apatite and calcite inclusions together with octahedral negative crystals to be most frequently present in Mogok spinels. The presence of dislocation systems and titanite inclusions are indicative inclusion features for spinels from Luc Yen. Trace elements such as Ti, Fe, Ni, Zn, Zr and Sn differ slightly in spinels from the sources investigated. A distinction of spinels from these deposits is therefore possible by trace element chemistry. This is especially helpful for gem spinels, which often show few inclusions or completely lack inclusion features.

  20. 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-six pig...... poorly reflected mRNA expression of the pro- and anti-inflammatory cytokines....

  1. Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection

    DEFF Research Database (Denmark)

    Rønn, S G; Börjesson, A; Bruun, C;

    2008-01-01

    The pro-inflammatory cytokines IL-1 and IFNgamma are critical molecules in immune-mediated beta cell destruction leading to type 1 diabetes mellitus. Suppressor of cytokine signalling (SOCS)-3 inhibits the cytokine-mediated destruction of insulinoma-1 cells. Here we investigate the effect of SOCS3...... in primary rodent beta cells and diabetic animal models....

  2. Rheumatoid factor and its interference with cytokine measurements

    DEFF Research Database (Denmark)

    Bartels, Else Marie; Falbe Wätjen, Inger; Littrup Andersen, Eva

    2011-01-01

    Use of cytokines as biomarkers for disease is getting more widespread. Cytokines are conveniently determined by immunoassay, but interference from present antibodies is known to cause problems. In rheumatoid arthritis (RA), interference of rheumatoid factor (RF) may be problematic. RF covers...... possible solutions for recognized problems. IL-1β, IL-4, IL-6, and IL-8 were determined with multiplex immunoassays (MIA) in samples from RA patients prior to and after polyethylene glycol (PEG 6000) precipitation. Presence of RF does interfere with MIA. PEG 6000 precipitation abolishes this RF...... a group of autoantibodies from immunoglobulin subclasses and is present in 65-80% of RA patients. Partly removal of RF is possible by precipitation. This study aims at determining the effects of presence of RF in blood and synovial fluid on cytokine measurements in samples from RA patients and finding...

  3. Cytokine profile in two siblings with neonatal lupus erythematosus.

    Science.gov (United States)

    Shimozawa, Hironori; Kono, Yumi; Matano, Miyuki; Suzuki, Yume; Koike, Yasunori; Yada, Yukari; Yamagata, Takanori; Takahashi, Naoto

    2015-12-01

    We studied the cytokine profile of two siblings with neonatal lupus erythematosus (NLE) born to a mother positive for serum anti-Ro and -La antibodies, who did not receive any medication during the two pregnancies. The first sibling was found to have complete atrioventricular block in utero and became severely ill after birth. He fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis on day 2. The second sibling did not have any fetal symptoms. He was generally stable after birth, but with typical skin rash. Laboratory data suggested that they both had hypercytokinemia during the neonatal period, requiring corticosteroid treatment. Interleukin (IL)-6, interferon-γ, IL-8 and monocyte chemotactic protein-1 were elevated in both cases, while IL-12, IL-13 and IL-17 were elevated only in the second sibling. Comparison of the cytokine profiles suggests the potential roles of different cytokines in the onset and clinical manifestations of NLE.

  4. Cytokines and chemokines in neuromyelitis optica: pathogenetic and therapeutic implications.

    Science.gov (United States)

    Uzawa, Akiyuki; Mori, Masahiro; Masahiro, Mori; Kuwabara, Satoshi

    2014-01-01

    Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extensive transverse myelitis. The discovery of an NMO-specific autoantibody to the aquaporin-4 (AQP4) water channel has improved knowledge of NMO pathogenesis. Many studies have focused on inflammatory and pathological biomarkers of NMO, including cytokines and chemokines. Increased concentrations of T helper (Th)17- and Th2-related cytokines and chemokines may be essential factors for developing NMO inflammatory lesions. For example, interleukin-6 could play important roles in NMO pathogenesis, as it is involved in the survival of plasmablasts that produce anti-AQP4 antibody in peripheral circulation and in the enhancement of inflammation in the central nervous system. Therefore, assessment of these useful biomarkers may become a supportive criterion for diagnosing NMO. Significant advances in the understanding of NMO pathogenesis will lead to the development of novel treatment strategies. This review focuses on the current advances in NMO immunological research, particularly that of cytokines and chemokines.

  5. Serum cytokine levels in Kleine-Levin syndrome

    DEFF Research Database (Denmark)

    Kornum, Birgitte Rahbek; Rico, Thomas; Lin, Ling;

    2015-01-01

    unknown. The objective of this study was to determine serum cytokine levels in patients with KLS during and between episodes. PATIENTS/METHODS: Fifty-two typical KLS patients were included in the study of whom 17 patients donated blood samples both during and between episodes. Blood samples were collected...... in USA, France, and Taiwan in a clinical setting. Processing of the samples was performed at the Stanford Center for Sleep Sciences and Medicine. RESULTS: We did not observe any changes in serum cytokine levels during KLS episodes compared to between episodes. In a small cohort of asymptomatic KLS...... patients and age- and gender matched healthy controls (n = 8/group) whose blood samples were all collected and processed at the same day; asymptomatic KLS patients had significantly higher levels of serum sVCAM1 cytokine compared to healthy controls. CONCLUSION: These data suggest that KLS episodes...

  6. ROCKing cytokine secretion balance in human T cells.

    Science.gov (United States)

    Zanin-Zhorov, Alexandra; Waksal, Samuel D

    2015-04-01

    Balanced regulation of cytokine secretion in T cells is critical for maintenance of immune homeostasis and prevention of autoimmunity. The Rho-associated kinase (ROCK) 2 signaling pathway was previously shown to be involved in controlling of cellular movement and shape. However, recent work from our group and others has demonstrated a new and important role of ROCK2 in regulating cytokine secretion in T cells. We found that ROCK2 promotes pro-inflammatory cytokines such as IL-17 and IL-21, whereas IL-2 and IL-10 secretion are negatively regulated by ROCK2 under Th17-skewing activation. Also, in disease, but not in steady state conditions, ROCK2 contributes to regulation of IFN-γ secretion in T cells from rheumatoid arthritis patients. Thus, ROCK2 signaling is a key pathway in modulation of T-cell mediated immune responses underscoring the therapeutic potential of targeted inhibition of ROCK2 in autoimmunity.

  7. The human kidney as a regulator of body cytokine homeostasis

    Directory of Open Access Journals (Sweden)

    A. Bonanni

    2011-01-01

    Full Text Available Evidence is accumulating that the human kidney is a major site for the removal of several cytokines and growth factors, which can accumulate in body pools in patients with acute and chronic kidney disease (CKD. In addition, progressive renal failure and the increase in circulating proinflammatory cytokines are associated with mortality, suggesting that altered cytokines handling by the kidney is associated with worse outcome. Also, the kidney itself may be damaged by signals arising by endothelia and peripheral tissues during the course of the metabolic syndrome, type 2 diabetes and obesity. In this paper we provide a review of kidney handling of several adipokines and myokines, with special emphasis to interleukin-6 (IL-6, leptin, resistin and transforming growth factor-beta (TGF-beta.

  8. The Role of Cytokines in Breast Cancer Development and Progression

    Science.gov (United States)

    Esquivel-Velázquez, Marcela; Ostoa-Saloma, Pedro; Palacios-Arreola, Margarita Isabel; Nava-Castro, Karen E.; Castro, Julieta Ivonne

    2015-01-01

    Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped into several protein families that are referred to as tumor necrosis factors, interleukins, interferons, and colony-stimulating factors. In recent years, it has become clear that some of these proteins as well as their receptors are produced in the organisms under physiological and pathological conditions. The exact initiation process of breast cancer is unknown, although several hypotheses have emerged. Inflammation has been proposed as an important player in tumor initiation, promotion, angiogenesis, and metastasis, all phenomena in which cytokines are prominent players. The data here suggest that cytokines play an important role in the regulation of both induction and protection in breast cancer. This knowledge could be fundamental for the proposal of new therapeutic approaches to particularly breast cancer and other cancer-related disorders. PMID:25068787

  9. Structural basis of receptor sharing by interleukin 17 cytokines

    Energy Technology Data Exchange (ETDEWEB)

    Ely, Lauren K.; Fischer, Suzanne; Garcia, K. Christopher; Stanford-MED

    2010-02-19

    Interleukin 17 (IL-17)-producing helper T cells (T{sub H}-17 cells), together with their effector cytokines, including members of the IL-17 family, are emerging as key mediators of chronic inflammatory and autoimmune disorders. Here we present the crystal structure of a complex of IL-17 receptor A (IL-17RA) bound to IL-17F in a 1:2 stoichiometry. The mechanism of complex formation was unique for cytokines and involved the engagement of IL-17 by two fibronectin-type domains of IL-17RA in a groove between the IL-17 homodimer interface. Binding of the first receptor to the IL-17 cytokines modulated the affinity and specificity of the second receptor-binding event, thereby promoting heterodimeric versus homodimeric complex formation. IL-17RA used a common recognition strategy to bind to several members of the IL-17 family, which allows it to potentially act as a shared receptor in multiple different signaling complexes.

  10. 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.

  11. Cytokine profile associated with human chronic schistosomiasis mansoni

    Directory of Open Access Journals (Sweden)

    Andréa Magalhães

    2004-08-01

    Full Text Available This study objective was to evaluate the cytokines associated with early events of hepatic fibrosis in schistosomiasis mansoni. Hepatic fibrosis was classified by ultrasonography in 94 patients. Immunological evaluation was performed by measurement of secreted cytokines (interleukin IL-5, IL-10, IL-13, interferon-gamma, tumor necrosis factor-alpha and transforming growth factors-beta in peripherl blood mononuclear cells stimulated by Schistosoma mansoni antigens. Significantly, higher levels of IL-5, IL-10 and IL-13 were found in supernatants of SEA-stimulated PBMC from subjects with degree III hepatic fibrosis as compared to patients with degree I or II fibrosis, Significant increases in IL-5 and IL-13 levels were also observed in some of the subjects who remained untreated for one year following initial assessment and developed more serious fibrosis during this period. The data suggests a role for type 2 cytokines in early stages of hepatic fibrosis in human schistosomiasis mansoni.

  12. Structural basis of receptor sharing by interleukin 17 cytokines

    Science.gov (United States)

    Ely, Lauren K.; Fischer, Suzanne; Garcia, K. Christopher

    2009-01-01

    T helper type 17 (TH-17) cells, together with their effector cytokines including interleukin 17 (IL-17) family members, are emerging as key mediators of chronic inflammatory and autoimmune disorders. Here we present the crystal structure of a 1:2 complex of IL-17RA bound to IL-17F. The manner of complex formation is unique for cytokines, and involves two fibronectin-type domains of IL-17RA engaging IL-17 within a groove between the IL-17 homodimer interface in a knob-and-hole fashion. The first receptor-binding event to the IL-17 cytokines modulates the affinity and specificity of the second receptor-binding event, thereby promoting heterodimeric versus homodimeric complex formation. IL-17RA utilizes a common recognition strategy to bind to several IL-17 family members, allowing it to potentially act as a shared receptor within multiple different signaling complexes. PMID:19838198

  13. Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis

    Science.gov (United States)

    Mitchell, Michael J.; Webster, Jamie; Chung, Amanda; Guimarães, Pedro P. G.; Khan, Omar F.; Langer, Robert

    2017-03-01

    Physical forces affect tumour growth, progression and metastasis. Here, we develop polymeric mechanical amplifiers that exploit in vitro and in vivo physical forces to increase immune cytokine-mediated tumour cell apoptosis. Mechanical amplifiers, consisting of biodegradable polymeric particles tethered to the tumour cell surface via polyethylene glycol linkers, increase the apoptotic effect of an immune cytokine on tumour cells under fluid shear exposure by as much as 50% compared with treatment under static conditions. We show that targeted polymeric particles delivered to tumour cells in vivo amplify the apoptotic effect of a subsequent treatment of immune cytokine, reduce circulating tumour cells in blood and overall tumour cell burden by over 90% and reduce solid tumour growth in combination with the antioxidant resveratrol. The work introduces a potentially new application for a broad range of micro- and nanoparticles to maximize receptor-mediated signalling and function in the presence of physical forces.

  14. Proinflammatory cytokine levels in patients with conversion disorder.

    Science.gov (United States)

    Tiyekli, Utkan; Calıyurt, Okan; Tiyekli, Nimet Dilek

    2013-06-01

    It was aimed to evaluate the relationship between proinflammatory cytokine levels and conversion disorder both commonly known as stress regulated. Baseline proinflammatory cytokine levels-[Tumour necrosis factor alpha (TNF-α), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6)]-were evaluated with enzyme-linked immunosorbent assay in 35 conversion disorder patients and 30 healthy controls. Possible changes in proinflammatory cytokine levels were evaluated again, after their acute phase in conversion disorder patients. Statistically significant decreased serum TNF-α levels were obtained in acute phase of conversion disorder. Those levels increased after acute conversion phase. There were no statistically significant difference observed between groups in serum IL-1β and (IL-6) levels. Stress associated with conversion disorder may suppress immune function in acute conversion phase and may have diagnostic and therapeutic value.

  15. Anti-cytokine vaccination: a new biotherapy of autoimmunity?

    Science.gov (United States)

    Semerano, Luca; Assier, Eric; Boissier, Marie-Christophe

    2012-09-01

    Anti-cytokine vaccination is an innovative strategy of targeted, active immunotherapy with potential application in autoimmune diseases. The principle is to design molecules capable of triggering a humoral immune response versus a cytokine with a recognized pathogenic role in a given disease. The most used vaccination approach is based on self-protein coupled to a carrier. This strategy proved particular efficacy in models of TNF-α-dependent diseases, and promising results come from recent clinical trials in rheumatoid arthritis and Crohn's disease. The benefit/risk ratio and long term safety of anti-cytokine vaccination need to be determined to further develop this therapeutic strategy. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. MicroRNA-Regulated Proinflammatory Cytokines in Sarcopenia

    Directory of Open Access Journals (Sweden)

    Jingjing Fan

    2016-01-01

    Full Text Available Sarcopenia has been defined as the aging-related disease with the declined mass, strength, and function of skeletal muscle, which is the major cause of frailty and falls in elders. The activation of inflammatory signal pathways due to diseases and aging is suggested to reveal the critical impact on sarcopenia. Several proinflammatory cytokines, especially interleukin-6 (IL-6 and tumor necrosis factor-alpha (TNF-α, play crucial roles in modulation of inflammatory signaling pathway during the aging-related loss of skeletal muscle. MicroRNAs (miRNAs have emerged as the important regulators for the mass and functional maintenance of skeletal muscle through regulating gene expression of proinflammatory cytokines. In this paper, we have systematically discussed regulatory mechanisms of miRNAs for the expression and secretion of inflammatory cytokines during sarcopenia, which will provide some novel targets and therapeutic strategies for controlling aging-related atrophy of skeletal muscle and corresponding chronic inflammatory diseases.

  17. Recent advances in cytokines: Therapeutic implications for inflammatory bowel diseases

    Institute of Scientific and Technical Information of China (English)

    Guillaume Bouguen; Jean-Baptiste Chevaux; Laurent Peyrin-Biroulet

    2011-01-01

    Inflammatory bowel diseases (IBDs) are complex and chronic disabling conditions resulting from a dysregulated dialogue between intestinal microbiota and components of both the innate and adaptive immune systems. Cytokines are essential mediators between activated immune and non-immune cells, including epithelial and mesenchymal cells. They are immunomodulatory peptides released by numerous cells and these have significant effects on immune function leading to the differentiation and survival of T cells. The physiology of IBD is becoming a very attractive field of research for development of new therapeutic agents. These include cytokines involved in intestinal immune inflammation. This review will focus on mechanisms of action of cytokines involved in IBD and new therapeutic opportunities for these diseases.

  18. Mice lacking Axl and Mer tyrosine kinase receptors are susceptible to experimental autoimmune orchitis induction.

    Science.gov (United States)

    Li, Nan; Liu, Zhenghui; Zhang, Yue; Chen, Qiaoyuan; Liu, Peng; Cheng, C Yan; Lee, Will M; Chen, Yongmei; Han, Daishu

    2015-03-01

    The mammalian testis is an immunoprivileged organ where male germ cell autoantigens are immunologically ignored. Both systemic immune tolerance to autoantigens and local immunosuppressive milieu contribute to the testicular immune privilege. Testicular immunosuppression has been intensively studied, but information on systemic immune tolerance to autoantigens is lacking. In the present study, we aimed to determine the role of Axl and Mer receptor tyrosine kinases in maintaining the systemic tolerance to male germ cell antigens using the experimental autoimmune orchitis (EAO) model. Axl and Mer double-knockout (Axl(-/-)Mer(-/-)) mice developed evident EAO after a single immunization with germ cell homogenates emulsified with complete Freund's adjuvant. EAO was characterized by the accumulation of macrophages and T lymphocytes in the testis. Damage to the seminiferous epithelium was also observed. EAO induction was associated with pro-inflammatory cytokine upregulation in the testes, impaired permeability of the blood-testis barrier and generation of autoantibodies against germ cell antigens in Axl(-/-)Mer(-/-) mice. Immunization also induced mild EAO in Axl or Mer single-gene-knockout mice. By contrast, a single immunization failed to induce EAO in wild-type mice. The results indicate that Axl and Mer receptors cooperatively regulate the systemic immune tolerance to male germ cell antigens.

  19. Multiple cytokine expression profiles reveal immune-based differences in occult hepatitis B genotype H-infected Mexican Nahua patients

    Directory of Open Access Journals (Sweden)

    Nora Alma Fierro

    2011-12-01

    Full Text Available A high prevalence of occult hepatitis B (OHB genotype H infections has been observed in the native Mexican Nahua population. In addition, a low incidence of hepatitis B virus (HBV-associated hepatocellular carcinoma has been described in Mexico. The immune response to infection among OHB-infected patients has been poorly evaluated in vivo. Therefore, we assessed the expression profiles of 23 cytokines in OHB genotype H-infected Nahua patients. A total of 41 sera samples from natives of the Nahua community were retrospectively analysed. Based on their HBV antibody profiles, patients were stratified into two groups: OHB patients (n = 21 and patients that had recovered from HBV infection (n = 20. Herein, we report distinctive cytokines profiles in OHB-infected individuals. Compared to healthy controls (n = 20 and patients who resolved HBV infection, OHB-infected patients displayed an increase in interleukin (IL-2 secretion in addition to a characteristic inflammation profile (decrease in IL-8 and tumour necrosis factor-alpha levels and increased levels of tumour growth factor-beta. IL-15 and interferon-gamma levels were reduced in OHB-infected individuals when compared to those patients who resolved HBV infection. In contrast, OHB patients showed an increase in monocyte chemoattractant protein (MCP-1 and MCP-2 compared to healthy controls and patients who resolved HBV infection. These findings suggest that cytokine expression can influence the severity of OHB disease and could lead to new investigation into the treatment of liver and other infectious diseases.

  20. Cell death and inflammation: the case for IL-1 family cytokines as the canonical DAMPs of the immune system.

    Science.gov (United States)

    Martin, Seamus J

    2016-07-01

    It is well known that necrotic cells are capable of promoting inflammation through releasing so-called endogenous 'danger signals' that can promote activation of macrophages, dendritic cells, and other sentinel cells of the innate immune system. However, the identity of these endogenous proinflammatory molecules, also called damage-associated molecular patterns (DAMPs), has been debated since the 'danger model' was first advanced 20 years ago. While a relatively large number of molecules have been proposed to act as DAMPs, little consensus has emerged concerning which of these represent the key activators of sterile inflammation. Here I argue that the canonical DAMPs have long been hiding in plain sight, in the form of members of the extended IL-1 cytokine family (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ). The latter cytokines possess all of the characteristics expected of endogenous DAMPs and initiate inflammation in a manner strikingly similar to that utilized by the other major category of inflammatory triggers, pathogen-associated molecular patterns (PAMPs). Furthermore, many PAMPs upregulate the expression of IL-1 family DAMPs, enabling robust synergy between these distinct classes of inflammatory triggers. Thus, multiple lines of evidence now suggest that IL-1 family cytokines represent the key initiators of necrosis-initiated sterile inflammation, as well as amplifiers of inflammation in response to infection-associated tissue injury.

  1. Cord Blood Cells Responses to IL2, IL7 and IL15 Cytokines for mTOR Expression

    Directory of Open Access Journals (Sweden)

    Anahita Mohammadian

    2017-04-01

    Full Text Available Purpose: Mammalian target of rapamycin (mTORis important in hematopoiesis and affect cell growth,differentiation and survival. Although previous studies were identified the effect of cytokines on the mononuclear cells development however the cytokines effect on mTOR in cord blood mononuclear cells was unclear. The aim of this study was to evaluate mTOR expression in cord blood mononuclear and cord blood stem cells (CD34+ cells in culture conditions for lymphoid cell development. Methods: Isolation of The mononuclear cells (MNCs from umbilical cord blood were done with use of Ficollpaque density gradient. We evaluated cultured cord blood mononuclear and CD34+ cells in presece of IL2, IL7 and IL15 at distinct time points during 21 days by using flow cytometry. In this study, we presented the role of IL2, IL7 and IL15 on the expression of mTOR in cord blood cells. Results: mTOR expression were increased in peresence of IL2, IL7 and IL15 in day 14 and afterword reduced. However in persence of IL2 and IL15 expression of mTOR significantly reduced. mTOR expression in CD34+ cells decreased significantly from day7 to day 21 in culture. Conclusion: cytokines play important role in mTOR expression during hematopoiesis and development of cord blood mononuclear cells.

  2. Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin-20 receptor-related cytokines.

    Directory of Open Access Journals (Sweden)

    Ayako Uto-Konomi

    Full Text Available Homeostatic regulation of epidermal keratinocytes is controlled by the local cytokine milieu. However, a role for suppressor of cytokine signaling (SOCS, a negative feedback regulator of cytokine networks, in skin homeostasis remains unclear. Keratinocyte specific deletion of Socs3 (Socs3 cKO caused severe skin inflammation with hyper-production of IgE, epidermal hyperplasia, and S100A8/9 expression, although Socs1 deletion caused no inflammation. The inflamed skin showed constitutive STAT3 activation and up-regulation of IL-6 and IL-20 receptor (IL-20R related cytokines, IL-19, IL-20 and IL-24. Disease development was rescued by deletion of the Il6 gene, but not by the deletion of Il23, Il4r, or Rag1 genes. The expression of IL-6 in Socs3 cKO keratinocytes increased expression of IL-20R-related cytokines that further facilitated STAT3 hyperactivation, epidermal hyperplasia and neutrophilia. These results demonstrate that skin homeostasis is strictly regulated by the IL-6-STAT3-SOCS3 axis. Moreover, the SOCS3-mediated negative feedback loop in keratinocytes has a critical mechanistic role in the prevention of skin inflammation caused by hyperactivation of STAT3.

  3. Distinctiveness of Saudi Arabian EFL Learners

    Directory of Open Access Journals (Sweden)

    Manssour Habbash

    2016-04-01

    Full Text Available In view of the increasing concern among English language teachers dealing with students from Saudi Arabia, as it manifests in TESOL community discussions, about the uniqueness of Saudi Arabian EFL learners, this paper attempts to document the outcome of a study of their distinctiveness from the perspective of expatriate teachers working for PYPs (Preparatory Year Programs in Saudi Arabia. This study examines the distinctiveness with regard to the learning attitudes of Saudi students that are often cultivated by the culture and academic environment in their homeland. Employing an emic approach for collecting the required data an analysis was carried out in light of the other studies on ‘education’ in Saudi Arabia that have particular reference to the factors that can positively influence student motivation, student success and the academic environment. The findings were used in constructing the rationale behind such distinctiveness. Assuming that the outcome of the discussion on the findings of this exploration can be helpful for teachers in adapting their teaching methodology and improving their teacher efficacy in dealing with students both from the kingdom and in the kingdom, some recommendations are made. Keywords: China Distinctiveness, Saudi Arabian University context, Expatriate teachers’ perspective, Distinctiveness Theory

  4. Association between serum cytokine concentrations and the presence of hypertriglyceridemia.

    Science.gov (United States)

    Mirhafez, Seyed Reza; Tajfard, Mohammad; Avan, Amir; Pasdar, Alireza; Nedaeinia, Reza; Aghasizade, Malihe; Davari, Hafezeh; Manian, Mostafa; Mahdizadeh, Adeleh; Meshkat, Zahra; Movahedi, Ali; Amini, Nahid Ghaed; Eskandari, Nahid; Salehi, Rasoul; Ferns, Gordon A; Ghayour-Mobarhan, Majid

    2016-07-01

    Hypertriglyceridemia is an established risk factor for coronary-heart-disease. Inflammatory cytokines are known to be important mediators of atherogenesis; however, the relationship between the concentrations of specific inflammatory cytokines and the presence of hypertriglyceridemia has not been well established. The purpose of this study was to investigate the relationship between the serum levels of several pro- and anti-inflammatory cytokines and the presence of hypertriglyceridemia. Four hundred and eighty-four subjects with/without established hypertriglyceridemia were recruited. Anthropometric parameters and biochemical analysis (including a full fasting lipid profile) were determined. The serum levels of several cytokines and growth factors including IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, MCP-1, IFN-γ, EGF, and VEGF were measured followed by univariate and multivariate analyses. Individuals with hypertriglyceridemia had a significantly higher body mass index, total-cholesterol and triglyceride, compared to the group without hypertriglyceridemia. Serum levels of MCP-1, TNF-α and IL-8 were significantly higher in subjects with hypertriglyceridemia [e.g., IL-8 from 7.8ng/L (95% CI: 4.6-18.9) versus 5.7ng/L (95% CI: 3.6-11.9), Phypertriglyceridemia. Subjects with serum triglycerides of ≥2.25mmol/L had an altered cytokine-profile, particularly with respect to serum IL-8, MCP-1 and TNF-α, which might partially account for its adverse clinical-consequences. Further-investigations in a large multi-center setting are warranted to unravel the potential functional-importance of these cytokines in individuals with hypertriglyceridemia. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  5. T-2 Toxin Regulated Ganoderma lucidum Induced Cytokine Release

    Directory of Open Access Journals (Sweden)

    Kazem Ahmadi

    2008-01-01

    Full Text Available The water-soluble extract of Ganoderma lucidum (Reishi has been used as immunomodulator to stimulate spleen cells proliferation and cytokine expression. It has also been shown that at some level of exposure, T-2 toxin typically act as immunosuppressive agent and can increase disease susceptibility. The aim of this study was to investigate the effect of T-2 toxin on cytokine production by Ganoderma lucidum (G. lucidum treated-cells. Mice peritoneal macrophages and lymphoid T cells were prepared by usual manner and plated out at 1106 or 1104 cell/well respectively in RPMI 1640 supplemented with 10% FCS, 50 µg streptomycin and 50U penicillin. Cells were incubated with different concentrations of G. lucidum in the presence or absence of 1 ng mL-­1 T-2 toxin at 37°C and 5% CO2 for 48 h. Cell free medium was removed and used for cytokine assay by ELISA method. The results showed that T-2 toxin in the absence of G.lucidum enhanced IL-2, IFN-γ release compared with control group, but it reduced the production of other cytokines. G. lucidum enhanced the production of IL-1β TNF-α, IL-12, IL-2 and IFN-γ compared with control group, but reduced IL-4 and IL-10 release. T-2 toxin, up regulated the enhancement effect of G. lucidum on IFN-γ, IL-2 and TNF-α, but it down regulated its effect on the production of other cytokines. In conclution our results indicate that T-2 toxin at 1 ng mL-1 may augment the immunomodulating effects of G. lucidum on cytokine release.

  6. [Significance of macrophage and cytokines in expression of stone matrix].

    Science.gov (United States)

    Ito, T

    1996-05-01

    (BACKGROUND). Urinary calculus consists of inorganic substances as a major component and organic substances as a minor component. In this study, the organic substances playing an important role in the formation of calculus, such as osteopontin, calprotectin, macrophage and cytokines, are investigated for their significance in the calculus formation mechanism. (METHODS). Using renal tissues of rats having intraperitoneal glyoxylic acid-induced calculus, mode of the expression of osteopontin was examined by in situ hybridization method, immunohistological staining and northern blot method. Then human renal tissues obtained from the nephrectomy specimen conducted for a renal calculus were subjected to immunohistological staining by an enzyme antibody method using antibodies against osteopontin, calprotectin, macrophage and cytokines. (RESULTS). In rats, while the expression of osteopontin mRNA was observed in renal distal tubular cells, no expression was observed in glomerulus or renal interstitial tissues. The level of osteopontin mRNA expression in calculus forming rats was higher than in control rats by northern blot method. In human tissues, all of osteopontin, calprotectin, macrophage exhibited positive results in the renal distal tubular cells and in the calculus nucleus in the renal distal tubular cavity. Calprotectin and macrophage exhibited positive result also in the renal interstitial tissues. Cytokines exhibited positive results for interleukin-1,6, tumor necrosis factor alpha and transforming growth factor beta. Cytokines exhibited positive results in the distal tubular cells. Negative results were observed for interleukin-2,4 and 5. (CONCLUSION). Based on the findings described above, it is concluded that accumulation of macrophage in the renal interstitial tissues takes place and then one type of cytokines sensitive to macrophage is secreted. Subsequently, in the renal distal tubular cells stimulated with macrophage and cytokines, the expression of

  7. 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.

  8. Secretion of immunoregulatory cytokines by mesenchymal stem cells

    Institute of Scientific and Technical Information of China (English)

    Dobroslav; Kyurkchiev; Ivan; Bochev; Ekaterina; Ivanova-Todorova; Milena; Mourdjeva; Tsvetelina; Oreshkova; Kalina; Belemezova; Stanimir; Kyurkchiev

    2014-01-01

    According to the minimal criteria of the International Society of Cellular Therapy, mesenchymal stem cells(MSCs) are a population of undifferentiated cells defined by their ability to adhere to plastic surfaces when cultured under standard conditions, express a certain panel of phenotypic markers and can differentiate into osteogenic, chondrogenic and adipogenic lineages when cultured in specific inducing media. In parallel with their major role as undifferentiated cell reserves, MSCs have immunomodulatory functions which are exerted by direct cell-to-cell contacts, secretion of cytokines and/or by a combination of both mechanisms. There are no convincing data about a principal difference in the profile of cytokines secreted by MSCs isolated from different tissue sources, although some papers report some quantitative but not qualitative differences in cytokine secretion. The present review focuses on the basic cytokines secreted by MSCs as described in the literature by which the MSCs exert immunodulatory effects. It should be pointed out that MSCs themselves are objects of cytokine regulation. Hypothetical mechanisms by which the MSCs exert their immunoregulatory effects are also discussed in this review. These mechanisms may either influence the target immune cells directly or indirectly by affecting the activities of predominantly dendritic cells. Chemokines are also discussed as participants in this process by recruiting cells of the immune systems and thus making them targets of immunosuppression. This review aims to present and discuss the published data and the personal experience of the authors regarding cytokines secreted by MSCs and their effects on the cells of the immune system.

  9. Influence of phthalates on cytokine production in monocytes and macrophages

    DEFF Research Database (Denmark)

    Frohnert, Juliana; Bendtzen, Klaus; Boas, Malene;

    2015-01-01

    BACKGROUND: Phthalates are a group of endocrine disrupting chemicals suspected to influence the immune system. The aim of this systematic review is to summarise the present knowledge on the influence of phthalates on monocyte and macrophage production and secretion of cytokines, an influence which......-α secretion/production from monocytes or macrophages. A summary of cytokine measurements was not possible since few studies were comparable in study design and due to insufficient reporting of raw data for most of the included studies. CONCLUSION: Results from this review have suggested that at least one...

  10. PORCINE CYTOKINE RESPONSES TO PAMP-STRUCTURES IN VITRO

    DEFF Research Database (Denmark)

    Sørensen, Nanna Skall; Skovgaard, Kerstin; Vorsholt, Henriette;

    monitored at mRNA-level only. However, mRNA levels do not always correlate with corresponding protein levels, and translational regulation is abundant, e.g. exerted by microRNAs through inhibition of mRNA-translation. Here, the kinetics and magnitude of induction of cytokines (IFN-α, IL-12 p40, IL-1β, TNF......, with the protein response in most cases being slower than the mRNA response, as expected. Different PAMPs induced different cytokines with varying kinetics of induction. In some cases qPCR appeared more sensitive than ELISA, but to what degree this could be explained by translational inhibition or by different...

  11. The Role of Cytokines and Chemokines in Filovirus Infection

    Directory of Open Access Journals (Sweden)

    Sandra L. Bixler

    2015-10-01

    Full Text Available Ebola- and marburgviruses are highly pathogenic filoviruses and causative agents of viral hemorrhagic fever. Filovirus disease is characterized by a dysregulated immune response, severe organ damage, and coagulation abnormalities. This includes modulation of cytokines, signaling mediators that regulate various components of the immune system as well as other biological processes. Here we examine the role of cytokines in filovirus infection, with an emphasis on understanding how these molecules affect development of the antiviral immune response and influence pathology. These proteins may present targets for immune modulation by therapeutic agents and vaccines in an effort to boost the natural immune response to infection and/or reduce immunopathology.

  12. Exploiting cytokines in adoptive T-cell therapy of cancer.

    Science.gov (United States)

    Petrozziello, Elisabetta; Sturmheit, Tabea; Mondino, Anna

    2015-01-01

    Adoptive immunotherapy with tumor-reactive autologous T cells, either expanded from tumor specimens or genetically engineered to express tumor-reactive T-cell receptors and chimeric antigen receptors, is holding promising results in clinical trials. Several critical issues have been identified and results underline the possibility to exploit cytokines to further ameliorate the efficacy of current treatment protocols, also encompassing adoptive T-cell therapy. Here we review latest developments on the use of cytokines to better direct the nature of the T-cell infusion product, T-cell function and persistence in vivo, as well as to modulate the tumor microenvironment.

  13. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

    Science.gov (United States)

    Handly-Santana, Abram; Biffi, Giulia; Elyada, Ela; Ponz-Sarvise, Mariano; Lee, Eun Jung; Chio, Iok In Christine; Tiriac, Hervé; Feig, Christine; Kultti, Anne; Crawford, James M.; Clevers, Hans; Park, Youngkyu

    2017-01-01

    Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated αSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development. PMID:28232471

  14. On Hobbes’s distinction of accidents

    Directory of Open Access Journals (Sweden)

    Lupoli Agostino

    2012-06-01

    Full Text Available An interpolation introduced by K. Schuhmann in his critical edition of "De corpore" (chap. VI, § 13 diametrically overturns the meaning of Hobbes’s doctrine of distinction of accidents in comparison with all previous editions. The article focuses on the complexity of this crucial juncture in "De corpore" argument on which depends the interpretation of Hobbes’s whole conception of science. It discusses the reasons pro and contra Schuhmann’s interpolation and concludes against it, because it is not compatible with the rationale underlying the complex architecture of "De corpore", which involves a symmetry between the ‘logical’ distinction of accidents and the ‘metaphysical’ distinction of phantasms.

  15. Distinctive Dynamic Capabilities for New Business Creation

    DEFF Research Database (Denmark)

    Rosenø, Axel; Enkel, Ellen; Mezger, Florian

    2013-01-01

    This study examines the distinctive dynamic capabilities for new business creation in established companies. We argue that these are very different from those for managing incremental innovation within a company's core business. We also propose that such capabilities are needed in both slow...... and fast-paced industries, and that similarities exist across industries. Hence, the study contributes to dynamic capabilities literature by: 1) identifying the distinctive dynamic capabilities for new business creation; 2) shifting focus away from dynamic capabilities in environments characterised by high...... clock-speed and uncertainty towards considering dynamic capabilities for the purpose of developing new businesses, which also implies a high degree of uncertainty. Based on interviews with 33 companies, we identify distinctive dynamic capabilities for new business creation, find that dynamic...

  16. Plasma cytokine concentration and the cytokine producing ability of whole blood cell cultures from healthy females with pharmacologically induced hyperprolactinemia.

    Science.gov (United States)

    Rovenský, J; Lackovic, V; Veselková, Z; Horváthová, M; Koska, J; Blazícková, S; Vigas, M

    1999-01-01

    We investigated the in vitro effect of domperidone-induced hyperprolactinemia on plasma cytokine concentration and blood leukocyte cytokine production in healthy female volunteers. No changes were found in the plasma concentration of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, IL-10, IL-6 and IL-13 during hyperprolactinemia when compared with control values. Using unseparated blood leukocytes, we found that the spontaneous production of IL-6 (4-8 h) and transforming growth factor (TGF)-beta 1 (2-4 h) was significantly decreased and that the in vitro stimulated production of IFN-gamma (2-8 h) and TNF (4 h) was significantly increased compared with control. Our data concerning the increased IFN-gamma and TNF producing capacity of unseparated leukocytes during pharmacologically induced hyperprolactinemia strongly support the possibility that the lymphocyte production of these cytokines can be rapidly amplified by prolactin via a priming mechanism.

  17. Intraosseous myoepithelioma: A rare, distinct tumor entity

    Directory of Open Access Journals (Sweden)

    Bharat Rekhi

    2014-01-01

    Full Text Available Primary musculoskeletal myoepithelial tumors (METs are distinctly rare tumors and are being increasingly recognized as a result of improved diagnostic criteria and objective confirmation with immunohistochemical markers, including epithelial markers. Recent studies have unraveled distinct molecular mechanisms underlying these tumors. Herein, we present our second diagnosed case of an intraosseous MET that occurred in the tibia of a 37-year-old lady. The case is discussed with regards to current clinicopathological perspectives on these rather uncommon tumors, including our personal experience.

  18. Fermionic bound states in distinct kinklike backgrounds

    Energy Technology Data Exchange (ETDEWEB)

    Bazeia, D. [Universidade Federal da Paraiba, Departamento de Fisica, Joao Pessoa, Paraiba (Brazil); Mohammadi, A. [Universidade Federal de Campina Grande, Departamento de Fisica, Caixa Postal 10071, Campina Grande, Paraiba (Brazil)

    2017-04-15

    This work deals with fermions in the background of distinct localized structures in the two-dimensional spacetime. Although the structures have a similar topological character, which is responsible for the appearance of fractionally charged excitations, we want to investigate how the geometric deformations that appear in the localized structures contribute to the change in the physical properties of the fermionic bound states. We investigate the two-kink and compact kinklike backgrounds, and we consider two distinct boson-fermion interactions, one motivated by supersymmetry and the other described by the standard Yukawa coupling. (orig.)

  19. Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Takuya Matsushita

    Full Text Available BACKGROUND: Differences in cytokine/chemokine profiles among patients with neuromyelitis optica (NMO, relapsing remitting multiple sclerosis (RRMS, and primary progressive MS (PPMS, and the relationships of these profiles with clinical and neuroimaging features are unclear. A greater understanding of these profiles may help in differential diagnosis. METHODS/PRINCIPAL FINDINGS: We measured 27 cytokines/chemokines and growth factors in CSF collected from 20 patients with NMO, 26 with RRMS, nine with PPMS, and 18 with other non-inflammatory neurological diseases (OND by multiplexed fluorescent bead-based immunoassay. Interleukin (IL-17A, IL-6, CXCL8 and CXCL10 levels were significantly higher in NMO patients than in OND and RRMS patients at relapse, while granulocyte-colony stimulating factor (G-CSF and CCL4 levels were significantly higher in NMO patients than in OND patients. In NMO patients, IL-6 and CXCL8 levels were positively correlated with disability and CSF protein concentration while IL-6, CXCL8, G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF and IFN-γ were positively correlated with CSF neutrophil counts at the time of sample collection. In RRMS patients, IL-6 levels were significantly higher than in OND patients at the relapse phase while CSF cell counts were negatively correlated with the levels of CCL2. Correlation coefficients of cytokines/chemokines in the relapse phase were significantly different in three combinations, IL-6 and GM-CSF, G-CSF and GM-CSF, and GM-CSF and IFN-γ, between RRMS and NMO/NMOSD patients. In PPMS patients, CCL4 and CXCL10 levels were significantly higher than in OND patients. CONCLUSIONS: Our findings suggest distinct cytokine/chemokine alterations in CSF exist among NMO, RRMS and PPMS. In NMO, over-expression of a cluster of Th17- and Th1-related proinflammatory cytokines/chemokines is characteristic, while in PPMS, increased CCL4 and CXCL10 levels may reflect on-going low grade T cell

  20. Monocyte/macrophage lineage commitment and distribution are affected by the lack of regulatory T cells in scurfy mice.

    Science.gov (United States)

    Skuljec, Jelena; Cabanski, Maciej; Surdziel, Ewa; Lachmann, Nico; Brennig, Sebastian; Pul, Refik; Jirmo, Adan C; Habener, Anika; Visic, Julia; Dalüge, Kathleen; Hennig, Christian; Moritz, Thomas; Happle, Christine; Hansen, Gesine

    2016-07-01

    Foxp3(+) regulatory T (Treg) cells play a pivotal role in maintaining immunological tolerance. Loss-of-function mutations in the Foxp3 gene result in multiorgan inflammation known as immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in humans and scurfy (Sf) disease in mice. While the impact of missing Treg cells on adaptive immune cells is well documented, their role in regulation of myeloid cells remains unclear. Here we report that Sf mice exhibit an altered composition of stem and progenitor cells, characterized by increased numbers of myeloid precursors and higher efficiency of macrophage generation ex vivo. The proportion of monocytes/macrophages in the bone marrow, blood, and spleen was significantly elevated in Sf mice, which was accompanied with tissue-specific monocyte expression of homing receptor and phagocytic activity. Sf mice displayed high levels of M-CSF and other inflammatory cytokines, including monocyte-recruiting chemokines. Adoptive transfer of WT CD4(+) cells and in vivo neutralization of M-CSF normalized frequencies of monocyte subsets and their progenitors and reduced high levels of monocyte-related cytokines in Sf mice, while Treg cell transfer to RAG2(-/-) mice had no effect on myelopoiesis and monocyte/macrophage counts. Our findings illustrate that deregulated myelopoiesis in Sf mice is mainly caused by the inflammatory reaction resulting from the lack of Treg cells.