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Sample records for elr-cxc chemokine antagonism

  1. Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: implications for neurodevelopmental psychiatric disorders.

    Science.gov (United States)

    Ballendine, Stephanie A; Greba, Quentin; Dawicki, Wojciech; Zhang, Xiaobei; Gordon, John R; Howland, John G

    2015-03-03

    Research suggests that maternal immune activation (MIA) during pregnancy increases the risk of neurodevelopmental disorders including schizophrenia and autism in the offspring. Current theories suggest that inflammatory mediators including cytokines and chemokines may underlie the increased risk of these disorders in humans. For example, elevated maternal interleukin-8 (IL-8) during pregnancy is associated with increased risk of schizophrenia in the offspring. Given this association, the present experiments examined ELR-CXC chemokines CXCL1 and CXCL2, rodent homologues of human IL-8, and activation of their receptors (CXCR1 and CXCR2) in an established rodent model of MIA. Pregnant Long Evans rats were treated with the viral mimetic polyinosinic-polycytidylic acid (polyI:C; 4 mg/kg, i.v.) on gestational day 15. Protein analysis using multiplex assays and ELISA showed that polyI:C significantly increased maternal serum concentrations of interleukin-1β, tumor necrosis factor, and CXCL1 3h after administration. Subsequent experiments tested the role of elevated maternal CXCL1 on behavior of the offspring by administering a CXCR1/CXCR2 antagonist (G31P; 500 μg/kg, i.p.; 1h before, 48 and 96 h after polyI:C treatment). The male offspring of dams treated with polyI:C demonstrated subtle impairments in prepulse inhibition (PPI), impaired associative and crossmodal recognition memory, and altered behavioral flexibility in an operant test battery. While G31P did not completely reverse the behavioral impairments caused by polyI:C, it enhanced PPI during adolescence and strategy set-shifting and reversal learning during young adulthood. These results suggest that while polyI:C treatment significantly increases maternal CXCL1, elevations of this chemokine are not solely responsible for the effects of polyI:C on the behavior of the offspring. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. PPAR-γ Activation Inhibits Angiogenesis by Blocking ELR+CXC Chemokine Production in Non-small Cell Lung Cancer

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    Venkateshwar G. Keshamouni

    2005-03-01

    Full Text Available Activation of peroxisome proliferator-activated receptor-γ (PPAR-γ results in inhibition of tumor growth in various types of cancers, but the mechanism(s by which PPAR-γ induces growth arrest has not been completely defined. In a recent study, we demonstrated that treatment of A549 (human non small cell lung cancer cell line tumor-bearing SCID mice with PPAR-γ ligands troglitazone (Tro and pioglitazone significantly inhibits primary tumor growth. In this study, immunohistochemical analysis of Tro-treated and Pio-treated tumors with factor VIII antibody revealed a significant reduction in blood vessel density compared to tumors in control animals, suggesting inhibition of angiogenesis. Further analysis showed that treatment of A549 cells in vitro with Tro or transient transfection of A549 cells with constitutively active PPAR-γ (VP16-PPAR-γ construct blocked the production of the angiogenic ELR +CXC chemokines IL-8 (CXCL8, ENA-78 (CXCL5, Gro-α (CXCL1. Similarly, an inhibitor of NF-ΚB activation (PDTC also blocked CXCL8, CXCL5, CXCL1 production, consistent with their NF-ΚB-dependent regulation. Conditioned media from A549 cells induce human microvascular endothelial cell (HMVEC chemotaxis. However, conditioned media from Tro-treated A549 cells induced significantly less HMVEC chemotaxis compared to untreated A549 cells. Furthermore, PPAR-γ activation inhibited NF-ΚB transcriptional activity, as assessed by TransAM reporter gene assay. Collectively, our data suggest that PPAR-γ ligands can inhibit tumor-associated angiogenesis by blocking the production of ELR+CXC chemokines, which is mediated through antagonizing NF-ΚB activation. These antiangiogenic effects likely contribute to the inhibition of primary tumor growth by PPAR-γ ligands.

  3. What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?

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    Kufareva, Irina; Gustavsson, Martin; Zheng, Yi; Stephens, Bryan S.; Handel, Tracy M. (UCSD)

    2017-05-22

    Chemokines and their cell surface G protein–coupled receptors are critical for cell migration, not only in many fundamental biological processes but also in inflammatory diseases and cancer. Recent X-ray structures of two chemokines complexed with full-length receptors provided unprecedented insight into the atomic details of chemokine recognition and receptor activation, and computational modeling informed by new experiments leverages these insights to gain understanding of many more receptor:chemokine pairs. In parallel, chemokine receptor structures with small molecules reveal the complicated and diverse structural foundations of small molecule antagonism and allostery, highlight the inherent physicochemical challenges of receptor:chemokine interfaces, and suggest novel epitopes that can be exploited to overcome these challenges. The structures and models promote unique understanding of chemokine receptor biology, including the interpretation of two decades of experimental studies, and will undoubtedly assist future drug discovery endeavors.

  4. The Viral KSHV Chemokine vMIP-II Inhibits the Migration of Naive and Activated Human NK Cells by Antagonizing Two Distinct Chemokine Receptors

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    Yamin, Rachel; Kaynan, Noa S.; Glasner, Ariella; Vitenshtein, Alon; Tsukerman, Pinchas; Bauman, Yoav; Ophir, Yael; Elias, Shlomo; Bar-On, Yotam; Gur, Chamutal; Mandelboim, Ofer

    2013-01-01

    Natural killer (NK) cells are innate immune cells able to rapidly kill virus-infected and tumor cells. Two NK cell populations are found in the blood; the majority (90%) expresses the CD16 receptor and also express the CD56 protein in intermediate levels (CD56Dim CD16Pos) while the remaining 10% are CD16 negative and express CD56 in high levels (CD56Bright CD16Neg). NK cells also reside in some tissues and traffic to various infected organs through the usage of different chemokines and chemokine receptors. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human virus that has developed numerous sophisticated and versatile strategies to escape the attack of immune cells such as NK cells. Here, we investigate whether the KSHV derived cytokine (vIL-6) and chemokines (vMIP-I, vMIP-II, vMIP-III) affect NK cell activity. Using transwell migration assays, KSHV infected cells, as well as fusion and recombinant proteins, we show that out of the four cytokine/chemokines encoded by KSHV, vMIP-II is the only one that binds to the majority of NK cells, affecting their migration. We demonstrate that vMIP-II binds to two different receptors, CX3CR1 and CCR5, expressed by naïve CD56Dim CD16Pos NK cells and activated NK cells, respectively. Furthermore, we show that the binding of vMIP-II to CX3CR1 and CCR5 blocks the binding of the natural ligands of these receptors, Fractalkine (Fck) and RANTES, respectively. Finally, we show that vMIP-II inhibits the migration of naïve and activated NK cells towards Fck and RANTES. Thus, we present here a novel mechanism in which KSHV uses a unique protein that antagonizes the activity of two distinct chemokine receptors to inhibit the migration of naïve and activated NK cells. PMID:23966863

  5. Chemokines

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    Richard Horuk

    2007-01-01

    Full Text Available Chemokines are a family of polypeptides that direct the migration of leukocytestoward a site of infection. They play a major role in autoimmune disease and chemokine receptors have recently been found to mediate HIV-1 fusion. In this short review we examine the role of chemokines in host defence and in the pathophysiology of autoimmune diseases. We conclude by discussing various therapeutic approaches that target chemokine receptors and that could be beneficial in disease.

  6. Overexpression of the duffy antigen receptor for chemokines (DARC by NSCLC tumor cells results in increased tumor necrosis

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    Burdick Marie D

    2004-06-01

    Full Text Available Abstract Background The Duffy antigen receptor for chemokines (DARC is known to be a promiscuous chemokine receptor that binds a variety of CXC and CC chemokines in the absence of any detectable signal transduction events. Within the CXC group of chemokines, DARC binds the angiogenic CXC chemokines including IL-8 (CXCL8, GROα (CXCL1 and ENA-78 (CXCL5, all of which have previously been shown to be important in non-small cell lung carcinoma (NSCLC tumor growth. We hypothesized that overexpression of DARC by a NSCLC tumor cell line would result in the binding of the angiogenic ELR+ CXC chemokines by the tumor cells themselves, and thus interfere with the stimulation of endothelial cells and induction of angiogenesis by the tumor cell-derived angiogenic chemokines. Results NSCLC tumor cells that constitutively expressed DARC were generated and their growth characteristics were compared to control transfected cells in vitro and in vivo in SCID animals. We found that tumors derived from DARC-expressing cells were significantly larger in size than tumors derived from control-transfected cells. However, upon histological examination we found that DARC-expressing tumors had significantly more necrosis and decreased tumor cellularity, as compared to control tumors. Expression of DARC by NSCLC cells was also associated with a decrease in tumor-associated vasculature and a reduction in metastatic potential. Conclusions The expression of DARC in the context of NSCLC tumors may act as a chemokine decoy receptor and interferes with normal tumor growth and chemokine-induced tumor neovascularization.

  7. Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases.

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    Antonelli, Alessandro; Ferrari, Silvia Martina; Giuggioli, Dilia; Ferrannini, Ele; Ferri, Clodoveo; Fallahi, Poupak

    2014-03-01

    (C-X-C motif) ligand (CXCL)10 (CXCL10) belongs to the ELR(-) CXC subfamily chemokine. CXCL10 exerts its function through binding to chemokine (C-X-C motif) receptor 3 (CXCR3), a seven trans-membrane receptor coupled to G proteins. CXCL10 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as type 1 diabetes, autoimmune thyroiditis, Graves' disease and ophthalmopathy), or systemic (such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, mixed cryoglobulinemia, Sjögren syndrome, or systemic sclerosis). The secretion of CXCL10 by cluster of differentiation (CD)4+, CD8+, natural killer (NK) and NK-T cells is dependent on interferon (IFN)-γ, which is itself mediated by the interleukin-12 cytokine family. Under the influence of IFN-γ, CXCL10 is secreted by several cell types including endothelial cells, fibroblasts, keratinocytes, thyrocytes, preadipocytes, etc. Determination of high level of CXCL10 in peripheral fluids is therefore a marker of host immune response, especially T helper (Th)1 orientated T-cells. In tissues, recruited Th1 lymphocytes may be responsible for enhanced IFN-γ and tumor necrosis factor-α production, which in turn stimulates CXCL10 secretion from a variety of cells, therefore creating an amplification feedback loop, and perpetuating the autoimmune process. Further studies are needed to investigate interactions between chemokines and cytokines in the pathogenesis of autoimmune diseases and to evaluate whether CXCL10 is a novel therapeutic target in various autoimmune diseases. © 2013.

  8. The prognostic importance of CXCR3 chemokine during organizing pneumonia on the risk of chronic lung allograft dysfunction after lung transplantation.

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    Michael Y Shino

    development when considered in the context of increased allograft expression of interferon-γ inducible ELR- CXC chemokines. We further demonstrate for the first time, the prognostic importance of BALF CXCR3 ligand concentrations during OP on subsequent CLAD risk.

  9. Chemokines and Chemokine Receptors in Multiple Sclerosis

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    Wenjing Cheng

    2014-01-01

    Full Text Available Multiple sclerosis is an autoimmune disease with classical traits of demyelination, axonal damage, and neurodegeneration. The migration of autoimmune T cells and macrophages from blood to central nervous system as well as the destruction of blood brain barrier are thought to be the major processes in the development of this disease. Chemokines, which are small peptide mediators, can attract pathogenic cells to the sites of inflammation. Each helper T cell subset expresses different chemokine receptors so as to exert their different functions in the pathogenesis of MS. Recently published results have shown that the levels of some chemokines and chemokine receptors are increased in blood and cerebrospinal fluid of MS patients. This review describes the advanced researches on the role of chemokines and chemokine receptors in the development of MS and discusses the potential therapy of this disease targeting the chemokine network.

  10. Plasma macrophage-derived chemokine (CCL22) and its receptor ...

    African Journals Online (AJOL)

    Plasma macrophage-derived chemokine (CCL22) and its receptor CCR4 on peripheral blood T lymphocytes of asthmatic children. ... Neutralization and manipulation of CCR4-expressing T cells, as well as MDC antagonism, may represent an adjuvant in the treatment of severe allergic disorders. Keywords: MDC; CCR4 ...

  11. Chemokine and Chemokine Receptor Gene Polymorphism in ...

    African Journals Online (AJOL)

    Introduction: Our aim was to investigate the possibility of a significant relationship between chemokines and chemokine receptor genes polymorphisms and the spontaneous clearance or the persistence of HCV infection. Methods: A total of 96 hemodialysis (HD) patients infected with HCV were classified into two groups: G1 ...

  12. Chemokines and immunity.

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    Palomino, Diana Carolina Torres; Marti, Luciana Cavalheiro

    2015-01-01

    Chemokines are a large family of small cytokines and generally have low molecular weight ranging from 7 to 15kDa. Chemokines and their receptors are able to control the migration and residence of all immune cells. Some chemokines are considered pro-inflammatory, and their release can be induced during an immune response at a site of infection, while others are considered homeostatic and are involved in controlling of cells migration during tissue development or maintenance. The physiologic importance of this family of mediators is resulting from their specificity - members of the chemokine family induce recruitment of well-defined leukocyte subsets. There are two major chemokine sub-families based upon cysteine residues position: CXC and CC. As a general rule, members of the CXC chemokines are chemotactic for neutrophils, and CC chemokines are chemotactic for monocytes and sub-set of lymphocytes, although there are some exceptions. This review discusses the potential role of chemokines in inflammation focusing on the two best-characterized chemokines: monocyte chemoattractant protein-1, a CC chemokine, and interleukin-8, a member of the CXC chemokine sub-family.

  13. Chemokines in Renal Diseases

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    Stephan Segerer

    2005-01-01

    Full Text Available The chemokines, members of a large family of chemotactic cytokines, act as directional cues for sorting inflammatory cell subsets to sites of inflammation or lymphoid microenvironments. In addition to their effects on migration, chemokines can also activate effector function in leukocytes and are involved in cell proliferation and angiogenesis. Therefore, it is not surprising that chemokines play important roles in a wide range of human diseases, including genetic immunodeficiencies, infections, autoimmune diseases, and malignant tumors. In this report, we have reviewed recent developments (since mid 2003 in chemokines in renal diseases. In animal models, chemokines are produced at the site of injury, leading to inflammatory cell recruitment. The therapeutic impact of the blockade of CCR1, CCR2, CCR4, CCR5, or the corresponding ligands has been further studied in various renal disease models. Recent studies on the role of the chemokine receptors in human diseases have demonstrated the expression of CXCR1, CXCR3, CCR2, and CCR5 on different subsets of inflammatory cells. The number of CCR5- and CXCR3-positive interstitial infiltrating cells (mainly T cells correlates with renal function and proteinuria in glomerular diseases. Polymorphisms of chemokines and chemokine receptors are of impact on renal disease courses and allograft survival. Chemokine receptor blockade has approached clinical applications in nonrenal diseases and awaits the application in patients with kidney diseases.

  14. Chemokines, lymphocytes, and HIV

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    Farber J.M.

    1998-01-01

    Full Text Available Chemokines are members of a family of more than 30 human cytokines whose best-described activities are as chemotactic factors for leukocytes and that are presumed to be important in leukocyte recruitment and trafficking. While many chemokines can act on lymphocytes, the roles of chemokines and their receptors in lymphocyte biology are poorly understood. The recent discoveries that chemokines can suppress infection by HIV-1 and that chemokine receptors serve, along with CD4, as obligate co-receptors for HIV-1 entry have lent urgency to studies on the relationships between chemokines and lymphocytes. My laboratory has characterized Mig and Crg-2/IP-10, chemokines that are induced by IFN-g and that specifically target lymphocytes, particularly activated T cells. We have demonstrated that the genes for these chemokines are widely expressed during experimental infections in mice with protozoan and viral pathogens, but that the patterns of mig and crg-2 expression differed, suggesting non-redundant roles in vivo. Our related studies to identify new chemokine receptors from activated lymphocytes resulted in the cloning of STRL22 and STRL33. We and others have shown that STRL22 is a receptor for the CC chemokine MIP-3a, and STRL22 has been re-named CCR6. Although STRL33 remains an orphan receptor, we have shown that it can function as a co-receptor for HIV-1 envelope glycoproteins, and that it is active with a broader range of HIV-1 envelope glycoproteins than the major co-receptors described to date. The ability of STRL33 to function with a wide variety of envelope glycoproteins may become particularly important if therapies are instituted to block other specific co-receptors. We presume that investigations into the roles of chemokines and their receptors in lymphocyte biology will provide information important for understanding the pathogenesis of AIDS and for manipulating immune and inflammatory responses for clinical benefit

  15. [Chemokines in ophthalmology].

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    Bleul, T; Schlunck, G; Reinhard, T; Lapp, T

    2017-12-07

    Chemokines are chemotactically active cytokines, which coordinate the distribution of immune cells within the body and also regulate the migration of leukocytes in malignant and inflammatory processes. Chemokines are a heterogeneous group of short-chain proteins that are divided into different subgroups on the basis of their structure. In addition to the chemokines (ligands) various chemokine receptors also exist. The chemokine system is given its complexity by the high redundancy of ligand-receptor interactions: one single ligand can bind to different receptors and a single receptor can interact with different ligands. In terms of receptors, distinct immune cell types have characteristic receptor expression patterns, which can be used for the immunological characterization of leukocytes. Important basic research is currently leading to a better understanding of the chemokine system. The essential importance of the chemokine system in various diseases of the anterior and posterior eye segments is becoming increasingly apparent. The following synopsis explains the individual clinical aspects as well as the underlying scientific work in the context of "chemokines in ophthalmology".

  16. Serum mucosa-associated epithelial chemokine (MEC/CCL28) in ...

    African Journals Online (AJOL)

    It may also represent an objective prognostic marker for disease severity. Further studies may pave way for CCL28 antagonism among the adjuvant therapeutic strategies. Keywords: Mucosa-associated epithelial chemokine, CCL28, allergic diseases, atopic dermatitis, bronchial asthma. Egypt J Pediatr Allergy Immunol ...

  17. Chemokines and Chemokine Receptors in the Development of Lupus Nephritis

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    Xiaofeng Liao

    2016-01-01

    Full Text Available Lupus nephritis (LN is a major cause of morbidity and mortality in the patients with systemic lupus erythematosus (SLE, an autoimmune disease with damage to multiple organs. Leukocyte recruitment into the inflamed kidney is a critical step to promote LN progression, and the chemokine/chemokine receptor system is necessary for leukocyte recruitment. In this review, we summarize recent studies on the roles of chemokines and chemokine receptors in the development of LN and discuss the potential and hurdles of developing novel, chemokine-based drugs to treat LN.

  18. Selected CC and CXC chemokines in children with atopic asthma

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    Edyta Machura

    2016-05-01

    Full Text Available Introduction : There are only limited data on CC and CXC chemokines regulation in children with asthma. Aim: We compared the serum profile of selected CC and CXC chemokines in patients with atopic asthma and healthy children. Material and methods : Serum concentration of CC chemokines RANTES, MCP-1, and CXC chemokines IP-10, MIG, IL-8, RANTES was measured using cytometric bead array in 44 children with atopic asthma and 17 healthy subjects. Results: The concentration of RANTES was significantly higher and the MIG level was lower in all children with asthma as compared to their control counterparts. We observed increased RANTES and decreased MIG levels also in patients with stable asthma when compared with children in the control group. The IP-10 concentration was similar between the whole asthma group and healthy controls, while significantly increased levels of this chemokine in acute asthma have been observed when compared to stable asthma. For MCP-1 and IL-8, the serum concentration was similar in all compared groups. The MIG concentration correlated positively with IP-10, IL-8, and CRP levels and negatively with the eosinophil count. A negative correlation between the IP-10 and eosinophil count and a negative correlation between FEV1 and IP-10 were found. Conclusions : An increased serum RANTES level in children with asthma may result in enhancement of Th2 lymphocyte recruitment into the airway. A decreased expression of Th1 chemokine MIG in children with stable asthma may contribute to a diminished antagonizing effect on Th2 cytokine production and hence intensify Th2 predominance. An increased IP-10 level in children during an asthma attack suggest that this chemokine is a serological marker of disease exacerbation.

  19. Teleost Chemokines and Their Receptors

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    Steve Bird

    2015-11-01

    Full Text Available Chemokines are a superfamily of cytokines that appeared about 650 million years ago, at the emergence of vertebrates, and are responsible for regulating cell migration under both inflammatory and physiological conditions. The first teleost chemokine gene was reported in rainbow trout in 1998. Since then, numerous chemokine genes have been identified in diverse fish species evidencing the great differences that exist among fish and mammalian chemokines, and within the different fish species, as a consequence of extensive intrachromosomal gene duplications and different infectious experiences. Subsequently, it has only been possible to establish clear homologies with mammalian chemokines in the case of some chemokines with well-conserved homeostatic roles, whereas the functionality of other chemokine genes will have to be independently addressed in each species. Despite this, functional studies have only been undertaken for a few of these chemokine genes. In this review, we describe the current state of knowledge of chemokine biology in teleost fish. We have mainly focused on those species for which more research efforts have been made in this subject, specially zebrafish (Danio rerio, rainbow trout (Oncorhynchus mykiss and catfish (Ictalurus punctatus, outlining which genes have been identified thus far, highlighting the most important aspects of their expression regulation and addressing any known aspects of their biological role in immunity. Finally, we summarise what is known about the chemokine receptors in teleosts and provide some analysis using recently available data to help characterise them more clearly.

  20. Teleost Chemokines and Their Receptors.

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    Bird, Steve; Tafalla, Carolina

    2015-11-11

    Chemokines are a superfamily of cytokines that appeared about 650 million years ago, at the emergence of vertebrates, and are responsible for regulating cell migration under both inflammatory and physiological conditions. The first teleost chemokine gene was reported in rainbow trout in 1998. Since then, numerous chemokine genes have been identified in diverse fish species evidencing the great differences that exist among fish and mammalian chemokines, and within the different fish species, as a consequence of extensive intrachromosomal gene duplications and different infectious experiences. Subsequently, it has only been possible to establish clear homologies with mammalian chemokines in the case of some chemokines with well-conserved homeostatic roles, whereas the functionality of other chemokine genes will have to be independently addressed in each species. Despite this, functional studies have only been undertaken for a few of these chemokine genes. In this review, we describe the current state of knowledge of chemokine biology in teleost fish. We have mainly focused on those species for which more research efforts have been made in this subject, specially zebrafish (Danio rerio), rainbow trout (Oncorhynchus mykiss) and catfish (Ictalurus punctatus), outlining which genes have been identified thus far, highlighting the most important aspects of their expression regulation and addressing any known aspects of their biological role in immunity. Finally, we summarise what is known about the chemokine receptors in teleosts and provide some analysis using recently available data to help characterise them more clearly.

  1. Chemokines in cancer related inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Allavena, Paola; Germano, Giovanni; Marchesi, Federica [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089, Rozzano, Milan (Italy); Mantovani, Alberto, E-mail: alberto.mantovani@humanitasresearch.it [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089, Rozzano, Milan (Italy); Department of Translational Medicine, University of Milan (Italy)

    2011-03-10

    Chemokines are key players of the cancer-related inflammation. Chemokine ligands and receptors are downstream of genetic events that cause neoplastic transformation and are abundantly expressed in chronic inflammatory conditions which predispose to cancer. Components of the chemokine system affect multiple pathways of tumor progression including: leukocyte recruitment, neo-angiogenesis, tumor cell proliferation and survival, invasion and metastasis. Evidence in pre-clinical and clinical settings suggests that the chemokine system represents a valuable target for the development of innovative therapeutic strategies.

  2. Probing Biased Signaling in Chemokine Receptors

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    Amarandi, Roxana Maria; Hjortø, Gertrud Malene; Rosenkilde, Mette Marie

    2016-01-01

    The chemokine system mediates leukocyte migration during homeostatic and inflammatory processes. Traditionally, it is described as redundant and promiscuous, with a single chemokine ligand binding to different receptors and a single receptor having several ligands. Signaling of chemokine receptors...

  3. CCR1 antagonism attenuates T cell trafficking to omentum and liver in obesity-associated cancer.

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    Conroy, Melissa J; Galvin, Karen C; Kavanagh, Maria E; Mongan, Ann Marie; Doyle, Suzanne L; Gilmartin, Niamh; O'Farrelly, Cliona; Reynolds, John V; Lysaght, Joanne

    2016-07-01

    Obesity is a global health problem presenting serious risk of disease fuelled by chronic inflammation, including type 2 diabetes mellitus, cardiovascular disease, liver disease and cancer. Visceral fat, in particular the omentum and liver of obese individuals are sites of excessive inflammation. We propose that chemokine-mediated trafficking of pro-inflammatory cells to the omentum and liver contributes to local and subsequent systemic inflammation. Oesophagogastric adenocarcinoma (OAC) is an exemplar model of obesity and inflammation driven cancer. We have demonstrated that T cells actively migrate to the secreted factors from the omentum and liver of OAC patients and that both CD4(+) and CD8(+) T cells bearing the chemokine receptor CCR5 are significantly more prevalent in these tissues compared to matched blood. The CCR5 ligand and inflammatory chemokine MIP-1α is also secreted at significantly higher concentrations in the omentum and liver of our OAC patient cohort compared to matched serum. Furthermore, we report that MIP-1α receptor antagonism can significantly reduce T cell migration to the secreted factors from OAC omentum and liver. These novel data suggest that chemokine receptor antagonism may have therapeutic potential to reduce inflammatory T cell infiltration to the omentum and liver and in doing so, may ameliorate pathological inflammation in obesity and obesity-associated cancer.

  4. Chemokines and chemokine receptors in inflammation of the nervous system

    DEFF Research Database (Denmark)

    Huang, D; Han, Yong-Chang; Rani, M R

    2000-01-01

    This article focuses on the production of chemokines by resident glial cells of the nervous system. We describe studies in two distinct categories of inflammation within the nervous system: immune-mediated inflammation as seen in experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis...... (MS) and post-traumatic inflammation. We provide evidence that chemokines play a role in amplifying the inflammatory reaction in EAE (and, probably, MS). In the context of neural trauma, chemokines appear to be primary stimuli for leukocyte recruitment. Strikingly, expression of monocyte...

  5. Intracellular allosteric antagonism of the CCR9 receptor.

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    Oswald, Christine; Rappas, Mathieu; Kean, James; Doré, Andrew S; Errey, James C; Bennett, Kirstie; Deflorian, Francesca; Christopher, John A; Jazayeri, Ali; Mason, Jonathan S; Congreve, Miles; Cooke, Robert M; Marshall, Fiona H

    2016-12-15

    Chemokines and their G-protein-coupled receptors play a diverse role in immune defence by controlling the migration, activation and survival of immune cells. They are also involved in viral entry, tumour growth and metastasis and hence are important drug targets in a wide range of diseases. Despite very significant efforts by the pharmaceutical industry to develop drugs, with over 50 small-molecule drugs directed at the family entering clinical development, only two compounds have reached the market: maraviroc (CCR5) for HIV infection and plerixafor (CXCR4) for stem-cell mobilization. The high failure rate may in part be due to limited understanding of the mechanism of action of chemokine antagonists and an inability to optimize compounds in the absence of structural information. CC chemokine receptor type 9 (CCR9) activation by CCL25 plays a key role in leukocyte recruitment to the gut and represents a therapeutic target in inflammatory bowel disease. The selective CCR9 antagonist vercirnon progressed to phase 3 clinical trials in Crohn's disease but efficacy was limited, with the need for very high doses to block receptor activation. Here we report the crystal structure of the CCR9 receptor in complex with vercirnon at 2.8 Å resolution. Remarkably, vercirnon binds to the intracellular side of the receptor, exerting allosteric antagonism and preventing G-protein coupling. This binding site explains the need for relatively lipophilic ligands and describes another example of an allosteric site on G-protein-coupled receptors that can be targeted for drug design, not only at CCR9, but potentially extending to other chemokine receptors.

  6. Chapter 8. Activation mechanisms of chemokine receptors

    DEFF Research Database (Denmark)

    Jensen, Pia C; Rosenkilde, Mette M

    2009-01-01

    , more research has to be done in this field. Chemokine receptors are interesting tools in this matter. First, the chemokine system has a high degree of promiscuity that allows several chemokines to target one receptor in different ways, as well as a single chemokine ligand to target several receptors...

  7. Chemokine receptors in allergic diseases.

    Science.gov (United States)

    Castan, L; Magnan, A; Bouchaud, G

    2017-05-01

    Under homeostatic conditions, as well as in various diseases, leukocyte migration is a crucial issue for the immune system that is mainly organized through the activation of bone marrow-derived cells in various tissues. Immune cell trafficking is orchestrated by a family of small proteins called chemokines. Leukocytes express cell-surface receptors that bind to chemokines and trigger transendothelial migration. Most allergic diseases, such as asthma, rhinitis, food allergies, and atopic dermatitis, are generally classified by the tissue rather than the type of inflammation, making the chemokine/chemokine receptor system a key point of the immune response. Moreover, because small antagonists can easily block such receptors, various molecules have been developed to suppress the recruitment of immune cells during allergic reactions, representing potential new drugs for allergies. We review the chemokines and chemokine receptors that are important in asthma, food allergies, and atopic dermatitis and their respectively developed antagonists. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Uncompetitive antagonism of AMPA receptors

    DEFF Research Database (Denmark)

    Andersen, Trine F; Tikhonov, Denis B; Bølcho, Ulrik

    2006-01-01

    Philanthotoxins are uncompetitive antagonists of Ca2+-permeable AMPA receptors presumed to bind to the pore-forming region, but a detailed molecular mechanism for this interaction is missing. Here a small library of novel philanthotoxins was designed and synthesized using a solid-phase strategy. ...... polyamine toxins antagonize the AMPA receptor ion channel and provide the basis for rational development of uncompetitive antagonists of AMPA receptors....

  9. Citrullinated Chemokines in Rheumatoid Arthritis

    Science.gov (United States)

    2016-12-01

    properties that significantly modify the inflammatory environment of the RA joint. Chemokines, including epithelial-derived neutrophil-activating peptide 78...tops in a specific pathogen-free environment . Severe combined immunodeficient (SCID) mice were ob- tained from the National Cancer Institute (NCI). C57...response to pro-fibrotic and angiogenic mediators, potentially due to epigenetic alteration of these cells in vivo. Histologic analysis of ST revealed

  10. Interaction of chemokines with their receptors--from initial chemokine binding to receptor activating steps

    DEFF Research Database (Denmark)

    Thiele, Stefanie; Rosenkilde, Mette Marie

    2014-01-01

    The human chemokine system comprises 19 seven-transmembrane helix (7TM) receptors and 45 endogenous chemokines that often interact with each other in a promiscuous manner. Due to the chemokine system's primary function in leukocyte migration, it has a central role in immune homeostasis and survei......The human chemokine system comprises 19 seven-transmembrane helix (7TM) receptors and 45 endogenous chemokines that often interact with each other in a promiscuous manner. Due to the chemokine system's primary function in leukocyte migration, it has a central role in immune homeostasis...

  11. Allosteric and orthosteric sites in CC chemokine receptor (CCR5), a chimeric receptor approach

    DEFF Research Database (Denmark)

    Thiele, Stefanie; Steen, Anne; Jensen, Pia C

    2011-01-01

    -allosteric molecules. A chimera was successfully constructed between CCR5 and the closely related CCR2 by transferring all extracellular regions of CCR2 to CCR5, i.e. a Trojan horse that resembles CCR2 extracellularly but signals through a CCR5 transmembrane unit. The chimera bound CCR2 (CCL2 and CCL7), but not CCR5...... preserved, the allosteric enhancement of chemokine binding was disrupted. In summary, the Trojan horse chimera revealed that orthosteric and allosteric sites could be structurally separated and still act together with transmission of agonism and antagonism across the different receptor units....

  12. Chemokines in the melanoma metastasis biomarkers portrait.

    Science.gov (United States)

    Neagu, Monica; Constantin, Carolina; Longo, Caterina

    2015-01-01

    Skin tumorigenesis is linked to inflammatory chemokines accumulation that can induce cancer-associated immune-suppression. Deregulation of the CXCR4/CXCL12 axis was reported in melanoma tumorigenesis while also linked to BRAF mutation. Some chemokine-receptor patterns can direct the organ-specific metastasis. CXCL10 can help to prognosticate high-risk patients as it is a chemokine that differentiated patients with vs. metastasis free ones. Besides serum/plasma, chemokine identification in the cerebrospinal fluid of melanoma patients can indicate brain metastasis. Interplay between suppressed and elevated chemokines in cerebrospinal fluid can pinpoint an aggressive melanoma brain metastasis. Chemokines are gaining rapid momentum in the biomarker discovery domain aiding melanoma prognosis and high-risk patients' stratification.

  13. Targeting cellular adhesion molecules, chemokines and chemokine receptors in rheumatoid arthritis

    NARCIS (Netherlands)

    Haringman, Jasper J.; Oostendorp, Roos L.; Tak, Paul P.

    2005-01-01

    The development of specific targeted therapies, such as anti-TNF-alpha treatment, for chronic inflammatory disorders such as rheumatoid arthritis, has significantly improved treatment, although not all patients respond. Targeting cellular adhesion molecules and chemokines/chemokine receptors as

  14. Chemokines CXCL10 and CCL2

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Sellebjerg, F; Jensen, C V

    2001-01-01

    Studies of chemokines in cerebrospinal fluid (CSF) of patients with active multiple sclerosis (MS) have indicated that specific chemokines may have important roles in disease pathogenesis. We previously reported that CSF concentrations of CXCL10 (previously known as IP-10) were elevated in MS...

  15. Chemokines and Chemokine Receptors: Accomplices for Human Immunodeficiency Virus Infection and Latency

    Directory of Open Access Journals (Sweden)

    Zhuo Wang

    2017-10-01

    Full Text Available Chemokines are small chemotactic cytokines that are involved in the regulation of immune cell migration. Multiple functional properties of chemokines, such as pro-inflammation, immune regulation, and promotion of cell growth, angiogenesis, and apoptosis, have been identified in many pathological and physiological contexts. Human immunodeficiency virus (HIV infection is characterized by persistent inflammation and immune activation during both acute and chronic phases, and the “cytokine storm” is one of the hallmarks of HIV infection. Along with immune activation after HIV infection, an extensive range of chemokines and other cytokines are elevated, thereby generating the so-called “cytokine storm.” In this review, the effects of the upregulated chemokines and chemokine receptors on the processes of HIV infection are discussed. The objective of this review was to focus on the main chemokines and chemokine receptors that have been found to be associated with HIV infection and latency. Elevated chemokines and chemokine receptors have been shown to play important roles in the HIV life cycle, disease progression, and HIV reservoir establishment. Thus, targeting these chemokines and receptors and the other proteins of related signaling pathways might provide novel therapeutic strategies, and the evidence indicates a promising future regarding the development of a functional cure for HIV.

  16. Chemokines and Chemokine Receptors: Accomplices for Human Immunodeficiency Virus Infection and Latency.

    Science.gov (United States)

    Wang, Zhuo; Shang, Hong; Jiang, Yongjun

    2017-01-01

    Chemokines are small chemotactic cytokines that are involved in the regulation of immune cell migration. Multiple functional properties of chemokines, such as pro-inflammation, immune regulation, and promotion of cell growth, angiogenesis, and apoptosis, have been identified in many pathological and physiological contexts. Human immunodeficiency virus (HIV) infection is characterized by persistent inflammation and immune activation during both acute and chronic phases, and the "cytokine storm" is one of the hallmarks of HIV infection. Along with immune activation after HIV infection, an extensive range of chemokines and other cytokines are elevated, thereby generating the so-called "cytokine storm." In this review, the effects of the upregulated chemokines and chemokine receptors on the processes of HIV infection are discussed. The objective of this review was to focus on the main chemokines and chemokine receptors that have been found to be associated with HIV infection and latency. Elevated chemokines and chemokine receptors have been shown to play important roles in the HIV life cycle, disease progression, and HIV reservoir establishment. Thus, targeting these chemokines and receptors and the other proteins of related signaling pathways might provide novel therapeutic strategies, and the evidence indicates a promising future regarding the development of a functional cure for HIV.

  17. Viral leads for chemokine-modulatory drugs

    DEFF Research Database (Denmark)

    Lindow, Morten; Lüttichau, Hans Rudolf; Schwartz, Thue W

    2003-01-01

    The chemokine system, which controls leukocyte trafficking, provides several potentially very attractive anti-inflammatory drug targets. However, the complexity and redundancy of this system makes it very difficult to exploit through classical drug discovery. Despite this, viruses have millions...

  18. The Antagonism Mechanism Of Trichoderma spp. Towards Fusarium solani Mold

    Directory of Open Access Journals (Sweden)

    Utami Sri Hastuti

    2016-09-01

    Full Text Available The antagonism ability of seven Trichoderma isolates towards F.solani have been observed and tested by dual culture technique. The antagonism mechanism observed by microscopic observation with light microscope and Scanning Electron Microscopy (SEM. The research result showed seven species of Trichoderma molds have different antagonism ability towards F.solani each other. The antagonism mechanism observed by light microscope and Scanning Electron Microscopy were mycoparasitism, antibiosis, and competition.

  19. SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon.

    Science.gov (United States)

    Totura, Allison L; Baric, Ralph S

    2012-06-01

    SARS-CoV is a pathogenic coronavirus that emerged from a zoonotic reservoir, leading to global dissemination of the virus. The association SARS-CoV with aberrant cytokine, chemokine, and Interferon Stimulated Gene (ISG) responses in patients provided evidence that SARS-CoV pathogenesis is at least partially controlled by innate immune signaling. Utilizing models for SARS-CoV infection, key components of innate immune signaling pathways have been identified as protective factors against SARS-CoV disease, including STAT1 and MyD88. Gene transcription signatures unique to SARS-CoV disease states have been identified, but host factors that regulate exacerbated disease phenotypes still remain largely undetermined. SARS-CoV encodes several proteins that modulate innate immune signaling through the antagonism of the induction of Interferon and by avoidance of ISG effector functions. Copyright © 2012. Published by Elsevier B.V.

  20. Molecular evolution of CXC chemokines: extant CXC chemokines originate from the CNS

    NARCIS (Netherlands)

    Huising, M.O.; Stet, R.J.M.; Kruiswijk, C.P.; Savelkoul, H.F.J.; Verburg-van Kemenade, B.M.L.

    2003-01-01

    The mammalian CXC chemokine system comprises 16 ligands and six receptors, and its actions stretch well beyond the immune system. Recent elucidation of the pufferfish genome, a representative of an evolutionary ancient vertebrate class, has enabled analysis of the mammalian CXC chemokine system in a

  1. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Tani, M; Jensen, J

    1999-01-01

    Chemokines direct tissue invasion by specific leukocyte populations. Thus, chemokines may play a role in multiple sclerosis (MS), an idiopathic disorder in which the central nervous system (CNS) inflammatory reaction is largely restricted to mononuclear phagocytes and T cells. We asked whether...

  2. Triclosan antagonizes fluconazole activity against Candida albicans.

    LENUS (Irish Health Repository)

    Higgins, J

    2012-01-01

    Triclosan is a broad-spectrum antimicrobial compound commonly used in oral hygiene products. Investigation of its activity against Candida albicans showed that triclosan was fungicidal at concentrations of 16 mg\\/L. However, at subinhibitory concentrations (0.5-2 mg\\/L), triclosan antagonized the activity of fluconazole. Although triclosan induced CDR1 expression in C. albicans, antagonism was still observed in cdr1Δ and cdr2Δ strains. Triclosan did not affect fluconazole uptake or alter total membrane sterol content, but did induce the expression of FAS1 and FAS2, indicating that its mode of action may involve inhibition of fatty acid synthesis, as it does in prokaryotes. However, FAS2 mutants did not exhibit increased susceptibility to triclosan, and overexpression of both FAS1 and FAS2 alleles did not alter triclosan susceptibility. Unexpectedly, the antagonistic effect was specific for C. albicans under hypha-inducing conditions and was absent in the non-filamentous efg1Δ strain. This antagonism may be due to the membranotropic activity of triclosan and the unique composition of hyphal membranes.

  3. Molecular piracy of chemokine receptors by herpesviruses.

    Science.gov (United States)

    Murphy, P M

    1994-01-01

    To succeed as a biological entity, viruses must exploit normal cellular functions and elude the host immune system; they often do so by molecular mimicry. One way that mimicry may occur is when viruses copy and modify host genes. The best studied examples of this are the oncogenes of RNA retroviruses, but a growing number of examples are also known for DNA viruses. So far they all come from just two groups of DNA viruses, the herpesviruses and poxviruses, and the majority of examples are for genes whose products regulate immune responses, such as cytokines, cytokine receptors, and complement control proteins. This review will focus on human and herpesvirus receptors for chemokines, a family of leukocyte chemoattractant and activating factors that are thought to be important mediators of inflammation. Although the biological roles of the viral chemokine receptor homologues are currently unknown, their connection to specific sets of chemokines has suggested a number of possible functions.

  4. Chemokines and chemokine receptors expression in the lesions of patients with American cutaneous leishmaniasis

    Directory of Open Access Journals (Sweden)

    Nilka Luisa Diaz

    2013-06-01

    Full Text Available American cutaneous leishmaniasis (ACL presents distinct active clinical forms with different grades of severity, known as localised (LCL, intermediate (ICL and diffuse (DCL cutaneous leishmaniasis. LCL and DCL are associated with a polarised T-helper (Th1 and Th2 immune response, respectively, whereas ICL, or chronic cutaneous leishmaniasis, is associated with an exacerbated immune response and a mixed cytokine expression profile. Chemokines and chemokine receptors are involved in cellular migration and are critical in the inflammatory response. Therefore, we evaluated the expression of the chemokines CXCL10, CCL4, CCL8, CCL11 and CXCL8 and the chemokine receptors CCR3, CXCR3, CCR5 and CCR7 in the lesions of patients with different clinical forms of ACL using immunohistochemistry. LCL patients exhibited a high density of CXCL10+, CCL4+ and CCL8+ cells, indicating an important role for these chemokines in the local Th1 immune response and the migration of CXCR3+ cells. LCL patients showed a higher density of CCR7+ cells than ICL or DCL patients, suggesting major dendritic cell (DC migration to lymph nodes. Furthermore, DCL was associated with low expression levels of Th1-associated chemokines and CCL11+ epidermal DCs, which contribute to the recruitment of CCR3+ cells. Our findings also suggest an important role for epidermal cells in the induction of skin immune responses through the production of chemokines, such as CXCL10, by keratinocytes.

  5. Furin is a chemokine-modifying enzyme

    DEFF Research Database (Denmark)

    Hensbergen, Paul J; Verzijl, Dennis; Balog, Crina I A

    2004-01-01

    Chemokines comprise a class of structurally related proteins that are involved in many aspects of leukocyte migration under basal and inflammatory conditions. In addition to the large number of genes, limited processing of these proteins by a variety of enzymes enhances the complexity of the total...... agonist activity on the virally encoded receptor ORF74 and the direct antibacterial activity of CXCL10 are fully retained. Hence, we have identified furin as a novel chemokine-modifying enzyme in vitro and most probably also in vivo, generating a C-terminally truncated CXCL10, which fully retains its...

  6. Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4.

    Science.gov (United States)

    Imai, T; Chantry, D; Raport, C J; Wood, C L; Nishimura, M; Godiska, R; Yoshie, O; Gray, P W

    1998-01-16

    Macrophage-derived chemokine (MDC) is a recently identified member of the CC chemokine family. MDC is not closely related to other chemokines, sharing most similarity with thymus- and activation-regulated chemokine (TARC), which contains 37% identical amino acids. Both chemokines are highly expressed in the thymus, with little expression seen in other tissues. In addition, the genes for MDC and TARC are encoded by human chromosome 16. To explore this relationship in greater detail, we have more precisely localized the MDC gene to chromosome 16q13, the same position reported for the TARC gene. We have also examined the interaction of MDC with CC chemokine receptor 4 (CCR4), recently shown to be a receptor for TARC. Using a fusion protein of MDC with secreted alkaline phosphatase, we observed high affinity binding of MDC-secreted alkaline phosphatase to CCR4-transfected L1.2 cells (Kd = 0.18 nM). MDC and TARC competed for binding to CCR4, while no binding competition was observed for six other chemokines (MCP-1, MCP-3, MCP-4, RANTES (regulated on activation normal T cell expressed and secreted), macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta). MDC was tested for calcium mobilization in L1.2 cells tranfected with seven different CC chemokine receptors. MDC induced a calcium flux in CCR4-transfected cells, but other receptors did not respond to MDC. TARC, which also induced calcium mobilization in CCR4 transfectants, was unable to desensitize the response to MDC. In contrast, MDC fully desensitized a subsequent response to TARC. Both MDC and TARC functioned as chemoattractants for CCR4 transfectants, confirming that MDC is also a functional ligand for CCR4. Since MDC and TARC are both expressed in the thymus, one role for these chemokines may be to attract CCR4-bearing thymocytes in the process of T cell education and differentiation.

  7. New insights in chemokine signaling [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Daniel F. Legler

    2018-01-01

    Full Text Available Chemokine signaling is essential for coordinated cell migration in health and disease to specifically govern cell positioning in space and time. Typically, chemokines signal through heptahelical, G protein-coupled receptors to orchestrate cell migration. Notably, chemokine receptors are highly dynamic structures and signaling efficiency largely depends on the discrete contact with the ligand. Promiscuity of both chemokines and chemokine receptors, combined with biased signaling and allosteric modulation of receptor activation, guarantees a tightly controlled recruitment and positioning of individual cells within the local environment at a given time. Here, we discuss recent insights in understanding chemokine gradient formation by atypical chemokine receptors and how typical chemokine receptors can transmit distinct signals to translate guidance cues into coordinated cell locomotion in space and time.

  8. Enhanced Chronic Pain Management Utilizing Chemokine Receptor Antagonists

    Science.gov (United States)

    2016-08-01

    treatment; Analgesia; Nociception; Antinociception; Inflammation; Chemokines; Chemokine receptor antagonists; Opioid analgesics; Animal models of pain...processes), affect the ability of opioid drugs to counteract pain. We predicted that one way of increasing the effectiveness of the pain-relieving...more chemokine receptors would not only diminish various types of pain, but could also increase the efficacy of given doses of opioid analgesics. Thus

  9. Natural Protection of Wood with Antagonism Fungi

    Directory of Open Access Journals (Sweden)

    Alba ZAREMSKI

    2011-03-01

    Full Text Available Biological environments contain a certain number of microbial populations which, within a givenecological niche, display various relations ranging from symbiosis to parasitism. Researchers have beeninterested in these types of relations for around fifty years, especially in one very particular type ofrelationship: the antagonism exerted between individuals of the same microbial population.Today, the role played by biological agents, bringing into play inhibitive or destructive antibioticsubstances, reveals a certain potential for their use in controlling microorganisms associated with suchdegradation processes.The work undertaken by HydroQuébec and CIRAD involved two types of experiment: 1 in Petri dishes toassess and characterize the antagonistic capacity of Trichoderma against white rot and brown rot fungi; 2on pieces taken from untreated poles in order to study confrontation between the basidiomycete and theantagonistic strain in wood.This study investigated the antagonism of three ascomycetes of the genus Trichoderma against two whiterot basidiomycetes, Pycnoporus sanguineus and Coriolus versicolor, and two brown rot basidiomycetes,Antrodia sp. and Coniophora puteana, through direct confrontation in Petri dishes and in the wood ofHydroQuébec poles.The results obtained seemed to complete each other coherently. They revealed that the Trichodermagroup of fungi was not aggressive to wood and the results obtained after direct confrontation in Petri disheswere confirmed in wood.By directly exposing the different basidiomycetes and antagonists to each other in Petri dishes, two bytwo, we effectively revealed an antagonism effect for a large majority of the pairs. However, there wassubstantial variability in reactions from one pair to the next.

  10. Chemokines and chemokine receptors in susceptibility to HIV-1 infection and progression to AIDS.

    Science.gov (United States)

    Chatterjee, Animesh; Rathore, Anurag; Vidyant, Sanjukta; Kakkar, Kavita; Dhole, Tapan N

    2012-01-01

    A multitude of host genetic factors plays a crucial role in susceptibility to HIV-1 infection and progression to AIDS, which is highly variable among individuals and populations. This review focuses on the chemokine-receptor and chemokine genes, which were extensively studied because of their role as HIV co-receptor or co-receptor competitor and influences the susceptibility to HIV-1 infection and progression to AIDS in HIV-1 infected individuals.

  11. Chemokines and Chemokine Receptors in Susceptibility to HIV-1 Infection and Progression to AIDS

    Directory of Open Access Journals (Sweden)

    Animesh Chatterjee

    2012-01-01

    Full Text Available A multitude of host genetic factors plays a crucial role in susceptibility to HIV-1 infection and progression to AIDS, which is highly variable among individuals and populations. This review focuses on the chemokine-receptor and chemokine genes, which were extensively studied because of their role as HIV co-receptor or co-receptor competitor and influences the susceptibility to HIV-1 infection and progression to AIDS in HIV-1 infected individuals.

  12. The role of chemokines and chemokine receptors in eosinophil activation during inflammatory allergic reactions

    Directory of Open Access Journals (Sweden)

    Oliveira S.H.P.

    2003-01-01

    Full Text Available Chemokines are important chemotactic cytokines that play a fundamental role in the trafficking of leukocytes to sites of inflammation. They are also potent cell-activating factors, inducing cytokine and histamine release and free radical production, a fact that makes them particularly important in the pathogenesis of allergic inflammation. The action of chemokines is regulated at the level of agonist production and processing as well as at the level of receptor expression and coupling. Therefore, an analysis of the ligands must necessarily consider receptors. Eosinophils are target cells involved in the allergic inflammatory response since they are able to release a wide variety of mediators including CC and CXC chemokines and express their receptors. These mediators could damage the airway epithelial cells and might be important to stimulate other cells inducing an amplification of the allergic response. This review focuses on recently emerging data pertaining to the importance of chemokines and chemokine receptors in promoting eosinophil activation and migration during the allergic inflammatory process. The analysis of the function of eosinophils and their chemokine receptors during allergic inflammation might be a good approach to understanding the determinants of asthma severity and to developing novel therapies.

  13. Identification and mechanism of ABA receptor antagonism

    KAUST Repository

    Melcher, Karsten

    2010-08-22

    The phytohormone abscisic acid (ABA) functions through a family of fourteen PYR/PYL receptors, which were identified by resistance to pyrabactin, a synthetic inhibitor of seed germination. ABA activates these receptors to inhibit type 2C protein phosphatases, such as ABI1, yet it remains unclear whether these receptors can be antagonized. Here we demonstrate that pyrabactin is an agonist of PYR1 and PYL1 but is unexpectedly an antagonist of PYL2. Crystal structures of the PYL2-pyrabactin and PYL1-pyrabactin-ABI1 complexes reveal the mechanism responsible for receptor-selective activation and inhibition, which enables us to design mutations that convert PYL1 to a pyrabactin-inhibited receptor and PYL2 to a pyrabactin-activated receptor and to identify new pyrabactin-based ABA receptor agonists. Together, our results establish a new concept of ABA receptor antagonism, illustrate its underlying mechanisms and provide a rational framework for discovering novel ABA receptor ligands. © 2010 Nature America, Inc. All rights reserved.

  14. Chemokines and chemokine receptors in HIV infection: Role in pathogenesis and therapeutics

    Directory of Open Access Journals (Sweden)

    Suresh P

    2006-01-01

    Full Text Available Chemokines are known to function as regulatory molecules in leukocyte maturation, traffic, homing of lymphocytes and in the development of lymphoid tissues. Besides these functions in the immune system, certain chemokines and their receptors are involved in HIV pathogenesis. In order to infect a target cell, the HIV envelope glycoprotein gp120 has to interact with the cellular receptor CD-4 and co-receptor, CC or CXC chemokine receptors. Genetic findings have yielded major insights into the in vivo roles of individual co-receptors and their ligands in providing resistance to HIV infection. Mutations in chemokine receptor genes are associated with protection against HIV infections and also involved in delayed progression to AIDS in infected individuals. Blocking of chemokine receptors interrupts HIV infection in vitro and this offers new options for therapeutic strategies. Approaches have been made to study the CCR-5 inhibitors as antiviral therapies and possibly as components of a topical microbicide to prevent HIV-1 sexual transmission. Immune strategies aimed at generating anti-CCR-5 antibodies at the level of the genital mucosa might be feasible and represent a strategy to induce mucosal HIV- protective immunity. It also remains to be seen how these types of agents will act in synergy with existing HIV-1 targeted anti viral, or those currently in developments. Beyond providing new perspectives in fundamental aspects of the HIV-1 transmission and pathogenesis, chemokines and their receptors suggest new areas for developing novel therapeutic and preventive strategies against HIV infections. Studies in this review were identified through a search for relevant literature in the pubmed database of the national library of medicine. In this review, some developments in chemokine research with particular focus on their roles in HIV pathogenesis, resistance and therapeutic applications have been discussed.

  15. Rosacea: the Cytokine and Chemokine Network

    Science.gov (United States)

    Gerber, Peter Arne; Buhren, Bettina Alexandra; Steinhoff, Martin; Homey, Bernhard

    2013-01-01

    Rosacea is one of the most common dermatoses of adults. Recent studies have improved our understanding of the pathophysiology of rosacea. Current concepts suggest that known clinical trigger factors of rosacea such as UV radiation, heat, cold, stress, spicy food, and microbes modulate Toll-like receptor signaling, induce reactive oxygen species, as well as enhance antimicrobial peptide and neuropeptide production. Downstream of these events cytokines and chemokines orchestrate an inflammatory response that leads to the recruitment and activation of distinct leukocyte subsets and induces the characteristic histopathological features of rosacea. Here we summarize the current knowledge of the cytokine and chemokine network in rosacea and propose pathways that may be of therapeutic interest. PMID:22076326

  16. Synthesis of a novel tripeptidomimetic scaffold and biological evaluation for CXC chemokine receptor 4 (CXCR4) antagonism

    DEFF Research Database (Denmark)

    Baumann, Markus; Nome, Lina Marie; Zachariassen, Zack G.

    2017-01-01

    We here report the preparation of a new 2,6,8-trisubstituted bicyclic tripeptidomimetic scaffold through TFA-mediated cyclization of a linear precursor containing three side chains. The introduction of a triphenylmethyl-protected thiol into carboxylic acid containing building blocks through sulfa...... the stereochemical outcome of the cyclization differently when the R1 side chain is positioned on C2 in the bicycles (present work) instead of C3 (previous work). Tripeptidomimetic compounds based on the new scaffold were synthesized and evaluated for antagonistic potency toward CXCR4, and one compound (45a...

  17. Agonism and antagonism at the insulin receptor

    DEFF Research Database (Denmark)

    Knudsen, Louise; Hansen, Bo Falck; Jensen, Pia

    2012-01-01

    Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR) binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new...... insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs) and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs). In the case of the IR, no natural ligand or insulin analogue has been...... shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B'29). However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR...

  18. Structural Analysis of Chemokine Receptor–Ligand Interactions

    Science.gov (United States)

    2017-01-01

    This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines. These studies demonstrate how the integration of new structural information on chemokine receptors with extensive structure–activity relationship and site-directed mutagenesis data facilitates the prediction of the structure of chemokine receptor–ligand complexes that have not been crystallized. Finally, a review of structure-based ligand discovery and design studies based on chemokine receptor crystal structures and homology models illustrates the possibilities and challenges to find novel ligands for chemokine receptors. PMID:28165741

  19. Mechanisms and implications of air pollution particle associations with chemokines.

    Science.gov (United States)

    Seagrave, Jeanclare

    2008-11-01

    Inflammation induced by inhalation of air pollutant particles has been implicated as a mechanism for the adverse health effects associated with exposure to air pollution. The inflammatory response is associated with upregulation of various pro-inflammatory cytokines and chemokines. We have previously shown that diesel exhaust particles (DEP), a significant constituent of air pollution particulate matter in many urban areas, bind and concentrate IL-8, an important human neutrophil-attracting chemokine, and that the chemokine remains biologically active. In this report, we examine possible mechanisms of this association and the effects on clearance of the chemokine. The binding appears to be the result of ionic interactions between negatively charged particles and positively charged chemokine molecules, possibly combined with intercalation into small pores in the particles. The association is not limited to diesel exhaust particles and IL-8: several other particle types also adsorb the chemokine and several other cytokines are adsorbed onto the diesel particles. However, there are wide ranges in the effectiveness of various particle types and various cytokines. Finally, male Fisher 344 rats were intratracheally instilled with chemokine alone or combined with diesel exhaust or silica particles under isofluorane anesthesia. In contrast to silica particles, which do not bind the chemokine, the presence of diesel exhaust particles, which bind the chemokine, prolonged the retention of the chemokine.

  20. Profiling Heparin-Chemokine Interactions Using Synthetic Tools

    Science.gov (United States)

    de Paz, Jose L.; Moseman, E. Ashley; Noti, Christian; Polito, Laura; von Andrian, Ulrich H.; Seeberger, Peter H.

    2009-01-01

    Glycosaminoglycans (GAGs), such as heparin or heparan sulfate, are required for the in vivo function of chemokines. Chemokines play a crucial role in the recruitment of leukocyte subsets to sites of inflammation and lymphocytes trafficking. GAG-chemokine interactions mediate cell migration and determine which leukocyte subsets enter tissues. Identifying the exact GAC sequences that bind to particular chemokines is key to understand chemokine function at the molecular level and develop strategies to interfere with chemokine-mediated processes. Here, we characterize the heparin binding profiles of eight chemokines (CCL21, IL-8, CXCL12, CXCL13, CCL19, CCL25, CCL28, and CXCL16) by employing heparin microarrays containing a small library of synthetic heparin oligosaccharides. The chemokines differ significantly in their interactions with heparin oligosaccharides: While some chemokines, (e.g., CCL21) strongly bind to a hexasaccharide containing the GlcNSO3(6-OSO3)-IdoA(2-OSO3) repeating unit, CCL19 does not bind and CXCL12 binds only weakly. The carbohydrate microarray binding results were validated by surface plasmon resonance experiments. In vitro chemotaxis assays revealed that dendrimers coated with the fully sulfated heparin hexasaccharide inhibit lymphocyte migration toward CCL21. Migration toward CXCL12 or CCL19 was not affected. These in vitro homing assays indicate that multivalent synthetic heparin dendrimers inhibit the migration of lymphocytes toward certain chemokine gradients by blocking the formation of a chemokine concentration gradient on GAG endothelial chains. These findings are in agreement with preliminary in vivo measurements of circulating lymphocytes. The results presented here contribute to the understanding of GAG-chemokine interactions, a first step toward the design of novel drugs that modulate chemokine activity. PMID:18030990

  1. Platelet Activating Factor (PAF) Receptor Deletion or Antagonism Attenuates Severe HSV-1 Meningoencephalitis.

    Science.gov (United States)

    Vilela, Márcia Carvalho; Lima, Graciela Kunrath; Rodrigues, David Henrique; Lacerda-Queiroz, Norinne; Pedroso, Vinicius Sousa Pietra; de Miranda, Aline Silva; Rachid, Milene Alvarenga; Kroon, Erna Geessien; Campos, Marco Antônio; Teixeira, Mauro Martins; Teixeira, Antonio Lucio

    2016-12-01

    Herpes simplex virus type 1 (HSV-1) is a human pathogen that may cause severe encephalitis. The exacerbated immune response against the virus contributes to the disease severity and death. Platelet activating factor (PAF) is a mediator capable of inducing increase in vascular permeability, production of cytokines on endothelial cells and leukocytes. We aimed to investigate the activation of PAF receptor (PAFR) and its contribution to the severity of the inflammatory response in the brain following HSV-1 infection. C57BL/6 wild-type (WT) and PAFR deficient (PAFR-/-) mice were inoculated intracranially with 104 plaque-forming units (PFU) of HSV-1. Visualization of leukocyte recruitment was performed using intravital microscopy. Cells infiltration in the brain tissue were analyzed by flow cytometry. Brain was removed for chemokine assessment by ELISA and for histopathological analysis. The pharmacological inhibition by the PAFR antagonist UK-74,505 was also analyzed. In PAFR-/- mice, there was delayed lethality but no difference in viral load. Histopathological analysis of infected PAFR-/- mice showed that brain lesions were less severe when compared to their WT counterparts. Moreover, PAFR-/- mice showed less TCD4+, TCD8+ and macrophages in brain tissue. This reduction of the presence of leukocytes in parenchyma may be mechanistically explained by a decrease in leukocytes rolling and adhesion. PAFR-/- mice also presented a reduction of the chemokine CXCL9 in the brain. In addition, by antagonizing PAFR, survival of C57BL/6 infected mice increased. Altogether, our data suggest that PAFR plays a role in the pathogenesis of experimental HSV-1 meningoencephalitis, and its blockade prevents severe disease manifestation.

  2. Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

    Directory of Open Access Journals (Sweden)

    Högberg Thomas

    2007-02-01

    Full Text Available Abstract Background Mast cell-derived prostaglandin D2 (PGD2, may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2, a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology. Methods Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A2 receptor mTP, CRTH2 receptor, and selected anaphylatoxin and chemokines receptors were determined in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model. Results TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other receptors including the related anaphylatoxin C3a and C5a receptors, selected chemokine receptors and the cyclooxygenase isoforms 1 and 2 which are all recognized players in allergic diseases. Furthermore, TM30089 and ramatroban, the latter used as a reference herein, similarly inhibited asthma pathology in vivo by reducing peribronchial eosinophilia and mucus cell hyperplasia. Conclusion This is the first report to demonstrate anti-allergic efficacy in vivo of a highly selective small molecule CRTH2 antagonist. Our data suggest that CRTH2 antagonism alone is effective in mouse allergic airway inflammation even to the extent that this mechanism can explain the efficacy of ramatroban.

  3. CXC and CC Chemokines as Angiogenic Modulators in Nonhaematological Tumors

    Directory of Open Access Journals (Sweden)

    Matteo Santoni

    2014-01-01

    Full Text Available Chemokines are a superfamily of structurally homologous heparin-binding proteins that includes potent inducers and inhibitors of angiogenesis. The imbalance between angiogenic and angiostatic chemokine activities can lead to abnormalities, such as chronic inflammation, dysplastic transformation, and even tumor development and spreading. In this review, we summarize the current literature regarding the role of chemokines as modulators of tumor angiogenesis and their potential role as therapeutic targets in patients with nonhaematological tumors.

  4. Does Mineralocorticoid Receptor Antagonism Prevent Calcineurin Inhibitor-Induced Nephrotoxicity?

    Directory of Open Access Journals (Sweden)

    Line Aas Mortensen

    2017-11-01

    Full Text Available Calcineurin inhibitors have markedly reduced acute rejection rates in renal transplantation, thus significantly improved short-term outcome. The beneficial effects are, however, tampered by acute and chronic nephrotoxicity leading to interstitial fibrosis and tubular atrophy, which impairs long-term allograft survival. The mineralocorticoid hormone aldosterone induces fibrosis in numerous organs, including the kidney. Evidence from animal models suggests a beneficial effect of aldosterone antagonism in reducing calcineurin inhibitor-induced nephrotoxicity. This review summarizes current evidence of mineralocorticoid receptor antagonism in animal models of calcineurin inhibitor-induced nephrotoxicity and the results from studies of mineralocorticoid antagonism in renal transplant patients.

  5. Genomic organization, annotation, and ligand-receptor inferences of chicken chemokines and chemokine receptor genes based on comparative genomics

    Directory of Open Access Journals (Sweden)

    Sze Sing-Hoi

    2005-03-01

    Full Text Available Abstract Background Chemokines and their receptors play important roles in host defense, organogenesis, hematopoiesis, and neuronal communication. Forty-two chemokines and 19 cognate receptors have been found in the human genome. Prior to this report, only 11 chicken chemokines and 7 receptors had been reported. The objectives of this study were to systematically identify chicken chemokines and their cognate receptor genes in the chicken genome and to annotate these genes and ligand-receptor binding by a comparative genomics approach. Results Twenty-three chemokine and 14 chemokine receptor genes were identified in the chicken genome. All of the chicken chemokines contained a conserved CC, CXC, CX3C, or XC motif, whereas all the chemokine receptors had seven conserved transmembrane helices, four extracellular domains with a conserved cysteine, and a conserved DRYLAIV sequence in the second intracellular domain. The number of coding exons in these genes and the syntenies are highly conserved between human, mouse, and chicken although the amino acid sequence homologies are generally low between mammalian and chicken chemokines. Chicken genes were named with the systematic nomenclature used in humans and mice based on phylogeny, synteny, and sequence homology. Conclusion The independent nomenclature of chicken chemokines and chemokine receptors suggests that the chicken may have ligand-receptor pairings similar to mammals. All identified chicken chemokines and their cognate receptors were identified in the chicken genome except CCR9, whose ligand was not identified in this study. The organization of these genes suggests that there were a substantial number of these genes present before divergence between aves and mammals and more gene duplications of CC, CXC, CCR, and CXCR subfamilies in mammals than in aves after the divergence.

  6. Insulin Antagonizes Thrombin-Induced Microvessel Leakage.

    Science.gov (United States)

    Liu, Yan; Chen, Xue Lian; Wang, Lei; Martins-Green, Manuela

    2017-01-01

    Sustained increase in microvessel permeability results in cell and tissue damage. To date, it has not been possible to safely and specifically block increased microvessel permeability in vivo. We showed that insulin stimulates angiogenesis and that the new microvessels are associated with more αSMA-producing cells, suggesting greater stability. In this study, we show that local injection of insulin under the skin of mice significantly inhibits thrombin-induced microvessel permeability and that insulin improves the barrier function of primary human endothelial cells under conditions that mimic endothelium in vivo. These findings indicate that insulin antagonizes thrombin-induced microvessel permeability. At the cell and molecular levels, we show that insulin interferes with thrombin-induced VE-cadherin signaling by decreasing the ability of thrombin to induce VE-cadherin translocation to the cytoskeleton/nuclear compartment, leading to microvessel leakage. Simultaneously, the rapid activation of Src by insulin followed by the activation of Rac1, a small GTPase involved in cytoskeletal reorganization, leads to the maintenance of endothelial barrier, short-circuiting the slower thrombin-induced Src-RhoA signaling that leads to endothelial permeability. This novel mechanism by which insulin inhibits thrombin-induced permeability provides support for the use of insulin treatment in pathological conditions that involve blood-barrier dysfunction, especially as resuscitation treatment methods for extensive burns, sepsis, and other severe pathological conditions. © 2017 S. Karger AG, Basel.

  7. CXCR2 in Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    F. M. Konrad

    2012-01-01

    Full Text Available In pulmonary inflammation, recruitment of circulating polymorphonuclear leukocytes is essential for host defense and initiates the following specific immune response. One pathological hallmark of acute lung injury and acute respiratory distress syndrome is the uncontrolled transmigration of neutrophils into the lung interstitium and alveolar space. Thereby, the extravasation of leukocytes from the vascular system into the tissue is induced by chemokines that are released from the site of inflammation. The most relevant chemokine receptors of neutrophils are CXC chemokine receptor (CXCR 1 and CXCR2. CXCR2 is of particular interest since several studies implicate a pivotal role of this receptor in development and promotion of numerous inflammatory disorders. CXCR2 gets activated by ELR+ chemokines, including MIP-2, KC (rodents and IL-8 (human. Since multiple ELR+ CXC chemokines act on both receptors—CXCR1 and CXCR2—a pharmacologic agent blocking both receptors seems to be advantageous. So far, several CXCR1/2 antagonists have been developed and have been tested successfully in experimental studies. A newly designed CXCR1 and CXCR2 antagonist can be orally administered and was for the first time found efficient in humans. This review highlights the role of CXCR2 in acute lung injury and discusses its potential as a therapeutic target.

  8. Viral chemokine-modulatory proteins : tools and targets

    NARCIS (Netherlands)

    Boomker, JM; de Leij, LFMH; The, TH; Harmsen, MC

    The chemokine network is an extensive system that regulates many immune functions such as leukocyte locomotion, T cell differentiation, angiogenesis and mast cell degranulation. Tight control of chemokines is vital for proper immune function. Not surprisingly, viruses have found ways to subvert or

  9. Neonatal chemokine levels and risk of autism spectrum disorders

    DEFF Research Database (Denmark)

    Abdallah, Morsi; Larsen, Nanna; Grove, Jakob

    2013-01-01

    A potential role of chemokines in the pathophysiology of Autism Spectrum Disorders (ASDs) has been previously suggested. In a recent study we examined levels of three inflammatory chemokines (MCP-1, MIP-1a and RANTES) in samples of amniotic fluid of children diagnosed later in life with ASD...

  10. Chemokine-Derived Peptides: Novel Antimicrobial and Antineoplasic Agents

    Directory of Open Access Journals (Sweden)

    Julio Valdivia-Silva

    2015-06-01

    Full Text Available Chemokines are a burgeoning family of chemotactic cytokines displaying a broad array of functions such as regulation of homeostatic leukocyte traffic and development, as well as activating the innate immune system. Their role in controlling early and late inflammatory stages is now well recognized. An improper balance either in chemokine synthesis or chemokine receptor expression contributes to various pathological disorders making chemokines and their receptors a useful therapeutic target. Research in this area is progressing rapidly, and development of novel agents based on chemokine/ chemokine receptors antagonist functions are emerging as attractive alternative drugs. Some of these novel agents include generation of chemokine-derived peptides (CDP with potential agonist and antagonist effects on inflammation, cancer and against bacterial infections. CDP have been generated mainly from N- and C-terminus chemokine sequences with subsequent modifications such as truncations or elongations. In this review, we present a glimpse of the different pharmacological actions reported for CDP and our current understanding regarding the potential use of CDP alone or as part of the novel therapies proposed in the treatment of microbial infections and cancer.

  11. Chemokine Involvement in Fetal and Adult Wound Healing

    Science.gov (United States)

    Balaji, Swathi; Watson, Carey L.; Ranjan, Rajeev; King, Alice; Bollyky, Paul L.; Keswani, Sundeep G.

    2015-01-01

    Significance: Fetal wounds heal with a regenerative phenotype that is indistinguishable from surrounding skin with restored skin integrity. Compared to this benchmark, all postnatal wound healing is impaired and characterized by scar formation. The biologic basis of the fetal regenerative phenotype can serve as a roadmap to recapitulating regenerative repair in adult wounds. Reduced leukocyte infiltration, likely mediated, in part, through changes in the chemokine milieu, is a fundamental feature of fetal wound healing. Recent Advances: The contributions of chemokines to wound healing are a topic of active investigation. Recent discoveries have opened the possibility of targeting chemokines therapeutically to treat disease processes and improve healing capability, including the possibility of achieving a scarless phenotype in postnatal wounds. Critical Issues: Successful wound healing is a complex process, in which there is a significant interplay between multiple cell types, signaling molecules, growth factors, and extracellular matrix. Chemokines play a crucial role in this interplay and have been shown to have different effects in various stages of the healing process. Understanding how these chemokines are locally produced and regulated during wound healing and how the chemokine milieu differs in fetal versus postnatal wounds may help us identify ways in which we can target chemokine pathways. Future Directions: Further studies on the role of chemokines and their role in the healing process will greatly advance the potential for using these molecules as therapeutic targets. PMID:26543680

  12. Biased and g protein-independent signaling of chemokine receptors

    DEFF Research Database (Denmark)

    Steen, Anne; Larsen, Olav; Thiele, Stefanie

    2014-01-01

    a single chemokine may bind to several receptors - in both cases with the same functional outcome. The ubiquitous biased signaling confers a hitherto unknown specificity to the chemokine system with a complex interaction pattern that is better described as promiscuous with context-defined roles...

  13. Chemokine receptor CCR5 in interferon-treated multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, F; Kristiansen, T B; Wittenhagen, P

    2007-01-01

    To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta).......To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta)....

  14. 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).......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)....

  15. Agonism and antagonism at the insulin receptor.

    Directory of Open Access Journals (Sweden)

    Louise Knudsen

    Full Text Available Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs. In the case of the IR, no natural ligand or insulin analogue has been shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B'29. However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR antagonist, exhibited partial agonistic effects in the 1-10 nM range, showing altogether a bell-shaped dose-response curve. Intriguingly, the agonistic effects of S961 were seen only on mitogenic endpoints ((3H-thymidine incorporation, and not on metabolic endpoints ((14C-glucose incorporation in adipocytes and muscle cells. The agonistic effects of S961 were observed in 3 independent cell lines, with complete concordance between mitogenicity ((3H-thymidine incorporation and phosphorylation of the IR and Akt. Together with the B29-B'29 crosslinked dimer, S961 is a rare example of a mixed agonist/antagonist for the human IR. A plausible mechanistic explanation based on the bivalent crosslinking model of IR activation is proposed.

  16. Role of chemokines in rabies pathogenesis and protection.

    Science.gov (United States)

    Niu, Xuefeng; Wang, Hualei; Fu, Zhen F

    2011-01-01

    Chemokines are a family of structurally related proteins that are expressed by almost all types of nucleated cells and mediate leukocyte activation and/or chemotactic activities. The role of chemokines in rabies pathogenesis and protection has only recently been investigated. Expression of chemokines is induced by infection with laboratory-adapted, but not street, rabies viruses (RABVs), and it has been hypothesized that expression of chemokines is one of the mechanisms by which RABV is attenuated. To further define the role of chemokines in rabies pathogenesis and protection, chemokine genes such as MIP-1α, RANTES, IP-10, and macrophage-derived chemokine (MDC) have been cloned into RABV genome. It has been found that recombinant RABVs expressing RANTES or IP-10 induce high and persistent expression of these chemokines, resulting in massive infiltration of inflammatory cells into the central nervous system (CNS) and development of diseases and death in the mouse model. However, recombinant RABVs expressing MIP-1α, MDC, as well as GM-CSF further attenuate RABV by inducing a transient expression of chemokines, infiltration of inflammatory cells, enhancement of blood-brain barrier (BBB) permeability. Yet, these recombinant RABVs show increased adaptive immune responses by recruiting/activating dendritic cells, T and B cells in the periphery as well as in the CNS. Further, direct administration of these recombinant RABVs into the CNS can prevent mice from developing rabies days after infection with street RABV. All these studies together suggest that chemokines are both protective and pathogenic in RABV infections. Those with protective roles could be exploited for development of future RABV vaccines or therapeutic agents. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. Pathophysiology of chemokines and chemokine receptors in dermatological science: A focus on psoriasis and cutaneous T-cell lymphoma

    Directory of Open Access Journals (Sweden)

    Chih-Hung Lee

    2012-12-01

    Full Text Available Skin is an immunological organ with a delicate immunological network that governs the homeostasis and homing of the pro- and anti-inflammatory immune cells. Dysregulated immune response may result in psoriasis, a common inflammatory skin disease. Inappropriate immune surveillance, on the other hand, may cause the development of cutaneous lymphomas. Such homing of the immune cells likely depends on the interactions of chemokine and its receptors. Chemokine receptors and their corresponding chemokine ligands play key roles in the migration and localization of normal T cells in psoriasis and neoplastic T cells in cutaneous T-cell lymphoma (CTCL. While important in immune cell homing in psoriatic skin, chemokines and chemokine receptors may also be used for arrest, homing, and survival of neoplastic T cells in CTCL. In this review, we discuss roles of chemokine receptors, including those of CCR4 and CCR10 in the pathogenesis of CTCL, and of CCR6 in the pathogenesis of psoriasis. Targeting chemokines and chemokine receptors may lead to more effective treatments in these two skin diseases.

  18. Ligand-specific conformational transitions and intracellular transport required for atypical chemokine receptor 3-mediated chemokine scavenging.

    Science.gov (United States)

    Montpas, Nicolas; St-Onge, Geneviève; Nama, Nassr; Rhainds, David; Benredjem, Besma; Girard, Mélanie; Hickson, Gilles; Pons, Véronique; Heveker, Nikolaus

    2017-11-27

    The atypical chemokine receptor ACKR3 contributes to chemotaxis by binding, internalizing, and degrading the chemokines CXCL11 and CXCL12 to shape and terminate chemotactic gradients during development and immune responses. Although unable to trigger G protein activation, both ligands activate G protein-independent ACKR3 responses and prompt arrestin recruitment. This offers a model to specifically study ligand-specific receptor conformations leading to G protein-independent signaling, and to functional parameters such as receptor transport and chemokine degradation. We here show chemokine specificity in arrestin recruitment, by different effects of single amino acid substitutions in ACKR3 on arrestin in response to CXCL12 or CXCL11. Chemokine specificity in receptor transport was also observed, as CXCL11 induced faster receptor internalization, slower recycling, and longer intracellular sojourn of ACKR3 than CXCL12. Internalization and recycling rates of the ACKR3-R1423.50A substitution in response to each chemokine were similar; however, ACKR3-R1423.50A degraded only CXCL12, but not CXCL11. This suggests that ligand-specific intracellular receptor transport is required for chemokine degradation. Remarkably, failure of ACKR3-R1423.50A to degrade CXCL11 was not caused by the lacking arrestin recruitment; rather, arrestin was entirely dispensable for scavenging of either chemokine. This suggests involvement of another, yet unidentified, ACKR3 effector in scavenging. In summary, our study correlates ACKR3 ligand-specific conformational transitions with chemokine-dependent receptor transport dynamics and points toward unexpected ligand specificity in the mechanisms of chemokine degradation. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.

  19. Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV.

    Science.gov (United States)

    Zheng, Yi; Han, Gye Won; Abagyan, Ruben; Wu, Beili; Stevens, Raymond C; Cherezov, Vadim; Kufareva, Irina; Handel, Tracy M

    2017-06-20

    CCR5 is the primary chemokine receptor utilized by HIV to infect leukocytes, whereas CCR5 ligands inhibit infection by blocking CCR5 engagement with HIV gp120. To guide the design of improved therapeutics, we solved the structure of CCR5 in complex with chemokine antagonist [5P7]CCL5. Several structural features appeared to contribute to the anti-HIV potency of [5P7]CCL5, including the distinct chemokine orientation relative to the receptor, the near-complete occupancy of the receptor binding pocket, the dense network of intermolecular hydrogen bonds, and the similarity of binding determinants with the FDA-approved HIV inhibitor Maraviroc. Molecular modeling indicated that HIV gp120 mimicked the chemokine interaction with CCR5, providing an explanation for the ability of CCR5 to recognize diverse ligands and gp120 variants. Our findings reveal that structural plasticity facilitates receptor-chemokine specificity and enables exploitation by HIV, and provide insight into the design of small molecule and protein inhibitors for HIV and other CCR5-mediated diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Yi; Han, Gye Won; Abagyan, Ruben; Wu, Beili; Stevens, Raymond C.; Cherezov, Vadim; Kufareva, Irina; Handel, Tracy M. (USC); (Chinese Aca. Sci.); (UCSD)

    2017-06-01

    CCR5 is the primary chemokine receptor utilized by HIV to infect leukocytes, whereas CCR5 ligands inhibit infection by blocking CCR5 engagement with HIV gp120. To guide the design of improved therapeutics, we solved the structure of CCR5 in complex with chemokine antagonist [5P7]CCL5. Several structural features appeared to contribute to the anti-HIV potency of [5P7]CCL5, including the distinct chemokine orientation relative to the receptor, the near-complete occupancy of the receptor binding pocket, the dense network of intermolecular hydrogen bonds, and the similarity of binding determinants with the FDA-approved HIV inhibitor Maraviroc. Molecular modeling indicated that HIV gp120 mimicked the chemokine interaction with CCR5, providing an explanation for the ability of CCR5 to recognize diverse ligands and gp120 variants. Our findings reveal that structural plasticity facilitates receptor-chemokine specificity and enables exploitation by HIV, and provide insight into the design of small molecule and protein inhibitors for HIV and other CCR5-mediated diseases.

  1. Breast Cancer Vaccines Based on Dendritic Cells and the Chemokines

    National Research Council Canada - National Science Library

    Mule, James

    1998-01-01

    The major objective of this project is to establish a new modality for the treatment of breast cancer that employs the combination of chemokine gene-modified fibroblasts with breast tumor-pulsed dendritic cells (DC...

  2. Breast Cancer Vaccines Based on Dendritic Cells and the Chemokines

    National Research Council Canada - National Science Library

    Mule, James

    1997-01-01

    The major objective of this project is to establish a new modality for the treatment of breast cancer that employs the combination of chemokine gene modified fibroblasts with breast tumor pulsed dendritic cells (DC...

  3. [Chemokines and their participation in leukemic cells migration].

    Science.gov (United States)

    Parfieńczyk, Adam; Kiersnowska-Rogowska, Beata; Rogowski, Franciszek

    2003-11-01

    Impaired migration of leukocytes is characteristic feature of leukaemias. Knowledge of the mechanisms of leukaemia cells migration has expanded greatly in recent years. Leukocytes infiltrates are formed in surrounding tissues due to changes in chemokines and adhesion molecules concentrations. The adhesive interactions of cells with other cells and between cells and with the extracellular matrix are started by activation leukaemic leukocytes by specific chemokines. There are four groups of chemokines receptors: CXC, CC, C and CX3C. Unfortunately pathological processes of cells activation in the curse of leukaemias have not been fully explained yet. The paper presents current opinions about structure and role of some chemokines and their receptors in leukaemic cells migration.

  4. Cultured rat microglia express functional beta-chemokine receptors

    NARCIS (Netherlands)

    Boddeke, EWGM; Meigel, [No Value; Frentzel, S; Gourmala, NG; Harrison, JK; Buttini, M; Spleiss, O; Gebicke-Harter, P

    1999-01-01

    We have investigated the functional expression of the beta-chemokine receptors CCR1 to 5 in cultured rat microglia. RT-PCR analysis revealed constitutive expression of CCR1, CCR2 and CCR5 mRNA. The beta-chemokines MCP-1 (1-30 nM) as well as RANTES and MIP-1 alpha (100-1000 nM) evoked calcium

  5. Staphylococcal SSL5 inhibits leukocyte activation by chemokines and anaphylatoxins.

    Science.gov (United States)

    Bestebroer, Jovanka; van Kessel, Kok P M; Azouagh, Hafida; Walenkamp, Annemiek M; Boer, Ingrid G J; Romijn, Roland A; van Strijp, Jos A G; de Haas, Carla J C

    2009-01-08

    Staphylococcus aureus secretes several virulence factors modulating immune responses. Staphylococcal superantigen-like (SSL) proteins are a family of 14 exotoxins with homology to superantigens, but with generally unknown function. Recently, we showed that SSL5 binds to P-selectin glycoprotein ligand 1 dependently of sialyl Lewis X and inhibits P-selectin-dependent neutrophil rolling. Here, we show that SSL5 potently and specifically inhibits leukocyte activation by anaphylatoxins and all classes of chemokines. SSL5 inhibited calcium mobilization, actin polymerization, and chemotaxis induced by chemokines and anaphylatoxins but not by other chemoattractants. Antibody competition experiments showed that SSL5 targets several chemokine and anaphylatoxin receptors. In addition, transfection studies showed that SSL5 binds glycosylated N-termini of all G protein-coupled receptors (GPCRs) but only inhibits stimuli of protein nature that require the receptor N-terminus for activation. Furthermore, SSL5 increased binding of chemokines to cells independent of chemokine receptors through their common glycosaminoglycan-binding site. Importance of glycans was shown for both GPCR and chemokine binding. Thus, SSL5 is an important immunomodulatory protein of S aureus that targets several crucial, initial stages of leukocyte extravasation. It is therefore a potential new antiinflammatory compound for diseases associated with chemoattractants and their receptors and disorders characterized by excessive recruitment of leukocytes.

  6. Trichoderma spp. from rhizosphere soil and their antagonism ...

    African Journals Online (AJOL)

    Trichoderma spp. from rhizosphere soil and their antagonism against Fusarium sambucinum. ... Trichoderma virens. Among these isolates, D-3-1 (T. longibrachiatum) showed the strongest inhibition of the growth of Fusarium sambucinum. Key words: Trichoderma, potato, dry rot, biological control, Fusarium sambucinum.

  7. Rhubarb Antagonizes Matrix Metalloproteinase-9-induced Vascular Endothelial Permeability

    Directory of Open Access Journals (Sweden)

    Yun-Liang Cui

    2016-01-01

    Conclusions: The rhubarb mixture of emodin, 3,8-dihydroxy-1-methyl-anthraquinone-2-carboxylic acid, 1-O-caffeoyl-2-(4-hydroxyl-O-cinnamoyl-β-D-glucose, daucosterol linoleate, and rhein, at a low concentration, antagonized the MMP9-induced HUVEC monolayer permeability by promoting HUVEC proliferation and reducing extracellular VE-cadherin concentrations.

  8. Analysis of Determinants in Filovirus Glycoproteins Required for Tetherin Antagonism

    Directory of Open Access Journals (Sweden)

    Kerstin Gnirß

    2014-04-01

    Full Text Available The host cell protein tetherin can restrict the release of enveloped viruses from infected cells. The HIV-1 protein Vpu counteracts tetherin by removing it from the site of viral budding, the plasma membrane, and this process depends on specific interactions between the transmembrane domains of Vpu and tetherin. In contrast, the glycoproteins (GPs of two filoviruses, Ebola and Marburg virus, antagonize tetherin without reducing surface expression, and the domains in GP required for tetherin counteraction are unknown. Here, we show that filovirus GPs depend on the presence of their authentic transmembrane domains for virus-cell fusion and tetherin antagonism. However, conserved residues within the transmembrane domain were dispensable for membrane fusion and tetherin counteraction. Moreover, the insertion of the transmembrane domain into a heterologous viral GP, Lassa virus GPC, was not sufficient to confer tetherin antagonism to the recipient. Finally, mutation of conserved residues within the fusion peptide of Ebola virus GP inhibited virus-cell fusion but did not ablate tetherin counteraction, indicating that the fusion peptide and the ability of GP to drive host cell entry are not required for tetherin counteraction. These results suggest that the transmembrane domains of filoviral GPs contribute to tetherin antagonism but are not the sole determinants.

  9. Exploitative and hierarchical antagonism in a cooperative bacterium.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available Social organisms that cooperate with some members of their own species, such as close relatives, may fail to cooperate with other genotypes of the same species. Such noncooperation may take the form of outright antagonism or social exploitation. Myxococcus xanthus is a highly social prokaryote that cooperatively develops into spore-bearing, multicellular fruiting bodies in response to starvation. Here we have characterized the nature of social interactions among nine developmentally proficient strains of M. xanthus isolated from spatially distant locations. Strains were competed against one another in all possible pairwise combinations during starvation-induced development. In most pairings, at least one competitor exhibited strong antagonism toward its partner and a majority of mixes showed bidirectional antagonism that decreased total spore production, even to the point of driving whole populations to extinction. Differential response to mixing was the primary determinant of competitive superiority rather than the sporulation efficiencies of unmixed populations. In some competitive pairings, the dominant partner sporulated more efficiently in mixed populations than in clonal isolation. This finding represents a novel form of exploitation in bacteria carried out by socially competent genotypes and is the first documentation of social exploitation among natural bacterial isolates. Patterns of antagonistic superiority among these strains form a highly linear dominance hierarchy. At least some competition pairs construct chimeric, rather than segregated, fruiting bodies. The cooperative prokaryote M. xanthus has diverged into a large number of distinct social types that cooperate with clone-mates but exhibit intense antagonism toward distinct social types of the same species. Most lengthy migration events in nature may thus result in strong antagonism between migratory and resident populations, and this antagonism may have large effects on local

  10. Duffy antigen receptor for chemokines mediates chemokine endocytosis through a macropinocytosis-like process in endothelial cells.

    Directory of Open Access Journals (Sweden)

    Yani Zhao

    Full Text Available The Duffy antigen receptor for chemokines (DARC shows high affinity binding to multiple inflammatory CC and CXC chemokines and is expressed by erythrocytes and endothelial cells. Recent evidence suggests that endothelial DARC facilitates chemokine transcytosis to promote neutrophil recruitment. However, the mechanism of chemokine endocytosis by DARC remains unclear.We investigated the role of several endocytic pathways in DARC-mediated ligand internalization. Here we report that, although DARC co-localizes with caveolin-1 in endothelial cells, caveolin-1 is dispensable for DARC-mediated (125I-CXCL1 endocytosis as knockdown of caveolin-1 failed to inhibit ligand internalization. (125I-CXCL1 endocytosis by DARC was also independent of clathrin and flotillin-1 but required cholesterol and was, in part, inhibited by silencing Dynamin II expression.(125I-CXCL1 endocytosis was inhibited by amiloride, cytochalasin D, and the PKC inhibitor Gö6976 whereas Platelet Derived Growth Factor (PDGF enhanced ligand internalization through DARC. The majority of DARC-ligand interactions occurred on the endothelial surface, with DARC identified along plasma membrane extensions with the appearance of ruffles, supporting the concept that DARC provides a high affinity scaffolding function for surface retention of chemokines on endothelial cells.These results show DARC-mediated chemokine endocytosis occurs through a macropinocytosis-like process in endothelial cells and caveolin-1 is dispensable for CXCL1 internalization.

  11. Defining the chemokine basis for leukocyte recruitment during viral encephalitis.

    Science.gov (United States)

    Michlmayr, Daniela; McKimmie, Clive S; Pingen, Marieke; Haxton, Ben; Mansfield, Karen; Johnson, Nicholas; Fooks, Anthony R; Graham, Gerard J

    2014-09-01

    The encephalitic response to viral infection requires local chemokine production and the ensuing recruitment of immune and inflammatory leukocytes. Accordingly, chemokine receptors present themselves as plausible therapeutic targets for drugs aimed at limiting encephalitic responses. However, it remains unclear which chemokines are central to this process and whether leukocyte recruitment is important for limiting viral proliferation and survival in the brain or whether it is predominantly a driver of coincident inflammatory pathogenesis. Here we examine chemokine expression and leukocyte recruitment in the context of avirulent and virulent Semliki Forest virus (SFV) as well as West Nile virus infection and demonstrate rapid and robust expression of a variety of inflammatory CC and CXC chemokines in all models. On this basis, we define a chemokine axis involved in leukocyte recruitment to the encephalitic brain during SFV infection. CXCR3 is the most active; CCR2 is also active but less so, and CCR5 plays only a modest role in leukocyte recruitment. Importantly, inhibition of each of these receptors individually and the resulting suppression of leukocyte recruitment to the infected brain have no effect on viral titer or survival following infection with a virulent SFV strain. In contrast, simultaneous blockade of CXCR3 and CCR2 results in significantly reduced mortality in response to virulent SFV infection. In summary, therefore, our data provide an unprecedented level of insight into chemokine orchestration of leukocyte recruitment in viral encephalitis. Our data also highlight CXCR3 and CCR2 as possible therapeutic targets for limiting inflammatory damage in response to viral infection of the brain. Brain inflammation (encephalitis) in response to viral infection can lead to severe illness and even death. This therefore represents an important clinical problem and one that requires the development of new therapeutic approaches. Central to the pathogenesis of

  12. Correlation between lymph node pathology and chemokine expression during bovine tuberculosis.

    Science.gov (United States)

    Widdison, Stephanie; Watson, Michael; Coffey, Tracey J

    2009-11-01

    Bovine tuberculosis is a disease of worldwide importance yet comparatively little is known about chemokine responses to infection. We report on the levels of chemokine expression within lymph nodes of cattle infected with Mycobacterium bovis when infection would be well established. Expression levels of a number of chemokines were increased in infected cattle and could be correlated to levels of respective chemokine receptors. Several chemokines were significantly correlated to pathology within the lymph node, indicating a direct relationship between chemokine expression and disease. Vaccinated animals challenged with M. bovis had lower levels of chemokine expression than unvaccinated, challenged animals, correlating with lower levels of disease in vaccinated animals. The chemokine expression profile correlated with previous evidence for a pro-inflammatory bias within the lymph node. At this stage of infection we suggest there is on-going chemokine expression by cells associated with the granuloma and continual recruitment of cells to control infection.

  13. A novel highly potent therapeutic antibody neutralizes multiple human chemokines and mimics viral immune modulation.

    Science.gov (United States)

    Scalley-Kim, Michelle L; Hess, Bruce W; Kelly, Ryan L; Krostag, Anne-Rachel F; Lustig, Kurt H; Marken, John S; Ovendale, Pamela J; Posey, Aaron R; Smolak, Pamela J; Taylor, Janelle D L; Wood, C L; Bienvenue, David L; Probst, Peter; Salmon, Ruth A; Allison, Daniel S; Foy, Teresa M; Raport, Carol J

    2012-01-01

    Chemokines play a key role in leukocyte recruitment during inflammation and are implicated in the pathogenesis of a number of autoimmune diseases. As such, inhibiting chemokine signaling has been of keen interest for the development of therapeutic agents. This endeavor, however, has been hampered due to complexities in the chemokine system. Many chemokines have been shown to signal through multiple receptors and, conversely, most chemokine receptors bind to more than one chemokine. One approach to overcoming this complexity is to develop a single therapeutic agent that binds and inactivates multiple chemokines, similar to an immune evasion strategy utilized by a number of viruses. Here, we describe the development and characterization of a novel therapeutic antibody that targets a subset of human CC chemokines, specifically CCL3, CCL4, and CCL5, involved in chronic inflammatory diseases. Using a sequential immunization approach, followed by humanization and phage display affinity maturation, a therapeutic antibody was developed that displays high binding affinity towards the three targeted chemokines. In vitro, this antibody potently inhibits chemotaxis and chemokine-mediated signaling through CCR1 and CCR5, primary chemokine receptors for the targeted chemokines. Furthermore, we have demonstrated in vivo efficacy of the antibody in a SCID-hu mouse model of skin leukocyte migration, thus confirming its potential as a novel therapeutic chemokine antagonist. We anticipate that this antibody will have broad therapeutic utility in the treatment of a number of autoimmune diseases due to its ability to simultaneously neutralize multiple chemokines implicated in disease pathogenesis.

  14. Structural basis of ligand interaction with atypical chemokine receptor 3

    Science.gov (United States)

    Gustavsson, Martin; Wang, Liwen; van Gils, Noortje; Stephens, Bryan S.; Zhang, Penglie; Schall, Thomas J.; Yang, Sichun; Abagyan, Ruben; Chance, Mark R.; Kufareva, Irina; Handel, Tracy M.

    2017-01-01

    Chemokines drive cell migration through their interactions with seven-transmembrane (7TM) chemokine receptors on cell surfaces. The atypical chemokine receptor 3 (ACKR3) binds chemokines CXCL11 and CXCL12 and signals exclusively through β-arrestin-mediated pathways, without activating canonical G-protein signalling. This receptor is upregulated in numerous cancers making it a potential drug target. Here we collected over 100 distinct structural probes from radiolytic footprinting, disulfide trapping, and mutagenesis to map the structures of ACKR3:CXCL12 and ACKR3:small-molecule complexes, including dynamic regions that proved unresolvable by X-ray crystallography in homologous receptors. The data are integrated with molecular modelling to produce complete and cohesive experimentally driven models that confirm and expand on the existing knowledge of the architecture of receptor:chemokine and receptor:small-molecule complexes. Additionally, we detected and characterized ligand-induced conformational changes in the transmembrane and intracellular regions of ACKR3 that elucidate fundamental structural elements of agonism in this atypical receptor.

  15. Structural basis of ligand interaction with atypical chemokine receptor 3

    Energy Technology Data Exchange (ETDEWEB)

    Gustavsson, Martin; Wang, Liwen; van Gils, Noortje; Stephens, Bryan S.; Zhang, Penglie; Schall, Thomas J.; Yang, Sichun; Abagyan, Ruben; Chance, Mark R.; Kufareva, Irina; Handel, Tracy M.

    2017-01-18

    Chemokines drive cell migration through their interactions with seven-transmembrane (7TM) chemokine receptors on cell surfaces. The atypical chemokine receptor 3 (ACKR3) binds chemokines CXCL11 and CXCL12 and signals exclusively through β-arrestin-mediated pathways, without activating canonical G-protein signalling. This receptor is upregulated in numerous cancers making it a potential drug target. Here we collected over 100 distinct structural probes from radiolytic footprinting, disulfide trapping, and mutagenesis to map the structures of ACKR3:CXCL12 and ACKR3:small-molecule complexes, including dynamic regions that proved unresolvable by X-ray crystallography in homologous receptors. The data are integrated with molecular modelling to produce complete and cohesive experimentally driven models that confirm and expand on the existing knowledge of the architecture of receptor:chemokine and receptor:small-molecule complexes. Additionally, we detected and characterized ligand-induced conformational changes in the transmembrane and intracellular regions of ACKR3 that elucidate fundamental structural elements of agonism in this atypical receptor.

  16. Neutrophil recruitment, chemokine receptors, and resistance to mucosal infection.

    Science.gov (United States)

    Godaly, G; Bergsten, G; Hang, L; Fischer, H; Frendéus, B; Lundstedt, A C; Samuelsson, M; Samuelsson, P; Svanborg, C

    2001-06-01

    Neutrophil migration to infected mucosal sites involves a series of complex interactions with molecules in the lamina propria and at the epithelial barrier. Much attention has focussed on the vascular compartment and endothelial cells, but less is known about the molecular determinants of neutrophil behavior in the periphery. We have studied urinary tract infections (UTIs) to determine the events that initiate neutrophil recruitment and interactions of the recruited neutrophils with the mucosal barrier. Bacteria activate a chemokine response in uroepithelial cells, and the chemokine repertoire depends on the bacterial virulence factors and on the specific signaling pathways that they activate. In addition, epithelial chemokine receptor expression is enhanced. Interleukin (IL)-8 and CXCR1 direct neutrophil migration across the epithelial barrier into the lumen. Indeed, mIL-8Rh knockout mice showed impaired transepithelial neutrophil migration, with tissue accumulation of neutrophils, and these mice developed renal scarring. They had a defective antibacterial defense and developed acute pyelonephritis with bacteremia. Low CXCR1 expression was also detected in children with acute pyelonephritis. These results demonstrate that chemokines and chemokine receptors are essential to orchestrate a functional antimicrobial defense of the urinary tract mucosa. Mutational inactivation of the IL-8R caused both acute disease and chronic tissue damage.

  17. Chemokines in tuberculosis: The good, the bad and the ugly

    Science.gov (United States)

    Monin, Leticia; Khader, Shabaana A.

    2014-01-01

    Mycobacterium tuberculosis (Mtb) infects about one third of the world’s population, with a majority of infected individuals exhibiting latent asymptomatic infection, while 5–10% of infected individuals progress to active pulmonary disease. Research in the past two decades has elucidated critical host immune mechanisms that mediate Mtb control. Among these, chemokines have been associated with numerous key processes that lead to Mtb containment, from recruitment of myeloid cells into the lung to activation of adaptive immunity, formation of protective granulomas and vaccine recall responses. However, imbalances in several key chemokine mediators can alter the delicate balance of cytokines and cellular responses that promote mycobacterial containment, instead precipitating terminal tissue destruction and spread of Mtb infection. In this review, we will describe recent insights in the involvement of chemokines in host responses to Mtb infection and Mtb containment (the good), chemokines contributing to inflammation during TB (the bad), and the role of chemokines in driving cavitation and lung pathology (the ugly). PMID:25444549

  18. Smoking effect on chemokines of the human chronic periodontitis.

    Science.gov (United States)

    Souto, Giovanna Ribeiro; Queiroz-Junior, Celso Martins; Costa, Fernando Oliveira; Mesquita, Ricardo Alves

    2014-08-01

    Evaluate the effects of smoking on chemokines of the human chronic periodontitis (CP). Gingival samples were obtained from 23 smokers (S) and 20 non-smokers (NS) diagnosed with CP. Periodontal examination was performed. The CCL2, CCL3, CCL5, CCL19, CCL20, and CXCL8 chemokine levels were measured in gingival tissues using enzyme-linked immunosorbent assay. Chemokines were compared between S and NS, and were correlated with the number of cigarettes per day (C/day) and time of the smoking habit in years (SH/years). CCL3 and CXCL8 of S were significantly smaller than that found in NS subjects, whereas the CCL5 levels increased in the S group. Negative correlations could be observed between CCL19 levels and SH/year. Smoking suppresses the immune response which may contribute to an increased susceptibility to periodontal disease in smokers. Copyright © 2014 Elsevier GmbH. All rights reserved.

  19. Chemokines in the corpus luteum: Implications of leukocyte chemotaxis

    Directory of Open Access Journals (Sweden)

    Liptak Amy R

    2003-11-01

    Full Text Available Abstract Chemokines are small molecular weight peptides responsible for adhesion, activation, and recruitment of leukocytes into tissues. Leukocytes are thought to influence follicular atresia, ovulation, and luteal function. Many studies in recent years have focused attention on the characterization of leukocyte populations within the ovary, the importance of leukocyte-ovarian cell interactions, and more recently, the mechanisms of ovarian leukocyte recruitment. Information about the role of chemokines and leukocyte trafficking (chemotaxis during ovarian function is important to understanding paracrine-autocrine relationships shared between reproductive and immune systems. Recent advances regarding chemokine expression and leukocyte accumulation within the ovulatory follicle and the corpus luteum are the subject of this mini-review.

  20. Convergent evolution of escape from hepaciviral antagonism in primates.

    Directory of Open Access Journals (Sweden)

    Maulik R Patel

    Full Text Available The ability to mount an interferon response on sensing viral infection is a critical component of mammalian innate immunity. Several viruses directly antagonize viral sensing pathways to block activation of the host immune response. Here, we show that recurrent viral antagonism has shaped the evolution of the host protein MAVS--a crucial component of the viral-sensing pathway in primates. From sequencing and phylogenetic analyses of MAVS from 21 simian primates, we found that MAVS has evolved under strong positive selection. We focused on how this positive selection has shaped MAVS' susceptibility to Hepatitis C virus (HCV. We functionally tested MAVS proteins from diverse primate species for their ability to resist antagonism by HCV, which uses its protease NS3/4A to cleave human MAVS. We found that MAVS from multiple primates are resistant to inhibition by the HCV protease. This resistance maps to single changes within the protease cleavage site in MAVS, which protect MAVS from getting cleaved by the HCV protease. Remarkably, most of these changes have been independently acquired at a single residue 506 that evolved under positive selection. We show that "escape" mutations lower affinity of the NS3 protease for MAVS and allow it to better restrict HCV replication. We further show that NS3 proteases from all other primate hepaciviruses, including the highly divergent GBV-A and GBV-C viruses, are functionally similar to HCV. We conclude that convergent evolution at residue 506 in multiple primates has resulted in escape from antagonism by hepaciviruses. Our study provides a model whereby insights into the ancient history of viral infections in primates can be gained using extant host and virus genes. Our analyses also provide a means by which primates might clear infections by extant hepaciviruses like HCV.

  1. Interaction, synergy and antagonism in prospective epidemiological studies

    OpenAIRE

    Orellana, Juan J.; Departamento de Salud Pública, Facultad de Medicina, Universidad de La Frontera. Temuco, Chile. Centro de Capacitación Investigación y Gestión en Salud para la Medicina Basada en Evidencias (CIGES), Facultad de Medicina, Universidad de La Frontera. Temuco, Chile. Magister en Salud Pública.; Kaufman, Jay S.; Department of Epidemiology, Biostatistics and Occupational Health, McGill University. Quebec, Canada. PhD en Epidemiología.; Pino, Paulina; Escuela de Salud Pública, Facultad de Medicina, Universidad de Chile. Santiago de Chile, Chile. doctor en Salud Pública.

    2014-01-01

    In public health there is a growing appreciation for the advantage of the additive scale to better understand the impacts of factors involved in a health event. It is necessary to always remember that the concept of statistical interaction is scale dependent. In the causal relationship between a response and the presence of two or more factors, the concepts interaction, synergy and antagonism are the key ideas. The aim of this note is to show an application of the concepts interaction, sy...

  2. CXCR4 Antagonism Attenuates the Development of Diabetic Cardiac Fibrosis.

    Directory of Open Access Journals (Sweden)

    Po-Yin Chu

    Full Text Available Heart failure (HF is an increasingly recognized complication of diabetes. Cardiac fibrosis is an important causative mechanism of HF associated with diabetes. Recent data indicate that inflammation may be particularly important in the pathogenesis of cardiovascular fibrosis. We sought to determine the mechanism by which cardiac fibrosis develops and to specifically investigate the role of the CXCR4 axis in this process. Animals with type I diabetes (streptozotocin treated mice or type II diabetes (Israeli Sand-rats and controls were randomized to treatment with a CXCR4 antagonist, candesartan or vehicle control. Additional groups of mice also underwent bone marrow transplantation (GFP+ donor marrow to investigate the potential role of bone marrow derived cell mobilization in the pathogenesis of cardiac fibrosis. Both type I and II models of diabetes were accompanied by the development of significant cardiac fibrosis. CXCR4 antagonism markedly reduced cardiac fibrosis in both models of diabetes, similar in magnitude to that seen with candesartan. In contrast to candesartan, the anti-fibrotic actions of CXCR4 antagonism occurred in a blood pressure independent manner. Whilst the induction of diabetes did not increase the overall myocardial burden of GFP+ cells, it was accompanied by an increase in GFP+ cells expressing the fibroblast marker alpha-smooth muscle actin and this was attenuated by CXCR4 antagonism. CXCR4 antagonism was also accompanied by increased levels of circulating regulatory T cells. Taken together the current data indicate that pharmacological inhibition of CXCR4 significantly reduces diabetes induced cardiac fibrosis, providing a potentially important therapeutic approach.

  3. Convergent evolution of escape from hepaciviral antagonism in primates.

    Science.gov (United States)

    Patel, Maulik R; Loo, Yueh-Ming; Horner, Stacy M; Gale, Michael; Malik, Harmit S

    2012-01-01

    The ability to mount an interferon response on sensing viral infection is a critical component of mammalian innate immunity. Several viruses directly antagonize viral sensing pathways to block activation of the host immune response. Here, we show that recurrent viral antagonism has shaped the evolution of the host protein MAVS--a crucial component of the viral-sensing pathway in primates. From sequencing and phylogenetic analyses of MAVS from 21 simian primates, we found that MAVS has evolved under strong positive selection. We focused on how this positive selection has shaped MAVS' susceptibility to Hepatitis C virus (HCV). We functionally tested MAVS proteins from diverse primate species for their ability to resist antagonism by HCV, which uses its protease NS3/4A to cleave human MAVS. We found that MAVS from multiple primates are resistant to inhibition by the HCV protease. This resistance maps to single changes within the protease cleavage site in MAVS, which protect MAVS from getting cleaved by the HCV protease. Remarkably, most of these changes have been independently acquired at a single residue 506 that evolved under positive selection. We show that "escape" mutations lower affinity of the NS3 protease for MAVS and allow it to better restrict HCV replication. We further show that NS3 proteases from all other primate hepaciviruses, including the highly divergent GBV-A and GBV-C viruses, are functionally similar to HCV. We conclude that convergent evolution at residue 506 in multiple primates has resulted in escape from antagonism by hepaciviruses. Our study provides a model whereby insights into the ancient history of viral infections in primates can be gained using extant host and virus genes. Our analyses also provide a means by which primates might clear infections by extant hepaciviruses like HCV.

  4. 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.

  5. Macrophage-derived chemokine induces human eosinophil chemotaxis in a CC chemokine receptor 3- and CC chemokine receptor 4-independent manner.

    Science.gov (United States)

    Bochner, B S; Bickel, C A; Taylor, M L; MacGlashan, D W; Gray, P W; Raport, C J; Godiska, R

    1999-03-01

    Chemokines are believed to contribute to selective cell recruitment. Macrophage-derived chemokine (MDC) is a CC chemokine that causes chemotaxis of dendritic cells, monocytes, and activated natural killer cells. MDC binds to CC chemokine receptor 4 (CCR4) but not to CCR1, CCR2, CCR3, CCR5, CCR6, or CCR7. Our aim was to determine the in vitro activity of MDC on human eosinophils by using chemotaxis and calcium flux assays. Eosinophils were purified from peripheral blood of allergic donors, and chemotactic activity of MDC and other CC chemokines was compared in microchemotaxis chamber assays. The role of CCR3 in these assays was determined by using a CCR3-blocking antibody. Measurements of cytosolic Ca++ mobilization were performed by using fura-2AM labeling, with eosinophils and cell lines transfected with CCR3 or CCR4. Eosinophil expression of CCR3 and CCR4 mRNA was determined by using RT-PCR. MDC (0.1 to 100 nmol/L) caused dose-dependent chemotaxis of purified human eosinophils (maximum approximately 3-fold control). Compared with other CC chemokines, the potency and efficacy for eosinophil chemotaxis were similar for MDC and eotaxin but were less than that observed for RANTES, monocyte chemoattractant protein (MCP)-4, and eotaxin-2. Although MDC can act by means of CCR4, RT-PCR analysis failed to reveal CCR4 mRNA in eosinophils. Effects of MDC on eosinophils was also independent of CCR3, as a blocking mAb to CCR3 failed to inhibit MDC-induced chemotaxis. Furthermore, CCR3-transfected human embryonic kidney cells labeled with Fura-2AM exhibited a rapid rise in intracellular free calcium after stimulation with eotaxin, eotaxin-2, or MCP-4, but not with MDC. Eosinophils cultured for 72 hours in 10 ng/mL IL-5 also demonstrated increased intracellular free calcium after stimulation with eotaxin-2 or MCP-4, but not with up to 100 nmol/L MDC. MDC is a CCR3- and CCR4-independent activator of eosinophil chemotaxis, but it does not appear to elicit measurable cytosolic

  6. New members of the chemokine receptor gene family.

    Science.gov (United States)

    Raport, C J; Schweickart, V L; Chantry, D; Eddy, R L; Shows, T B; Godiska, R; Gray, P W

    1996-01-01

    Chemokines are relatively small peptides with potent chemoattractant and activation activities for leukocytes. Several chemokine receptors have been cloned and characterized and all are members of the G protein-coupled receptor superfamily. Using degenerate oligonucleotides and polymerase chain reaction, we have identified seven novel receptors. Two of these sequences are presented here for the first time. We have shown, with gene mapping studies, that receptors with the highest sequence similarity are closely linked on human chromosomes. This close genetic association suggests a functional relationship as well.

  7. Dual GPCR and GAG mimicry by the M3 chemokine decoy receptor

    Energy Technology Data Exchange (ETDEWEB)

    Alexander-Brett, Jennifer M.; Fremont, Daved H. (WU-MED)

    2008-09-23

    Viruses have evolved a myriad of evasion strategies focused on undermining chemokine-mediated immune surveillance, exemplified by the mouse {gamma}-herpesvirus 68 M3 decoy receptor. Crystal structures of M3 in complex with C chemokine ligand 1/lymphotactin and CC chemokine ligand 2/monocyte chemoattractant protein 1 reveal that invariant chemokine features associated with G protein-coupled receptor binding are primarily recognized by the decoy C-terminal domain, whereas the N-terminal domain (NTD) reconfigures to engage divergent basic residue clusters on the surface of chemokines. Favorable electrostatic forces dramatically enhance the association kinetics of chemokine binding by M3, with a primary role ascribed to acidic NTD regions that effectively mimic glycosaminoglycan interactions. Thus, M3 employs two distinct mechanisms of chemical imitation to potently sequester chemokines, thereby inhibiting chemokine receptor binding events as well as the formation of chemotactic gradients necessary for directed leukocyte trafficking.

  8. The chemokines secretion and the oxidative stress are targets of low-level laser therapy in allergic lung inflammation.

    Science.gov (United States)

    Costa Carvalho, Jorge Luis; de Brito, Auriléia Aparecida; de Oliveira, Ana Paula Ligeiro; de Castro Faria Neto, Hugo Caire; Pereira, Thiago Martini; de Carvalho, Regiane Albertini; Anatriello, Elen; Aimbire, Flávio

    2016-12-01

    Recent studies show that low-level laser therapy (LLLT) has an important anti-inflammatory action in acute lung inflammation. The present work explored if laser therapy is able to antagonize eosinophils and allergic inflammation induced by oxidative stress in Balb/c mice. Forty-eight hours after challenge, the leukocyte counting, ROS and nitrite/nitrate level, RANTES, CCL3, CCL8 as well as eotaxins were measured in the bronchoalveolar lavage fluid (BALF) of laser-treated mice or not. Into the lung, some chemokines receptors, the iNOS activity and mRNA expression, and the activities of superoxide dismutase (SOD), catalase, gluthatione, NADPH oxidase activities and thiobarbituric acid reactive species (T-Bars) were measured. Laser-treated allergic mice presented reduction of both the ICAM-1 and eosinophil in the lungs. RANTES, CCL8, CCL3 and eotaxins were reduced in BALF of laser-treated allergic mice. In allergic mice lung LLLT decreased the CCR1 and CCR3 and restored the oxidative stress balance as well. Laser decreased the lipidic peroxidation in allergic mice lung as much as increased SOD, GPx and GR. It shows that LLLT on allergic lung inflammation involves leukocyte-attractant chemokines and endogenous antioxidant. Based on results, LLLT may ultimately become a non- invasive option in allergic lung disease treatment. The top figure illustrates the laser decreasing the eosinophils migration into BALF and the bottom figure shows the laser upregulating the expression of heme-oxygenase (anti-oxidant enzyme) in lung tissue anti-oxidant. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Development of specific cytokine and Chemokine ELISAs for Bottlenose Dolphins

    Science.gov (United States)

    Earlier detection of changes in the health status of bottlenose dolphins (Tursiops truncatus) is expected to further improve their medical care. Cytokines and chemokines are critical mediators of the cellular immune response, and studies have suggested that these molecules may serve as important bio...

  10. Plasma concentration of thymus and activation-regulated chemokine ...

    African Journals Online (AJOL)

    Background: Thymus and activation-regulated chemokine (TARC) is responsible for trafficking of T helper 2 lymphocytes into sites of allergic inflammation. However, its role in assessing the severity of acute asthma in children is still unclear. Objective: We sought to evaluate plasma TARC as a marker for monitoring asthma ...

  11. Generating substrate bound functional chemokine gradients in vitro

    DEFF Research Database (Denmark)

    Hjortø, Gertrud Malene; Hansen, Morten; Larsen, Niels Bent

    2009-01-01

    Microcontact printing (mCP) is employed to generate discontinuous microscale gradients of active fractalkine, a chemokine expressed by endothelial cells near sites of inflammation where it is believed to form concentration gradients descending away from the inflamed area. In vivo, fractalkine...

  12. Lipid-cytokine-chemokine cascades orchestrate leukocyte recruitment in inflammation.

    Science.gov (United States)

    Sadik, Christian D; Luster, Andrew D

    2012-02-01

    Chemoattractants are pivotal mediators of host defense, orchestrating the recruitment of immune cells into sites of infection and inflammation. Chemoattractants display vast chemical diversity and include bioactive lipids, proteolytic fragments of serum proteins, and chemokines (chemotactic cytokines). All chemoattractants induce chemotaxis by activating seven-transmembrane-spanning GPCRs expressed on immune cells, establishing the concept that all chemoattractants are related in function. However, although chemoattractants have overlapping functions in vitro, recent in vivo data have revealed that they function, in many cases, nonredundantly in vivo. The chemically diverse nature of chemoattractants contributes to the fine control of leukocyte trafficking in vivo, with sequential chemoattractant use guiding immune cell recruitment into inflammatory sites. Lipid mediators frequently function as initiators of leukocyte recruitment, attracting the first immune cells into tissues. These initial responding immune cells produce cytokines locally, which in turn, induce the local release of chemokines. Local chemokine production then markedly amplifies subsequent waves of leukocyte recruitment. These new discoveries establish a paradigm for leukocyte recruitment in inflammation--described as lipid-cytokine-chemokine cascades--as a driving force in the effector phase of immune responses.

  13. Plasma macrophage-derived chemokine (CCL22) and its receptor ...

    African Journals Online (AJOL)

    Ehab

    childhood asthma in relation to disease activity, attack severity, and response to therapy, and to outline its value in differentiating ... adjuvant in the treatment of severe allergic disorders. Key words: MDC; CCR4; T-lymphocytes; ...... Williams TJ, Pease JE. Chemokines, innate and adaptive immunity, and respiratory disease.

  14. Chemokine receptor CCR5 in interferon-treated multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, F; Kristiansen, Thomas Birk; Wittenhagen, P

    2007-01-01

    OBJECTIVE: To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta). METHODS: The CCR5 Delta32 allele and a CCR5 promoter polymorphism associated with cell surface expression of CCR5 were...

  15. Cytokine and chemokine levels in tears from healthy subjects.

    Science.gov (United States)

    Carreño, Ester; Enríquez-de-Salamanca, Amalia; Tesón, Marisa; García-Vázquez, Carmen; Stern, Michael E; Whitcup, Scott M; Calonge, Margarita

    2010-11-01

    There is growing evidence for the existence of an 'immune tone' in normal tears. The aim of this study was to determine the levels of a large panel of cytokines and chemokines in tears obtained from healthy subjects. These levels can then serve as baseline values for comparison with patients suffering from ocular surface diseases. Nine healthy subjects participated in this study, and normal ocular surface health was documented by the results of a dry eye questionnaire, Schirmer strip wetting, and vital staining of the cornea. Four microliters of tears were collected from each eye and analysed separately with multiplex bead-based assays for the concentration of 30 cytokines and chemokines. Twenty-five cytokines/chemokines were detected. CCL11/Eotaxin1, GM-CSF, G-CSF, IFN-γ, IL-2, IL-3, IL-4, IL-5, IL-10, IL-13, IL-12p70, IL-15, CX3CL1/Fractalkine, TNF-α, epidermal growth factor, and CCL4/MIP-1β were present at 5-100 pg/ml. IL-1β, IL-6, IL-7A, CXCL8/IL-8, and CCL2/MCP-1 were present at 100-400 pg/ml. IL-1Ra, CXCL10/IP-10 and vascular endothelial growth factor were present at more than 1000 pg/ml. Multiplex bead-based assays are convenient for cytokine/chemokine detection in tears. Fracktalkine has been detected in human healthy tears for the first time. The knowledge of cytokine/chemokine concentrations in tears from normal subjects is an important reference for further comparison with patients suffering from ocular surface diseases. Variability in their levels can reflect a phenomenon of potential importance for the understanding of the ocular surface cytokine pattern. © 2010 The Authors. Journal compilation © 2010 Acta Ophthalmol.

  16. Role of Conserved Disulfide Bridges and Aromatic Residues in Extracellular Loop 2 of Chemokine Receptor CCR8 for Chemokine and Small Molecule Binding

    DEFF Research Database (Denmark)

    Barington, Line; Rummel, Pia C; Lückmann, Michael

    2016-01-01

    and aromatic residues in extracellular loop 2 (ECL2) for ligand binding and activation in the chemokine receptor CCR8. We used IP3 accumulation and radioligand binding experiments to determine the impact of receptor mutagenesis on both chemokine and small molecule agonist and antagonist binding and action...... in CCR8. We find that the 7 transmembrane (7TM) receptor conserved disulfide bridge (7TM bridge) linking transmembrane helix (TM)III and ECL2 is crucial for chemokine and small molecule action, whereas the chemokine receptor conserved disulfide bridge between the N terminus and TMVII is needed only...... for chemokines. Furthermore, we find that two distinct aromatic residues in ECL2, Y184 (Cys+1) and Y187 (Cys+4), are crucial for binding of the CC chemokines CCL1 (agonist) and MC148 (antagonist), respectively, but not for small molecule binding. Finally, using in silico modeling, we predict an aromatic cluster...

  17. Imbalances of chemokines, chemokine receptors and cytokines in Hodgkin lymphoma: classical Hodgkin lymphoma vs. Hodgkin-like ATLL.

    Science.gov (United States)

    Ohshima, Koichi; Karube, Kennosuke; Hamasaki, Makoto; Suefuji, Hiroaki; Tutiya, Takeshi; Yamaguchi, Takahiro; Suzumiya, Junji; Kikuchi, Masahiro

    2003-09-20

    Classical Hodgkin lymphoma (HL) is characterized by the presence of Hodgkin and Reed-Sternberg cells (H&RS) and a prominent lymphocytic infiltration. We previously reported Hodgkin-like adult T-cell leukemia/lymphoma (HL-like ATLL) (new WHO classification). Various CXC and CC chemokines are expressed on H&RS cells and the relationships between chemokines and the chemokine receptor (R) are thought to be important for selectivity of local immunity of Th1 and Th2 T cells. To clarify the role of T-cell immunity in classical HL and Hodgkin-like ATLL, we performed gene expression profiling (chemokine, chemokine R and cytokine DNA chips) in 12 cases [classical HL, 8 cases [mixed cellularity (MC) type, 4; nodular sclerosis (NS) type, 4]; Hodgkin-like ATLL, 4 cases] and immunohistochemical staining in 29 cases (MC, 10; NS, 10; Hodgkin-like ATLL, 9). EBV-infected H&RS cells were detected in 9 of 10 cases of HL MC, 5 of 9 of HL-like ATLL and 2 of 10 HL NS. T-cell-directed chemokine thymus- and activation-regulated chemokine (TARC)- and/or macrophage-derived chemokine (MDC)-positive H&RS cells were detected in all 20 cases of HL MC and HL NS but only in 5 of 9 cases of HL-like ATLL. Interferon-gamma-inducible protein-10 (IP10)- and monokine induced by interferon-gamma (MIG)-positive H&RS cells were detected in all 10 HL MC but only in 5 of 10 cases of HL NS and 2 of 9 cases of HL-like ATLL. However, 2 of 5 cases of HL-like ATLL with EBV infection and 2 of 2 HL NS with EBV had IP10/MIG-positive H&RS cells. The chemokine expressions in H&RS cells seemed to be associated with EBV infection rather than histologic subtypes. In the DNA chip expression analysis, classical HL and HL-like ATLL had a mixed Th1/Th2-type profile, and HL MC (EBV-positive) and HL NS (EBV-negative) were differentially clustered. However, 2 cases of HL-like ATLL clustered with HL MS and the other 2 cases of HL-like ATLL clustered with HL NS. The former HL-like ATLL had EBV infection in H&RS cells, whereas the

  18. What is pharmacological 'affinity'? Relevance to biased agonism and antagonism.

    Science.gov (United States)

    Kenakin, Terry

    2014-09-01

    The differences between affinity measurements made in binding studies and those relevant to receptor function are described. There are theoretical and practical reasons for not utilizing binding data and, in terms of the quantification of signaling bias, it is unnecessary to do so. Finally, the allosteric control of ligand affinity through receptor-signaling protein interaction is discussed within the context of biased antagonism. In this regard, it is shown that both the bias and relative efficacy of a ligand are essential data for fully predicting biased effects in vivo. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Building a new research framework for social evolution: intralocus caste antagonism.

    Science.gov (United States)

    Pennell, Tanya M; Holman, Luke; Morrow, Edward H; Field, Jeremy

    2018-01-16

    The breeding and non-breeding 'castes' of eusocial insects provide a striking example of role-specific selection, where each caste maximises fitness through different morphological, behavioural and physiological trait values. Typically, queens are long-lived egg-layers, while workers are short-lived, largely sterile foragers. Remarkably, the two castes are nevertheless produced by the same genome. The existence of inter-caste genetic correlations is a neglected consequence of this shared genome, potentially hindering the evolution of caste dimorphism: alleles that increase the productivity of queens may decrease the productivity of workers and vice versa, such that each caste is prevented from reaching optimal trait values. A likely consequence of this 'intralocus caste antagonism' should be the maintenance of genetic variation for fitness and maladaptation within castes (termed 'caste load'), analogous to the result of intralocus sexual antagonism. The aim of this review is to create a research framework for understanding caste antagonism, drawing in part upon conceptual similarities with sexual antagonism. By reviewing both the social insect and sexual antagonism literature, we highlight the current empirical evidence for caste antagonism, discuss social systems of interest, how antagonism might be resolved, and challenges for future research. We also introduce the idea that sexual and caste antagonism could interact, creating a three-way antagonism over gene expression. This includes unpacking the implications of haplodiploidy for the outcome of this complex interaction. © 2018 The Authors. Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.

  20. The role of chemokines in hypertension and consequent target organ damage.

    Science.gov (United States)

    Rudemiller, Nathan P; Crowley, Steven D

    2017-05-01

    Immune cells infiltrate the kidney, vasculature, and central nervous system during hypertension, consequently amplifying tissue damage and/or blood pressure elevation. Mononuclear cell motility depends partly on chemokines, which are small cytokines that guide cells through an increasing concentration gradient via ligation of their receptors. Tissue expression of several chemokines is elevated in clinical and experimental hypertension. Likewise, immune cells have enhanced chemokine receptor expression during hypertension, driving immune cell infiltration and inappropriate inflammation in cardiovascular control centers. T lymphocytes and monocytes/macrophages are pivotal mediators of hypertensive inflammation, and these cells migrate in response to several chemokines. As powerful drivers of diapedesis, the chemokines CCL2 and CCL5 have long been implicated in hypertension, but experimental data highlight divergent, context-specific effects of these chemokines on blood pressure and tissue injury. Several other chemokines, particularly those of the CXC family, contribute to blood pressure elevation and target organ damage. Given the significant interplay and chemotactic redundancy among chemokines during disease, future work must not only describe the actions of individual chemokines in hypertension, but also characterize how manipulating a single chemokine modulates the expression and/or function of other chemokines and their cognate receptors. This information will facilitate the design of precise chemotactic immunotherapies to limit cardiovascular and renal morbidity in hypertensive patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Alcohol, TLR4-TGF-β Antagonism, and Liver Cancer

    Science.gov (United States)

    Tsukamoto, Hidekazu; Mishra, Lopa; Machida, Keigo

    2016-01-01

    Alcohol abuse and obesity are two known risk factors for hepatocellular carcinoma (HCC) that also synergistically promote HBV/HCV-related carcinogenesis. TLR4, the PAMP for endotoxin participates in inflammatory processes such as M1 activation of hepatic macrophages in alcoholic liver disease. However its role in liver carcinogenesis via ectopic expression and activation, has only recently been revealed in alcohol/HCV-associated HCC models. Alcohol feeding to mice expressing the HCV Ns5a in a hepatocyte specific manner, aggravates liver inflammation via activation of overexpressed TLR4 in the parenchymal cells. Long-term alcohol feeding produces liver tumors in these transgenic mice in a manner dependent on TLR4. From these mice, CD133+/CD49f+ tumor initiating stem cell-like cells (TICs) have been isolated. These TICs exhibit self-renewal and tumorigenic activities driven by TLR4-dependent upregulation of the stem cell factor NANOG. Defective TGF-β tumor suppressor pathway is identified in the TICs and mediated by NANOG target genes Igf2bp3 and Yap1. This TGF-β pathway antagonism is responsible in part for TIC’s tumorigenic activity and chemoresistance. Conversely, mice with attenuated TGF-β pathway due to haploinsufficiency of β2-Spectrin, spontaneously develop liver tumors and alcohol-feeding increases tumor incidence in a TLR4 dependent manner. This reciprocal antagonism between TLR4 and TGF-β pathways may serve as a novel therapeutic target for HCC. PMID:26201318

  2. Fstl1 Antagonizes BMP Signaling and Regulates Ureter Development

    Science.gov (United States)

    Gong, Jianfeng; Yu, Mingyan; Zhang, Fangxiong; Sha, Haibo; Gao, Xiang

    2012-01-01

    Bone morphogenetic protein (BMP) signaling pathway plays important roles in urinary tract development although the detailed regulation of its activity in this process remains unclear. Here we report that follistatin-like 1 (Fstl1), encoding a secreted extracellular glycoprotein, is expressed in developing ureter and antagonizes BMP signaling activity. Mouse embryos carrying disrupted Fstl1 gene displayed prominent hydroureter arising from proximal segment and ureterovesical junction defects. These defects were associated with significant reduction in ureteric epithelial cell proliferation at E15.5 and E16.5 as well as absence of subepithelial ureteral mesenchymal cells in the urinary tract at E16.5 and E18.5. At the molecular level, increased BMP signaling was found in Fstl1 deficient ureters, indicated by elevated pSmad1/5/8 activity. In vitro study also indicated that Fstl1 can directly bind to ALK6 which is specifically expressed in ureteric epithelial cells in developing ureter. Furthermore, Sonic hedgehog (SHH) signaling, which is crucial for differentiation of ureteral subepithelial cell proliferation, was also impaired in Fstl1-/- ureter. Altogether, our data suggest that Fstl1 is essential in maintaining normal ureter development by antagonizing BMP signaling. PMID:22485132

  3. Antagonism trait facets and comprehensive psychosocial disability: Comparing information across self, informant, and interviewer reports.

    Science.gov (United States)

    Ro, Eunyoe; Nuzum, Hallie; Clark, Lee Anna

    2017-10-01

    It is widely known that personality traits collectively discussed as the Dark Triad are antagonistic and associated with poor interpersonal relationships, but few studies have examined how specific facets of antagonism are associated with psychosocial adjustment or how antagonism relates to psychosocial adjustment other than interpersonal functioning. The purpose of this study was to examine how 6 antagonism facets-manipulativeness, grandiosity, attention-seeking, hostility, callousness, and deceitfulness-relate to comprehensive psychosocial functional domains (i.e., well-being, interpersonal relationships, basic daily functioning) using information about both antagonism and functioning from 3 sources-self, informant, and interviewer. Data were from 318 primary participants and informants. We present 3 main findings: (1) When psychosocial functioning and antagonism traits were both rated by informants, all psychosocial disability domains were consistently positively associated with antagonism traits. (2) We next created a single psychosocial-disability factor score via principal factors analysis of all raters' psychosocial-functioning scores. When all 3 raters' reports of domain-level antagonism were used as independent variables in a simultaneous regression analysis to predict this overall functioning score, informant-reported antagonism most strongly predicted psychosocial functioning, followed by interviewer-rated antagonism. (3) We then created 6 facet scores by summing the 3 raters' scores on each. When we used these scores to predict psychosocial functioning, hostility was the main trait significantly predicting psychosocial functioning. The study provides further insight into associations of psychosocial disability with antagonism facets from different raters' perspectives. The findings thus further our understanding of psychosocial outcomes associated with antagonism, the core of the dark traits. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  4. Characterisation of SNP haplotype structure in chemokine and chemokine receptor genes using CEPH pedigrees and statistical estimation.

    Science.gov (United States)

    Clark, Vanessa J; Dean, Michael

    2004-03-01

    Chemokine signals and their cell-surface receptors are important modulators of HIV-1 disease and cancer. To aid future case/control association studies, aim to further characterise the haplotype structure of variation in chemokine and chemokine receptor genes. To perform haplotype analysis in a population-based association study, haplotypes must be determined by estimation, in the absence of family information or laboratory methods to establish phase. Here, test the accuracy of estimates of haplotype frequency and linkage disequilibrium by comparing estimated haplotypes generated with the expectation maximisation (EM) algorithm to haplotypes determined from Centre d'Etude Polymorphisme Humain (CEPH) pedigree data. To do this, they have characterised haplotypes comprising alleles at 11 biallelic loci in four chemokine receptor genes (CCR3, CCR2, CCR5 and CCRL2), which span 150 kb on chromosome 3p21, and haplotyes of nine biallelic loci in six chemokine genes [MCP-1(CCL2), Eotaxin(CCL11), RANTES(CCL5), MPIF-1(CCL23), PARC(CCL18) and MIP-1alpha(CCL3)] on chromosome 17q11-12. Forty multi-generation CEPH families, totalling 489 individuals, were genotyped by the TaqMan 5'-nuclease assay. Phased haplotypes and haplotypes estimated from unphased genotypes were compared in 103 grandparents who were assumed to have mated at random. For the 3p21 single nucleotide polymorphism (SNP) data, haplotypes determined by pedigree analysis and haplotypes generated by the EM algorithm were nearly identical. Linkage disequilibrium, measured by the D' statistic, was nearly maximal across the 150 kb region, with complete disequilibrium maintained at the extremes between CCR3-Y17Y and CCRL2-I243V. D'-values calculated from estimated haplotypes on 3p21 had high concordance with pairwise comparisons between pedigree-phased chromosomes. Conversely, there was less agreement between analyses of haplotype frequencies and linkage disequilibrium using estimated haplotypes when compared with

  5. Characterisation of SNP haplotype structure in chemokine and chemokine receptor genes using CEPH pedigrees and statistical estimation

    Directory of Open Access Journals (Sweden)

    Clark Vanessa J

    2004-03-01

    Full Text Available Abstract Chemokine signals and their cell-surface receptors are important modulators of HIV-1 disease and cancer. To aid future case/control association studies, aim to further characterise the haplotype structure of variation in chemokine and chemokine receptor genes. To perform haplotype analysis in a population-based association study, haplotypes must be determined by estimation, in the absence of family information or laboratory methods to establish phase. Here, test the accuracy of estimates of haplotype frequency and linkage disequilibrium by comparing estimated haplotypes generated with the expectation maximisation (EM algorithm to haplotypes determined from Centre d'Etude Polymorphisme Humain (CEPH pedigree data. To do this, they have characterised haplotypes comprising alleles at 11 biallelic loci in four chemokine receptor genes (CCR3, CCR2, CCR5 and CCRL2, which span 150 kb on chromosome 3p21, and haplotyes of nine biallelic loci in six chemokine genes [MCP-1(CCL2, Eotaxin(CCL11, RANTES(CCL5, MPIF-1(CCL23, PARC(CCL18 and MIP-1α(CCL3 ] on chromosome 17q11-12. Forty multi-generation CEPH families, totalling 489 individuals, were genotyped by the TaqMan 5'-nuclease assay. Phased haplotypes and haplotypes estimated from unphased genotypes were compared in 103 grandparents who were assumed to have mated at random. For the 3p21 single nucleotide polymorphism (SNP data, haplotypes determined by pedigree analysis and haplotypes generated by the EM algorithm were nearly identical. Linkage disequilibrium, measured by the D' statistic, was nearly maximal across the 150 kb region, with complete disequilibrium maintained at the extremes between CCR3-Y17Y and CCRL2-1243V. D'-values calculated from estimated haplotypes on 3p21 had high concordance with pairwise comparisons between pedigree-phased chromosomes. Conversely, there was less agreement between analyses of haplotype frequencies and linkage disequilibrium using estimated haplotypes when

  6. Chemokine Receptor Signatures in Allogeneic Stem Cell Transplantation

    Science.gov (United States)

    2015-08-01

    Porter DL (2015). “Reduced-intensity conditioning for allogeneic hematopoietic stem-cell transplantation in adults with acute myeloid leukemia .” Bone...Tallman MS, Wirk B, Bunjes DW, Devine SM, de Lima M, Weisdorf DJ, Uy GL (2015). “Allogeneic Hematopoietic Cell Transplant for Acute Myeloid Leukemia ...in target organs of GVHD. 15. SUBJECT TERMS CCR5, Chemokines, graft-versus-host disease 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT

  7. Chemokine Function in Periodontal Disease and Oral Cavity Cancer

    Directory of Open Access Journals (Sweden)

    Sinem Esra Sahingur

    2015-05-01

    Full Text Available The chemotactic cytokines, or chemokines, comprise a superfamily of polypeptides with a wide range of activities that include recruitment of immune cells to sites of infection and inflammation, as well as stimulation of cell proliferation. As such, they function as antimicrobial molecules and play a central role in host defenses against pathogen challenge. However, their ability to recruit leukocytes and potentiate or prolong the inflammatory response may have profound implications for the progression of oral diseases such as chronic periodontitis, where tissue destruction may be widespread. Moreover, it is increasingly recognized that chronic inflammation is a key component of tumor progression. Interaction between cancer cells and their microenvironment is mediated in large part by secreted factors such as chemokines, and serves to enhance the malignant phenotype in oral and other cancers. In this article, we will outline the biological and biochemical mechanisms of chemokine action in host-microbiome interactions in periodontal disease and in oral cancer, and how these may overlap and contribute to pathogenesis.

  8. Chemokine Function in Periodontal Disease and Oral Cavity Cancer

    Science.gov (United States)

    Sahingur, Sinem Esra; Yeudall, W. Andrew

    2015-01-01

    The chemotactic cytokines, or chemokines, comprise a superfamily of polypeptides with a wide range of activities that include recruitment of immune cells to sites of infection and inflammation, as well as stimulation of cell proliferation. As such, they function as antimicrobial molecules and play a central role in host defenses against pathogen challenge. However, their ability to recruit leukocytes and potentiate or prolong the inflammatory response may have profound implications for the progression of oral diseases such as chronic periodontitis, where tissue destruction may be widespread. Moreover, it is increasingly recognized that chronic inflammation is a key component of tumor progression. Interaction between cancer cells and their microenvironment is mediated in large part by secreted factors such as chemokines, and serves to enhance the malignant phenotype in oral and other cancers. In this article, we will outline the biological and biochemical mechanisms of chemokine action in host–microbiome interactions in periodontal disease and in oral cancer, and how these may overlap and contribute to pathogenesis. PMID:25999952

  9. Inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma.

    Science.gov (United States)

    Han, Ke-Qi; He, Xue-Qun; Ma, Meng-Yu; Guo, Xiao-Dong; Zhang, Xue-Min; Chen, Jie; Han, Hui; Zhang, Wei-Wei; Zhu, Quan-Gang; Nian, Hua; Ma, Li-Jun

    2015-04-28

    To study the inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma (HCC) in nude mice. CBRH-7919 HCC cells were injected into the subcutaneous region of nude mice. Beginning two weeks after the challenge, tumor growth was measured every week for six weeks. The stromal microenvironment and inflammatory cell infiltration was assessed by immunohistochemistry in paired tumor and adjacent peritumoral samples, and macrophage phenotype was assessed using double-stain immunohistochemistry incorporating expression of an intracellular enzyme. A chemokine PCR array, comprised of 98 genes, was used to screen differential gene expressions, which were validated by Western blotting. Additionally, expression of identified chemokines was knocked-down by RNA interference, and the effect on tumor growth was assessed. Inflammatory cell infiltrates are a key feature of adjacent peritumoral tissues with increased macrophage, neutrophil, and T cell (specifically helper and activated subsets) infiltration. Macrophages within adjacent peritumoral tissues express inducible nitric oxide synthase, suggestive of a proinflammatory phenotype. Fifty-one genes were identified in tumor tissues during the progression period, including 50 that were overexpressed (including CXCL1, CXCL2 and CXCL3) and three that were underexpressed (CXCR1, Ifg and Actb). RNA interference of CXCL1 in the CBRH-7919 cells decreased the growth of tumors in nude mice and inhibited expression of CXCL2, CXCL3 and interleukin-1β protein. These findings suggest that CXCL1 plays a critical role in tumor growth and may serve as a potential molecular target for use in HCC therapy.

  10. The herpesvirus 8-encoded chemokine vMIP-II, but not the poxvirus-encoded chemokine MC148, inhibits the CCR10 receptor

    DEFF Research Database (Denmark)

    Lüttichau, H R; Lewis, I C; Gerstoft, J

    2001-01-01

    The viral chemokine antagonist vMIP-II encoded by human herpesvirus 8 (HHV8) and MC148 encoded by the poxvirus - Molluscum contagiosum - were tested against the newly identified chemokine receptor CCR10. As the CCR10 ligand ESkine / CCL27 had the highest identity to MC148 and because both...

  11. Calcitonin gene-related peptide antagonism and cluster headache

    DEFF Research Database (Denmark)

    Ashina, Håkan; Newman, Lawrence; Ashina, Sait

    2017-01-01

    Calcitonin gene-related peptide (CGRP) is a key signaling molecule involved in migraine pathophysiology. Efficacy of CGRP monoclonal antibodies and antagonists in migraine treatment has fueled an increasing interest in the prospect of treating cluster headache (CH) with CGRP antagonism. The exact...... role of CGRP and its mechanism of action in CH have not been fully clarified. A search for original studies and randomized controlled trials (RCTs) published in English was performed in PubMed and in ClinicalTrials.gov . The search term used was "cluster headache and calcitonin gene related peptide......" and "primary headaches and calcitonin gene related peptide." Reference lists of identified articles were also searched for additional relevant papers. Human experimental studies have reported elevated plasma CGRP levels during both spontaneous and glyceryl trinitrate-induced cluster attacks. CGRP may play...

  12. Neuraxial Opioid-Induced Itch and Its Pharmacological Antagonism

    Science.gov (United States)

    2015-01-01

    Given its profound analgesic nature, neuraxial opioids are frequently used for pain management. Unfortunately, the high incident rate of itch/pruritus after spinal administration of opioid analgesics reported in postoperative and obstetric patients greatly diminishes patient satisfaction and thus the value of the analgesics. Many endeavors to solve the mystery behind neuraxial opioid-induced itch had not been successful, as the pharmacological antagonism other than the blockade of mu opioid receptors remains elusive. Nevertheless, as the characteristics of all opioid receptor subtypes have become more understood, more studies have shed light on the potential effective treatments. This review discusses the mechanisms underlying neuraxial opioid-induced itch and compares pharmacological evidence in nonhuman primates with clinical findings across diverse drugs. Both nonhuman primate and human studies corroborate that mixed mu/kappa opioid partial agonists seem to be the most effective drugs in ameliorating neuraxial opioid-induced itch while retaining neuraxial opioid-induced analgesia. PMID:25861787

  13. Interferon Induction by RNA Viruses and Antagonism by Viral Pathogens

    Directory of Open Access Journals (Sweden)

    Yuchen Nan

    2014-12-01

    Full Text Available Interferons are a group of small proteins that play key roles in host antiviral innate immunity. Their induction mainly relies on host pattern recognition receptors (PRR. Host PRR for RNA viruses include Toll-like receptors (TLR and retinoic acid-inducible gene I (RIG-I like receptors (RLR. Activation of both TLR and RLR pathways can eventually lead to the secretion of type I IFNs, which can modulate both innate and adaptive immune responses against viral pathogens. Because of the important roles of interferons, viruses have evolved multiple strategies to evade host TLR and RLR mediated signaling. This review focuses on the mechanisms of interferon induction and antagonism of the antiviral strategy by RNA viruses.

  14. Serum mucosa-associated epithelial chemokine in atopic dermatitis : A specific marker for severity

    Directory of Open Access Journals (Sweden)

    Ezzat MHM

    2009-01-01

    Full Text Available Background: Mucosa-associated epithelial chemokine (MEC; CCL28 is considered pivotal in mediating migration of CCR3 and CCR10-expressing skin-homing memory CLA + T cells. CCL28 is selectively and continuously expressed by epidermal keratinocytes, but highly upregulated in inflammatory skin diseases such as atopic dermatitis (AD. Aims: This controlled longitudinal study was designed to evaluate the expression of CCL28 serum levels in childhood AD and bronchial asthma (BA and its possible relations to disease severity and activity. Methods: Serum CCL28 levels were measured in 36 children with AD, 23 children with BA, and 14 children who had both conditions as well as in 21 healthy age and gender-matched subjects serving as controls. Sixteen patients in the AD group were followed-up and re-sampled for serum CCL28 after clinical remission. Serum CCL28 levels were correlated with some AD disease activity and severity variables. Results: Serum CCL28 levels in patients with AD whether during flare (median = 1530; mean ± SD = 1590.4 ± 724.3 pg/ml or quiescence (median = 1477; mean ± SD = 1575.2 ± 522.1 pg/ml were significantly higher than the values in healthy children (median = 301; mean ± SD = 189.6 ± 92.8 pg/ml. However, the levels during flare and quiescence were statistically comparable. The serum levels in BA (median = 340; mean ± SD = 201.6 ± 109.5 pg/ml were significantly lower than the AD group and comparable with the healthy control values. Serum CCL28 levels in severe AD were significantly higher as compared with mild and moderate cases and correlated positively to the calculated severity scores (LSS and SCORAD. CCL28 levels during exacerbation of AD could be positively correlated to the corresponding values during remission, the peripheral absolute eosinophil counts, and the serum lactate dehydrogenase levels. Serum CCL28 did not vary with the serum total IgE values in AD. Conclusion: Our data reinforce the concept that CCL28 might

  15. Hypothalamic Inflammation and Energy Balance Disruptions: Spotlight on Chemokines

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    Ophélia Le Thuc

    2017-08-01

    Full Text Available The hypothalamus is a key brain region in the regulation of energy balance as it controls food intake and both energy storage and expenditure through integration of humoral, neural, and nutrient-related signals and cues. Many years of research have focused on the regulation of energy balance by hypothalamic neurons, but the most recent findings suggest that neurons and glial cells, such as microglia and astrocytes, in the hypothalamus actually orchestrate together several metabolic functions. Because glial cells have been described as mediators of inflammatory processes in the brain, the existence of a causal link between hypothalamic inflammation and the deregulations of feeding behavior, leading to involuntary weight loss or obesity for example, has been suggested. Several inflammatory pathways that could impair the hypothalamic control of energy balance have been studied over the years such as, among others, toll-like receptors and canonical cytokines. Yet, less studied so far, chemokines also represent interesting candidates that could link the aforementioned pathways and the activity of hypothalamic neurons. Indeed, chemokines, in addition to their role in attracting immune cells to the inflamed site, have been suggested to be capable of neuromodulation. Thus, they could disrupt cellular activity together with synthesis and/or secretion of multiple neurotransmitters/mediators involved in the maintenance of energy balance. This review discusses the different inflammatory pathways that have been identified so far in the hypothalamus in the context of feeding behavior and body weight control impairments, with a particular focus on chemokines signaling that opens a new avenue in the understanding of the major role played by inflammation in obesity.

  16. Hypothalamic Inflammation and Energy Balance Disruptions: Spotlight on Chemokines.

    Science.gov (United States)

    Le Thuc, Ophélia; Stobbe, Katharina; Cansell, Céline; Nahon, Jean-Louis; Blondeau, Nicolas; Rovère, Carole

    2017-01-01

    The hypothalamus is a key brain region in the regulation of energy balance as it controls food intake and both energy storage and expenditure through integration of humoral, neural, and nutrient-related signals and cues. Many years of research have focused on the regulation of energy balance by hypothalamic neurons, but the most recent findings suggest that neurons and glial cells, such as microglia and astrocytes, in the hypothalamus actually orchestrate together several metabolic functions. Because glial cells have been described as mediators of inflammatory processes in the brain, the existence of a causal link between hypothalamic inflammation and the deregulations of feeding behavior, leading to involuntary weight loss or obesity for example, has been suggested. Several inflammatory pathways that could impair the hypothalamic control of energy balance have been studied over the years such as, among others, toll-like receptors and canonical cytokines. Yet, less studied so far, chemokines also represent interesting candidates that could link the aforementioned pathways and the activity of hypothalamic neurons. Indeed, chemokines, in addition to their role in attracting immune cells to the inflamed site, have been suggested to be capable of neuromodulation. Thus, they could disrupt cellular activity together with synthesis and/or secretion of multiple neurotransmitters/mediators involved in the maintenance of energy balance. This review discusses the different inflammatory pathways that have been identified so far in the hypothalamus in the context of feeding behavior and body weight control impairments, with a particular focus on chemokines signaling that opens a new avenue in the understanding of the major role played by inflammation in obesity.

  17. Chemokines in Cancer Development and Progression and Their Potential as Targeting Molecules for Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Naofumi Mukaida

    2014-01-01

    Full Text Available Chemokines were initially identified as bioactive substances, which control the trafficking of inflammatory cells including granulocytes and monocytes/macrophages. Moreover, chemokines have profound impacts on other types of cells associated with inflammatory responses, such as endothelial cells and fibroblasts. These observations would implicate chemokines as master regulators in various inflammatory responses. Subsequent studies have further revealed that chemokines can regulate the movement of a wide variety of immune cells including lymphocytes, natural killer cells, and dendritic cells in both physiological and pathological conditions. These features endow chemokines with crucial roles in immune responses. Furthermore, increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of cancer cells. It is widely acknowledged that cancer develops and progresses to invade and metastasize in continuous interaction with noncancerous cells present in cancer tissues, such as macrophages, lymphocytes, fibroblasts, and endothelial cells. The capacity of chemokines to regulate both cancerous and noncancerous cells highlights their crucial roles in cancer development and progression. Here, we will discuss the roles of chemokines in carcinogenesis and the possibility of chemokine targeting therapy for the treatment of cancer.

  18. Transcriptional Regulation of Chemokine Genes: A Link to Pancreatic Islet Inflammation?

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    Susan J. Burke

    2015-05-01

    Full Text Available Enhanced expression of chemotactic cytokines (aka chemokines within pancreatic islets likely contributes to islet inflammation by regulating the recruitment and activation of various leukocyte populations, including macrophages, neutrophils, and T-lymphocytes. Because of the powerful actions of these chemokines, precise transcriptional control is required. In this review, we highlight what is known about the signals and mechanisms that govern the transcription of genes encoding specific chemokine proteins in pancreatic islet β-cells, which include contributions from the NF-κB and STAT1 pathways. We further discuss increased chemokine expression in pancreatic islets during autoimmune-mediated and obesity-related development of diabetes.

  19. Chemokines accentuating protumoral activities in oral cancer microenvironment possess an imperious stratagem for therapeutic resolutions.

    Science.gov (United States)

    Panda, Swagatika; Padhiary, Subrat Kumar; Routray, Samapika

    2016-09-01

    Chemokines, the chemotactic cytokines have established their role in tumorigenesis and tumor progression. Studies, which explored their role in oral cancer for protumoral activity, point towards targeting chemokines for oral squamous cell carcinoma therapy. The need of the hour is to emphasize/divulge in the activities of chemokine ligands and their receptors in the tumor microenvironment for augmentation of such stratagems. This progressing sentience of chemokines and their receptors has inspired this review which is an endeavour to comprehend their role as an aid in accentuating hallmarks of cancer and targeted therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Chemokine in inflamed periodontal tissues activates healthy periodontal-ligament stem cell migration.

    Science.gov (United States)

    Lee, Jung-Seok; Lee, Jong-Bin; Cha, Jae-Kook; Choi, Eun-Young; Park, So-Yon; Cho, Kyoo-Sung; Kim, Chang-Sung

    2017-05-01

    The present study aimed to characterize the expression pattern of chemokines obtained from inflamed periodontal defects and to determine the characteristics of human periodontal-ligament stem cells (hPDLSCs) migrated by each specific chemokine. Both inflamed and healthy periodontal tissues were obtained from periodontitis patients (n = 11), and the chemokine expression levels were analyzed. The periodontal-tissue-specific chemokines were applied to healthy hPDLSCs from extracted teeth (n = 3), with FGF-2 acting as a positive control. Cells were separated by selected chemokines using transwell method into migrated/unmigrated hPDLSCs. The characteristics of the hPDLSC subpopulation recruited by each chemokine were assessed, and gene expression pattern was analyzed by microarray. Chemokines were categorized into three groups by specific patterns of "appearing," "increasing," and "decreasing/disappearing" from healthy to inflamed tissues. A representative chemokine from each group enhanced the capacities for colony formation and osteogenic/adipogenic differentiation while maintaining the surface markers of hPDLSCs. RANTES/CCL5 significantly increased the cellular migration of hPDLSCs, via enhancement of signaling pathways, regulation of the actin skeleton, and focal adhesion. The present study found a specific chemokine profile induced by inflammation in periodontal tissues, with RANTES/CCL5 appearing to play a role in the migration of hPDLSCs into inflammatory periodontal lesions. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. The evolution of reduced antagonism--A role for host-parasite coevolution.

    Science.gov (United States)

    Gibson, A K; Stoy, K S; Gelarden, I A; Penley, M J; Lively, C M; Morran, L T

    2015-11-01

    Why do some host-parasite interactions become less antagonistic over evolutionary time? Vertical transmission can select for reduced antagonism. Vertical transmission also promotes coevolution between hosts and parasites. Therefore, we hypothesized that coevolution itself may underlie transitions to reduced antagonism. To test the coevolution hypothesis, we selected for reduced antagonism between the host Caenorhabditis elegans and its parasite Serratia marcescens. This parasite is horizontally transmitted, which allowed us to study coevolution independently of vertical transmission. After 20 generations, we observed a response to selection when coevolution was possible: reduced antagonism evolved in the copassaged treatment. Reduced antagonism, however, did not evolve when hosts or parasites were independently selected without coevolution. In addition, we found strong local adaptation for reduced antagonism between replicate host/parasite lines in the copassaged treatment. Taken together, these results strongly suggest that coevolution was critical to the rapid evolution of reduced antagonism. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

  2. CD8 chemokine receptors in chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Smyth, L J C; Starkey, C; Gordon, F S

    2008-01-01

    Increased lung CD8 cells and their expression of chemokine receptors CXCR3 and CCR5 have been previously reported in chronic obstructive pulmonary disease (COPD). Alterations of CD8-CCR3 and -CCR4 expression and their ligands in COPD patients have not been fully investigated. The objective...... there was low level CCL11 production. CD8CCR3 and CCR5 expression appear to be regulated by cigarette smoke exposure. We show that COPD lung tissue released more CCL5, suggesting a role for CCL5-CCR3 signalling in pulmonary CD8 recruitment in COPD....

  3. Circulating chemokine ligand levels before and after successful kidney transplantation

    Directory of Open Access Journals (Sweden)

    Hamdi Elmoselhi

    2016-10-01

    Full Text Available Abstract Background Chemokine ligands (CCLs play a pivotal role in tissue injury before and after kidney transplantation. Meanwhile, transplantation improves patient’s survival and diminishes morbidity. It is hypothesized, then, that kidney transplantation diminishes pre-transplant (pre-TX levels of circulating inflammatory CCLs. This retrospective study compared circulating levels and profiles of CCLs before transplantation (pre-TX and after transplantation (post-TX. Methods Nineteen CCLs (1, 2, 3, 4, 5, 8, 11, 13, 15, 17, 21, 24, 26, 27, CXCL 5, 8, 10, 12 and 13 were measured in 47 stable post-TX recipients, and their stored pre-TX plasma was analyzed by multiplexed fluorescent bead-based immunoassay. Twenty normal controls were included for comparisons. Normalized data was presented as mean ± SD and non-normalized data as median (5–95 % CI. Significance was measured at p < 0.01. Arbitrary upper and lower margins for each CCL at the 95 % CI or 2SD levels in each group were chosen to calculate the percentile of patients in the other group who exceeded these limits. Significant CCL levels present in more than 75 % of patients in a group that exceeded the arbitrary upper or lower set margins in the other two groups were labeled as preferentially characteristic for the respective group. Results More than 75 % of pre- and post-TX patients had levels that exceeded the upper control for CCL1, 11, 15 and CCL15, CCL26 and CXCL13 levels, respectively. More than 75 % of pre- and post-TX patients exceeded the lower control for CCL3, 21, and CCL5 limits, respectively. More than 75 % of post-TX patients demonstrated elevated levels of CCL2, 3, 21, 26 and CXCL13 above the upper pre-TX cut offs. Meanwhile, more than 75 % of post-TX patients exceeded the lower pre-TX levels for CCL1, 4, 5, 8, 13, 15, 17, 24 and CXCL8 and10. Pre-TX was preferentially characterized by elevated CCL1 and 15 and diminished CCL3 and 21. Post-TX was preferentially

  4. The role of chemokines and cytokines in lung fibrosis

    Directory of Open Access Journals (Sweden)

    M. P. Keane

    2008-12-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF exhibits a complex and poorly understood pathogenesis. Overt inflammation in the lungs of patients with established IPF is absent, and classic anti-inflammatory therapies are inefficacious; however, inflammation may contribute to the disruption of the normal alveolar architecture, allowing interaction between fibroblasts and the epithelium. The polarisation of the inflammatory response toward a type-2 helper T-cell phenotype may also be important in the development of pulmonary fibrosis, as fibroproliferation could be favoured over repair. Furthermore, evidence has emerged regarding an imbalance between angiogenic and angiostatic chemokine levels, leading to an overall angiogenic pattern of expression in both animal models and tissue specimens from IPF patients. The precise role of vascular remodelling in IPF remains to be determined. Therefore, numerous questions exist regarding the role and importance of chemokines and cytokines in pulmonary fibrosis. Further investigation is required to facilitate the elucidation of IPF pathogenesis and identification of novel targets for treatment of this dismal disease.

  5. Role of chemokines in the pathogenesis of rheumatoid synovitis

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    N. Pipitone

    2011-09-01

    Full Text Available Chemokines play a central role in the pathogenesis of rheumatoid arthritis (RA synovitis which is characterised by new blood vessel formation, thickening of the lining layer and infiltration of immune cells. The inflammatory infiltrate is generated by a series of events which include the recruitment of leukocytes from the blood stream into the tissue, their local retention and activation to effector cells. All these processes are finely regulated by the interplay of different cell adhesion molecules (CAMs and chemoattractant factors called chemokines (CK. CK are a superfamily of small proteins that play a crucial role in immune and inflammatory reactions. These chemoattractant cytokines share structural similarities including four conserved cysteine residues which form disulphide bonds in the tertiary structure of the proteins. CK mediate their effects by binding specific receptors (CK-R characterised by a domain structure which spans the cell membrane seven times and signal through heterotrimeric GPT-binding proteins. Activation of the CK network results in an amplification of the inflammatory cascade and consequently in the progressive destruction of RA joints. The recognition of the central role of CK in inflammation has paved the way to the development of new agents capable of interfering with CK and CK-R. This review will focus in particular on the role of CK in regulating leukocyte trafficking in RA joints.

  6. Chemokine receptor expression by inflammatory T cells in EAE

    DEFF Research Database (Denmark)

    Mony, Jyothi Thyagabhavan; Khorooshi, Reza; Owens, Trevor

    2014-01-01

    for IFNγ, IL-17A, and the Th1 and Th17-associated transcription factors T-bet and RORγt was detected in both CCR6(+) and CXCR3(+) CD4(+) T cells. IFNγ, but not IL-17A mRNA expression was detected in CD8(+) T cells in CNS. CCR6 and CD4 were co-localized in spinal cord infiltrates by double......Chemokines direct cellular infiltration to tissues, and their receptors and signaling pathways represent targets for therapy in diseases such as multiple sclerosis (MS). The chemokine CCL20 is expressed in choroid plexus, a site of entry of T cells to the central nervous system (CNS). The CCL20...... receptor CCR6 has been reported to be selectively expressed by CD4(+) T cells that produce the cytokine IL-17 (Th17 cells). Th17 cells and interferon-gamma (IFNγ)-producing Th1 cells are implicated in induction of MS and its animal model experimental autoimmune encephalomyelitis (EAE). We have assessed...

  7. Atypical chemokine receptor 4 shapes activated B cell fate.

    Science.gov (United States)

    Kara, Ervin E; Bastow, Cameron R; McKenzie, Duncan R; Gregor, Carly E; Fenix, Kevin A; Babb, Rachelle; Norton, Todd S; Zotos, Dimitra; Rodda, Lauren B; Hermes, Jana R; Bourne, Katherine; Gilchrist, Derek S; Nibbs, Robert J; Alsharifi, Mohammed; Vinuesa, Carola G; Tarlinton, David M; Brink, Robert; Hill, Geoffrey R; Cyster, Jason G; Comerford, Iain; McColl, Shaun R

    2018-01-31

    Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate. © 2018 Kara et al.

  8. [Hypothalamic inflammation and energy balance deregulations: focus on chemokines.

    Science.gov (United States)

    Le Thuc, Ophélia; Rovère, Carole

    2016-01-01

    The hypothalamus is a key brain region in the regulation of energy balance. It especially controls food intake and both energy storage and expenditure through integration of humoral, neural and nutrient-related signals and cues. Hypothalamic neurons and glial cells act jointly to orchestrate, both spatially and temporally, regulated metabolic functions of the hypothalamus. Thus, the existence of a causal link between hypothalamic inflammation and deregulations of feeding behavior, such as involuntary weight-loss or obesity, has been suggested. Among the inflammatory mediators that could induce deregulations of hypothalamic control of the energy balance, chemokines represent interesting candidates. Indeed, chemokines, primarily known for their chemoattractant role of immune cells to the inflamed site, have also been suggested capable of neuromodulation. Thus, chemokines could disrupt cellular activity together with synthesis and/or secretion of multiple neurotransmitters/mediators that are involved in the maintenance of energy balance. Here, we relate, on one hand, recent results showing the primary role of the central chemokinergic signaling CCL2/CCR2 for metabolic and behavioral adaptation to high-grade inflammation, especially loss of appetite and weight, through its activity on hypothalamic neurons producing the orexigenic peptide Melanin-Concentrating Hormone (MCH) and, on the other hand, results that suggest that chemokines could also deregulate hypothalamic neuropeptidergic circuits to induce an opposite phenotype and eventually participate in the onset/development of obesity. In more details, we will emphasize a study recently showing, in a model of high-grade acute inflammation of LPS injection in mice, that central CCL2/CCR2 signaling is of primary importance for several aspects explaining weight loss associated with inflammation: after LPS injection, animals lose weight, reduce their food intake, increase their fat oxidation (thus energy consumption from

  9. The imidazobenzodiazepine Ro 15-4513 antagonizes methoxyflurane anesthesia.

    Science.gov (United States)

    Moody, E J; Skolnick, P

    1988-01-01

    Parenteral administration of the imidazobenzodiazepine Ro 15-4513 (a high affinity ligand of the benzodiazepine receptor with partial inverse agonist qualities) produced a dose dependent reduction in sleep time of mice exposed to the inhalation anesthetic, methoxyflurane. The reductions in methoxyflurane sleep time ranged from approximately 20% at 4 mg/kg to approximately 38% at 32 mg/kg of Ro 15-4513. Co-administration of the benzodiazepine receptor antagonist Ro 15-1788 (16 mg/kg) or the inverse agonists DMCM (5-20 mg/kg) and FG 7142 (22.5 mg/kg) blocks this effect which suggests that the reductions in methoxyflurane sleep time produced by Ro 15-4513 are mediated via occupation of benzodiazepine receptors. Moreover, neither DMCM (5-20 mg/kg) nor FG 7142 (22.5 mg/kg) reduced methoxyflurane sleep time which suggests this effect of Ro 15-4513 cannot be attributed solely to its partial inverse agonist properties. These observations support recent findings that inhalation anesthetics may produce their depressant effects via perturbation of the benzodiazepine/GABA receptor chloride channel complex, and suggest that Ro 15-4513 may serve as a prototype of agents capable of antagonizing the depressant effects of inhalation anesthetics such as methoxyflurane.

  10. Kefiran antagonizes cytopathic effects of Bacillus cereus extracellular factors.

    Science.gov (United States)

    Medrano, Micaela; Pérez, Pablo Fernando; Abraham, Analía Graciela

    2008-02-29

    Kefiran, the polysaccharide produced by microorganisms present in kefir grains, is a water-soluble branched glucogalactan containing equal amounts of D-glucose and D-galactose. In this study, the effect of kefiran on the biological activity of Bacillus cereus strain B10502 extracellular factors was assessed by using cultured human enterocytes (Caco-2 cells) and human erythrocytes. In the presence of kefiran concentrations ranging from 300 to 1000 mg/L, the ability of B. cereus B10502 spent culture supernatants to detach and damage cultured human enterocytes was significantly abrogated. In addition, mitochondrial dehydrogenase activity was higher when kefiran was present during the cell toxicity assays. Protection was also demonstrated in hemolysis and apoptosis/necrosis assays. Scanning electron microscopy showed the protective effect of kefiran against structural cell damages produced by factors synthesized by B. cereus strain B10502. Protective effect of kefiran depended on strain of B. cereus. Our findings demonstrate the ability of kefiran to antagonize key events of B. cereus B10502 virulence. This property, although strain-specific, gives new perspectives for the role of bacterial exopolysaccharides in functional foods.

  11. Efficacy of Tie2 Receptor Antagonism in Angiosarcoma

    Directory of Open Access Journals (Sweden)

    Jason R. Hasenstein

    2012-02-01

    Full Text Available Angiosarcomas are malignant endothelial cell tumors with few effective systemic treatments. Despite a unique endothelial origin, molecular candidates for targeted therapeutic intervention have been elusive. In this study, we explored the tunica internal endothelial cell kinase 2 (Tie2 receptor as a potential therapeutic target in angiosarcoma. Human angiosarcomas from diverse sites were shown to be universally immunoreactive for Tie2. Tie2 and vascular endothelial growth factor receptor (VEGFR antagonists inhibited SVR and MS1-VEGF angiosarcoma cell survival in vitro. In the high-grade SVR cell line, Tie2 and VEGF antagonists inhibited cell survival synergistically, whereas effects were largely additive in the low-grade MS1-VEGF cell line. Xenograft modeling using these cell lines closely recapitulated the human disease. In vivo, Tie2 and VEGFR inhibition resulted in significant angiosarcoma growth delay. The combination proved more effective than either agent alone. Tie2 inhibition seemed to elicit tumor growth delay through increased tumor cell apoptosis, whereas VEGFR inhibition reduced tumor growth by lowering tumor cell proliferation. These data identify Tie2 antagonism as a potential novel, targeted therapy for angiosarcomas and provide a foundation for further investigation of Tie2 inhibition, alone and in combinations, in the management of this disease.

  12. Tachykinin receptors antagonism for asthma: a systematic review

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    Couto Nuno

    2011-08-01

    Full Text Available Abstract Background Tachykinins substance P, neurokinin A and neurokinin B seem to account for asthma pathophysiology by mediating neurogenic inflammation and several aspects of lung mechanics. These neuropeptides act mainly by their receptors NK1, NK2 and NK3, respectively which may be targets for new asthma therapy. Methods This review systematically examines randomized controlled trials evaluating the effect of tachykinins receptors antagonism on asthma. Symptoms, airway inflammation, lung function and airway inflammation were considered as outcomes. We searched the Cochrane Airways Group Specialized Register of Asthma Trials, Cochrane Database of Systematic Reviews, MEDLINE/PubMed and EMBASE. The search is as current as June 2010. Quality rating of included studies followed the Cochrane Collaboration and GRADE Profiler approaches. However, data were not pooled together due to different measures among the studies. Results Our systematic review showed the potential of NK receptor antagonist to decrease airway responsiveness and to improve lung function. However, effects on airway inflammation and asthma symptoms were poorly or not described. Conclusion The limited available evidence suggests that tachykinin receptors antagonists may decrease airway responsiveness and improve lung function in patients with asthma. Further large randomized trials are still required.

  13. Calcineurin Antagonizes AMPK to Regulate Lipolysis in Caenorhabditis elegans.

    Science.gov (United States)

    Wang, Yanli; Xie, Cangsang; Diao, Zhiqing; Liang, Bin

    2017-06-26

    Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase, and the target of immunosuppressive agent tacrolimus (TAC). The dysfunction of calcineurin, or clinical applications of tacrolimus, have been reported to be associated with dyslipidemia. The underlying mechanisms of calcineurin and tacrolimus in lipid metabolism are largely unknown. Here, we showed that mutations of tax-6 and cnb-1, which respectively encode the catalytic subunit and the regulatory subunit of calcineurin, together with tacrolimus treatment, consistently led to decreased fat accumulation and delayed growth in the nematode Caenorhabditis elegans. In contrast, disruption of the AMP-activated protein kinase (AMPK) encoded by aak-1 and aak-2 reversed the above effects in worms. Moreover, calcineurin deficiency and tacrolimus treatment consistently activated the transcriptional expression of the lipolytic gene atgl-1, encoding triglyceride lipase. Furthermore, RNAi knockdown of atgl-1 recovered the decreased fat accumulation in both calcineurin deficient and tacrolimus treated worms. Collectively, our results reveal that immunosuppressive agent tacrolimus and their target calcineurin may antagonize AMPK to regulate ATGL and lipolysis, thereby providing potential therapy for the application of immunosuppressive agents.

  14. Calcineurin Antagonizes AMPK to Regulate Lipolysis in Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    Yanli Wang

    2017-06-01

    Full Text Available Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase, and the target of immunosuppressive agent tacrolimus (TAC. The dysfunction of calcineurin, or clinical applications of tacrolimus, have been reported to be associated with dyslipidemia. The underlying mechanisms of calcineurin and tacrolimus in lipid metabolism are largely unknown. Here, we showed that mutations of tax-6 and cnb-1, which respectively encode the catalytic subunit and the regulatory subunit of calcineurin, together with tacrolimus treatment, consistently led to decreased fat accumulation and delayed growth in the nematode Caenorhabditis elegans. In contrast, disruption of the AMP-activated protein kinase (AMPK encoded by aak-1 and aak-2 reversed the above effects in worms. Moreover, calcineurin deficiency and tacrolimus treatment consistently activated the transcriptional expression of the lipolytic gene atgl-1, encoding triglyceride lipase. Furthermore, RNAi knockdown of atgl-1 recovered the decreased fat accumulation in both calcineurin deficient and tacrolimus treated worms. Collectively, our results reveal that immunosuppressive agent tacrolimus and their target calcineurin may antagonize AMPK to regulate ATGL and lipolysis, thereby providing potential therapy for the application of immunosuppressive agents.

  15. Acute cocaine toxicity: antagonism by agents interacting with adrenoceptors.

    Science.gov (United States)

    Derlet, R W; Albertson, T E

    1990-06-01

    Agents which interact with alpha- or beta-adrenoceptors were evaluated for efficacy in preventing seizures and death from a lethal dose of cocaine. Rats were first pretreated with the test drug(s), then subjected to an intraperitoneal LD86 of cocaine (70 mg/kg). In this model, control vehicle-pretreated animals developed seizures within six minutes, followed by death within 10 minutes. Significant protection against death was afforded by pretreatment with clonidine (0.25 mg/kg), prazocin (5.0 to 20 mg/kg), propranolol (8.0 to 32 mg/kg), or labetalol (40 mg/kg). Surviving animals still experienced seizures as judged through behavior and EEG recordings. Phentolamine did not affect the incidence of seizures or death. Two nonadrenoceptor agents were also studied: hydralazine reduced the incidence of death and seizures at 5.0 and 10 mg/kg, but reserpine did not alter the incidence of death or seizures. A combination of prazocin and propranolol did not provide additional protection compared to single agents. We conclude that the pathogenesis of acute cocaine death is complex, and that this toxicity can be antagonized by agents having either central or peripheral effects.

  16. Antagonism of methoxyflurane-induced anesthesia in rats by benzodiazepine inverse agonists.

    Science.gov (United States)

    Miller, D W; Yourick, D L; Tessel, R E

    1989-11-28

    Injection of the partial benzodiazepine inverse agonist Ro15-4513 (1-32 mg/kg i.p.) or nonconvulsant i.v. doses of the full benzodiazepine inverse agonist beta-CCE immediately following cessation of exposure of rats to an anesthetic concentration of methoxyflurane significantly antagonized the duration of methoxyflurane anesthesia as measured by recovery of the righting reflex and/or pain sensitivity. This antagonism was inhibited by the benzodiazepine antagonist Ro15-1788 at doses which alone did not alter the duration of methoxyflurane anesthesia. In addition, high-dose Ro15-4513 pretreatment (32 mg/kg) antagonized the induction and duration of methoxyflurane anesthesia but was unable to prevent methoxyflurane anesthesia or affect the induction or duration of anesthesia induced by the dissociative anesthetic ketamine (100 mg/kg). These findings indicate that methoxyflurane anesthesia can be selectively antagonized by the inverse agonistic action of Ro15-4513 and beta-CCE.

  17. A highly selective CCR2 chemokine agonist encoded by human herpesvirus 6

    DEFF Research Database (Denmark)

    Lüttichau, Hans R; Clark-Lewis, Ian; Jensen, Peter Østrup

    2003-01-01

    The chemokine-like, secreted protein product of the U83 gene from human herpesvirus 6, here named vCCL4, was chemically synthesized to be characterized in a complete library of the 18 known human chemokine receptors expressed individually in stably transfected cell lines. vCCL4 was found to cause...

  18. Maternal Plasma and Amniotic Fluid Chemokines Screening in Fetal Down Syndrome

    Directory of Open Access Journals (Sweden)

    Piotr Laudanski

    2014-01-01

    Full Text Available Objective. Chemokines exert different inflammatory responses which can potentially be related to certain fetal chromosomal abnormalities. The aim of the study was to determine the concentration of selected chemokines in plasma and amniotic fluid of women with fetal Down syndrome. Method. Out of 171 amniocentesis, we had 7 patients with confirmed fetal Down syndrome (15th–18th weeks of gestation. For the purpose of our control, we chose 14 women without confirmed chromosomal aberration. To assess the concentration of chemokines in the blood plasma and amniotic fluid, we used a protein macroarray, which allows the simultaneous determination of 40 chemokines per sample. Results. We showed significant decrease in the concentration of 4 chemokines, HCC-4, IL-28A, IL-31, and MCP-2, and increase in the concentration of CXCL7 (NAP-2 in plasma of women with fetal Down syndrome. Furthermore, we showed decrease in concentration of 3 chemokines, ITAC, MCP-3, MIF, and increase in concentration of 4 chemokines, IP-10, MPIF-1, CXCL7, and 6Ckine, in amniotic fluid of women with fetal Down syndrome. Conclusion. On the basis of our findings, our hypothesis is that the chemokines may play role in the pathogenesis of Down syndrome. Defining their potential as biochemical markers of Down syndrome requires further investigation on larger group of patients.

  19. Virus-encoded chemokine receptors--putative novel antiviral drug targets

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M

    2005-01-01

    as such a paramount role in the antiviral immune responses. It is therefore not surprising that viruses have found ways to exploit and subvert the chemokine system by means of molecular mimicry. By ancient acts of molecular piracy and by induction and suppression of endogenous genes, viruses have utilized chemokines...

  20. Targeting spare CC chemokine receptor 5 (CCR5) as a principle to inhibit HIV-1 entry.

    Science.gov (United States)

    Jin, Jun; Colin, Philippe; Staropoli, Isabelle; Lima-Fernandes, Evelyne; Ferret, Cécile; Demir, Arzu; Rogée, Sophie; Hartley, Oliver; Randriamampita, Clotilde; Scott, Mark G H; Marullo, Stefano; Sauvonnet, Nathalie; Arenzana-Seisdedos, Fernando; Lagane, Bernard; Brelot, Anne

    2014-07-04

    CCR5 binds the chemokines CCL3, CCL4, and CCL5 and is the major coreceptor for HIV-1 entry into target cells. Chemokines are supposed to form a natural barrier against human immunodeficiency virus, type 1 (HIV-1) infection. However, we showed that their antiviral activity is limited by CCR5 adopting low-chemokine affinity conformations at the cell surface. Here, we investigated whether a pool of CCR5 that is not stabilized by chemokines could represent a target for inhibiting HIV infection. We exploited the characteristics of the chemokine analog PSC-RANTES (N-α-(n-nonanoyl)-des-Ser(1)-[l-thioprolyl(2), l-cyclohexylglycyl(3)]-RANTES(4-68)), which displays potent anti-HIV-1 activity. We show that native chemokines fail to prevent high-affinity binding of PSC-RANTES, analog-mediated calcium release (in desensitization assays), and analog-mediated CCR5 internalization. These results indicate that a pool of spare CCR5 may bind PSC-RANTES but not native chemokines. Improved recognition of CCR5 by PSC-RANTES may explain why the analog promotes higher amounts of β-arrestin 2·CCR5 complexes, thereby increasing CCR5 down-regulation and HIV-1 inhibition. Together, these results highlight that spare CCR5, which might permit HIV-1 to escape from chemokines, should be targeted for efficient viral blockade. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Quantitative analysis of the secretion of the MCP family of chemokines by muscle cells

    DEFF Research Database (Denmark)

    Henningsen, Jeanette; Pedersen, Bente Klarlund; Kratchmarova, Irina

    2011-01-01

    by Amino acids in Cell culture (SILAC) method for quantitative analysis resulted in the identification and generation of quantitative profiles of 59 growth factors and cytokines, including 9 classical chemokines. The members of the CC chemokine family of proteins such as monocyte chemotactic proteins 1, 2...

  2. Targeting the chemokine receptor CXCR3 and its ligand CXCL10 in the central nervous system

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke

    2004-01-01

    focuses on the present data regarding CXCL10 (previously known as IP-10) and CXRC3 in multiple sclerosis, since consistent data has suggested that this chemokine/chemokine receptor pair has a pivotal role in leukocyte recruitment into the central nervous system (CNS) in multiple sclerosis....

  3. 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. G...

  4. Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells

    DEFF Research Database (Denmark)

    Spiess, Katja; Jeppesen, Mads G.; Malmgaard-Clausen, Mikkel

    2017-01-01

    of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin...

  5. Chemokine receptor expression on B cells and effect of interferon-beta in multiple sclerosis

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Roed, Hanne; Sellebjerg, Finn

    2002-01-01

    We investigated the B-cell expression of chemokine receptors CXCR3, CXCR5 and CCR5 in the blood and cerebrospinal fluid (CSF) from patients in relapse of multiple sclerosis (MS) and in neurological controls. Chemokine receptor expression was also studied in interferon-beta-treated patients with r...

  6. Chemokines CXCL10 and CCL2: differential involvement in intrathecal inflammation in multiple sclerosis

    DEFF Research Database (Denmark)

    Sørensen, T.L.; Sellebjerg, F; Jensen, C.V.

    2001-01-01

    Studies of chemokines in cerebrospinal fluid (CSF) of patients with active multiple sclerosis (MS) have indicated that specific chemokines may have important roles in disease pathogenesis. We previously reported that CSF concentrations of CXCL10 (previously known as IP-10) were elevated in MS...

  7. Chemokine stromal cell-derived factor 1alpha activates basophils by means of CXCR4

    DEFF Research Database (Denmark)

    Jinquan, T; Jacobi, H H; Jing, C

    2000-01-01

    The CXC chemokine receptor 4 (CXCR4) is predominantly expressed on inactivated naive T lymphocytes, B lymphocytes, dendritic cells, and endothelial cells. CXC chemokine stromal cell-derived factor 1alpha (SDF-1alpha) is the only known ligand for CXCR4. To date, the CXCR4 expression and function o...

  8. C(X)CR in silico: Computer-aided prediction of chemokine receptor-ligand interactions

    NARCIS (Netherlands)

    Roumen, L.; Scholten, D.J.; de Kruijf, P.; de Esch, I.J.P.; Leurs, R.; de Graaf, C.

    2012-01-01

    This review will focus on the construction, refinement, and validation of chemokine receptor models for the purpose of structure-based virtual screening and ligand design. The review will present a comparative analysis of ligand binding pockets in chemokine receptors, including a review of the

  9. The role of chemokines in lymphocyte infiltration in ovarian cancer: from MRNA microarray to tissue microarray

    NARCIS (Netherlands)

    Gooden, M.J.M.; Leffers, N.; Fehrmann, R.S.N.; Ten Hoor, K.A.; Daemen, T.; Van Der Zee, A.G.J.; De Bock, G.H.; Walenkamp, A.M.E.; Nijman, H.W.

    2011-01-01

    Introduction: High numbers of CD8+ cytotoxic T lymphocytes (CTL) are associated with a survival advantage in ovarian cancer. Chemokines may play a role in T lymphocyte recruitment to the tumor, but they are also linked to metastasis and angiogenesis. Aim: To determine to what extent chemokines are

  10. CXC chemokines and leukocyte chemotaxis in common carp (Cyprinus carpio L.)

    NARCIS (Netherlands)

    Huising, M.O.; Stolte, H.H.; Flik, G.; Savelkoul, H.F.J.; Verburg-van Kemenade, B.M.L.

    2003-01-01

    CXC chemokines, structurally recognizable by the position of four conserved cysteine residues, are prominent mediators of chemotaxis. Here we report a novel carp CXC chemokine obtained through homology cloning and compare it with fish orthologues genes and with a second, recently elucidated, carp

  11. Biased signaling of G protein-coupled receptors - From a chemokine receptor CCR7 perspective

    DEFF Research Database (Denmark)

    Jørgensen, Astrid Sissel; Rosenkilde, Mette M; Hjortø, Gertrud M

    2018-01-01

    Chemokines (chemotactic cytokines) and their associated G protein-coupled receptors (GPCRs) work in a concerted manner to govern immune cell positioning in time and space. Promiscuity of both ligands and receptors, but also biased signaling within the chemokine system, adds to the complexity of how...

  12. Antagonism of the antibacterial action of some penicillins by other penicillins and cephalosporins.

    Science.gov (United States)

    Acar, J F; Sabath, L D; Ruch, P A

    1975-03-01

    There are many examples of two penicillins acting synergistically, usually by one competitively inhibiting beta-lactamase, thus protecting the other from inactivation. There are few reports on penicillins antagonizing each other. Eight strains of three genera (Proteus, Escherichia, Pseudomonas) isolated at Boston City Hospital or Institut Pasteur, Paris, showed antagonism of carbenicillin or ampicillin by cephaloridine, cloxacillin, or 6-aminopenicillanic acid. Broth dilution tests showed that with seven of the eight strains the minimum inhibiting concentration (MIC) of the more active antibiotic was increased by 800-6,400% by low concentrations (often one-tenth the MIC) of the antagonist, whereas higher concentrations of "antagonist" were not as antagonistic, This suggested that two or more receptor sites of action for penicillins were present; the antagonist thus blocks the antibacterial action at the more sensitive site but acts additively with the antagonized antibiotic at the less sensitive site. The possibility that the mechanism of antagonism was induction of inactivating enzymes (beta-lactamase, penicillin acylase) was studied in two strains(one Escherichia coli and one Proteus rettgeri), and two antagonists were studied in detail. With E. coli cephaloridine was a poorer inducer of beta-lactamase than were the antagonized antibiotic and 6-aminopenicillanic acid. From these organisms, the good inducers of a beta-lactamase that acted on benzylpenicillin did not induce enzymes that inactivated carbenicillin. Thus, the mechanism of antagonism was not due to beta-lactamase induction.

  13. Biased agonism at chemokine receptors: obstacles or opportunities for drug discovery?

    Science.gov (United States)

    Anderson, Caroline A; Solari, Roberto; Pease, James E

    2016-06-01

    Chemokine receptors are typically promiscuous, binding more than one ligand, with the ligands themselves often expressed in different spatial localizations by multiple cell types. This is normally a tightly regulated process; however, in a variety of inflammatory disorders, dysregulation results in the excessive or inappropriate expression of chemokines that drives disease progression. Biased agonism, the phenomenon whereby different ligands of the same receptor are able to preferentially activate one signaling pathway over another, adds another level of complexity to an already complex system. In this minireview, we discuss the concept of biased agonism within the chemokine family and report that targeting single signaling axes downstream of chemokine receptors is not only achievable, but may well present novel opportunities to target chemokine receptors, allowing the fine tuning of receptor responses in the context of allergic inflammation and beyond. © Society for Leukocyte Biology.

  14. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor

    Energy Technology Data Exchange (ETDEWEB)

    Burg, John S.; Ingram, Jessica R.; Venkatakrishnan, A.J.; Jude, Kevin M.; Dukkipati, Abhiram; Feinberg, Evan N.; Angelini, Alessandro; Waghray, Deepa; Dror, Ron O.; Ploegh, Hidde L.; Garcia, K. Christopher (Stanford); (Stanford-MED); (Whitehead); (MIT)

    2015-03-05

    Chemokines are small proteins that function as immune modulators through activation of chemokine G protein-coupled receptors (GPCRs). Several viruses also encode chemokines and chemokine receptors to subvert the host immune response. How protein ligands activate GPCRs remains unknown. We report the crystal structure at 2.9 angstrom resolution of the human cytomegalovirus GPCR US28 in complex with the chemokine domain of human CX3CL1 (fractalkine). The globular body of CX3CL1 is perched on top of the US28 extracellular vestibule, whereas its amino terminus projects into the central core of US28. The transmembrane helices of US28 adopt an active-state-like conformation. Atomic-level simulations suggest that the agonist-independent activity of US28 may be due to an amino acid network evolved in the viral GPCR to destabilize the receptor’s inactive state.

  15. Immunological assays for chemokine detection in in-vitro culture of CNS cells

    Directory of Open Access Journals (Sweden)

    Mahajan Supriya D.

    2003-01-01

    Full Text Available Herein we review the various methods currently in use for determining the expression of chemokines by CNS cells in vitro. Chemokine detection assays are used in conjuction with one another to provide a comprehensive, biologically relevant assessment of the chemokines which is necessary for correct data interpretation of a specific observed biological effect. The methods described include bioassays for soluble chemokine receptors, RNA extraction, RT-PCR, Real - time quantitative PCR, gene array analysis, northern blot analysis, Ribonuclease Protection assay, Flow cytometry, ELISPOT, western blot analysis, and ELISA. No single method of analysis meets the criteria for a comprehensive, biologically relevant assessment of the chemokines, therefore more than one assay might be necessary for correct data interpretation, a choice that is based on development of a scientific rationale for the method with emphasis on the reliability and relevance of the method.

  16. Role of circulating soluble chemokines in septic shock.

    Science.gov (United States)

    de Pablo, R; Monserrat, J; Prieto, A; Alvarez-Mon, M

    2013-11-01

    Chemokines are a large superfamily of small proteins that function not only in leukocyte trafficking, but are also necessary for linkage between innate and adaptive immunity. Little is known about their role in septic shock. We hypothesized that serum levels of the most important chemokines are related to organ failure, disease severity and outcome. A prospective observational study was carried out. Surgical-clinical Intensive Care Unit. Ninety-two patients diagnosed with septic shock using international criteria. Forty patients were excluded due to acquired immunity disturbances. Samples from 36 healthy controls were also analyzed. None. In 46% of the patients who suffered acute respiratory distress syndrome (ARDS), IL-8 levels were higher than in patients without ARDS (499.9±194.1 vs. 190.8±91.7 pg/ml; P=.039). This molecule was also higher in 36% of the patients with sepsis-induced acute renal failure (ARF) (453.3±181.6 vs. 201.3±95.9 pg/ml; P=.049). Coagulopathy was found in 19% of the septic shock patients with elevated serum IL-8 levels (635.8±292.3 vs. 218.7±87.0 pg/ml; P=.010), elevated MIP-1α (91.4±27.3 vs. 58.8±11.1 pg/ml; P=.044), and low circulating RANTES levels (8162.2±6321.0 vs. 18781.8±11.1 pg/ml; P=.027). No significant differences were found between survivors and non-survivors at any time of follow-up. Upon admission to the ICU, IL-8 is a reliable biomarker of sepsis-induced AFR, ARDS and coagulopathy. Altered circulating MIP-1α and RANTES levels are also found in patients with septic shock and coagulopathy. However, chemokines do not appear to be good biomarkers of mortality in septic shock. Copyright © 2012 Elsevier España, S.L. and SEMICYUC. All rights reserved.

  17. Mechanistic understanding of MeHg-Se antagonism in soil-rice systems: the key role of antagonism in soil

    Science.gov (United States)

    Wang, Yongjie; Dang, Fei; Evans, R. Douglas; Zhong, Huan; Zhao, Jiating; Zhou, Dongmei

    2016-01-01

    Methylmercury (MeHg) accumulation in rice has great implications for human health. Here, effects of selenium (Se) on MeHg availability to rice are explored by growing rice under soil or foliar fertilization with Se. Results indicate that soil amendment with Se could reduce MeHg levels in soil and grain (maximally 73%). In contrast, foliar fertilization with Se enhanced plant Se levels (3–12 folds) without affecting grain MeHg concentrations. This evidence, along with the distinct distribution of MeHg and Se within the plant, demonstrate for the first time that Se-induced reduction in soil MeHg levels (i.e., MeHg-Se antagonism in soil) rather than MeHg-Se interactions within the plant might be the key process triggering the decreased grain MeHg levels under Se amendment. The reduction in soil MeHg concentrations could be mainly attributed to the formation of Hg-Se complexes (detected by TEM-EDX and XANES) and thus reduced microbial MeHg production. Moreover, selenite and selenate were equally effective in reducing soil MeHg concentrations, possibly because of rapid changes in Se speciation. The dominant role of Se-induced reduction in soil MeHg levels, which has been largely underestimated previously, together with the possible mechanisms advance our mechanistic understanding about MeHg dynamics in soil-rice systems. PMID:26778218

  18. Mechanistic understanding of MeHg-Se antagonism in soil-rice systems: the key role of antagonism in soil

    Science.gov (United States)

    Wang, Yongjie; Dang, Fei; Evans, R. Douglas; Zhong, Huan; Zhao, Jiating; Zhou, Dongmei

    2016-01-01

    Methylmercury (MeHg) accumulation in rice has great implications for human health. Here, effects of selenium (Se) on MeHg availability to rice are explored by growing rice under soil or foliar fertilization with Se. Results indicate that soil amendment with Se could reduce MeHg levels in soil and grain (maximally 73%). In contrast, foliar fertilization with Se enhanced plant Se levels (3-12 folds) without affecting grain MeHg concentrations. This evidence, along with the distinct distribution of MeHg and Se within the plant, demonstrate for the first time that Se-induced reduction in soil MeHg levels (i.e., MeHg-Se antagonism in soil) rather than MeHg-Se interactions within the plant might be the key process triggering the decreased grain MeHg levels under Se amendment. The reduction in soil MeHg concentrations could be mainly attributed to the formation of Hg-Se complexes (detected by TEM-EDX and XANES) and thus reduced microbial MeHg production. Moreover, selenite and selenate were equally effective in reducing soil MeHg concentrations, possibly because of rapid changes in Se speciation. The dominant role of Se-induced reduction in soil MeHg levels, which has been largely underestimated previously, together with the possible mechanisms advance our mechanistic understanding about MeHg dynamics in soil-rice systems.

  19. The role of CC chemokine receptor 5 in antiviral immunity

    DEFF Research Database (Denmark)

    Nansen, Anneline; Christensen, Jan Pravsgaard; Andreasen, Susanne Ørding

    2002-01-01

    The CC chemokine receptor CCR5 is an important coreceptor for human immunodeficiency virus (HIV), and there is a major thrust to develop anti-CCR5-based therapies for HIV-1. However, it is not known whether CCR5 is critical for a normal antiviral T-cell response. This study investigated the immune...... response to lymphocytic choriomeningitis virus in mice lacking CCR5 (CCR5(-/-) mice). This infection is a classical model for studying antiviral immunity, and influx of CCR5-expressing CD8(+) T cells and macrophages is essential for both virus control and associated immunopathology. Results showed...... influence of CCR5 was found, not even when viral peptide was used as local trigger instead of live virus. Finally, long-term CD8(+) T cell-mediated immune surveillance was efficiently sustained in CCR5(-/-) mice. Taken together, these results indicate that expression of CCR5 is not critical for T cell...

  20. Concentration-Dependent Antagonism and Culture Conversion in Pulmonary Tuberculosis.

    Science.gov (United States)

    Rockwood, Neesha; Pasipanodya, Jotam G; Denti, Paolo; Sirgel, Frederick; Lesosky, Maia; Gumbo, Tawanda; Meintjes, Graeme; McIlleron, Helen; Wilkinson, Robert J

    2017-05-15

    There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion. One hundred patients with pulmonary tuberculosis (65% human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7-8 weeks of therapy, and PK parameters determined using nonlinear mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5-6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 0- to 24-hour area under the curve (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC (%TMIC). Twenty-six percent of patients had Cmax of rifampicin conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was conversion. For patients with isoniazid Cmax >4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion. PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.

  1. Platelets and their chemokines in atherosclerosis – clinical applications

    Directory of Open Access Journals (Sweden)

    Philipp evon Hundelshausen

    2014-08-01

    Full Text Available The concept of platelets as important players in the process of atherogenesis has become increasingly accepted due to accumulating experimental and clinical evidence. Despite the progress in understanding the molecular details of atherosclerosis, particularly by using animal models, the inflammatory and thrombotic roles of activated platelet s especially in the human system remain difficult to dissect, as often only the complications of atherosclerosis i.e. stroke and myocardial infarction are definable but not the plaque burden.Platelet indices including platelet count and mean platelet volume and soluble mediators released by activated platelets are associated with atherosclerosis. The chemokine CXCL4 has multiple atherogenic activities e.g. altering the differentiation of T cells and macrophages by inhibiting neutrophil and monocyte apoptosis and by increasing the uptake of oxLDL and synergizing with CCL5. CCL5 is released and deposited on endothelium by activated platelets thereby triggering atherogenic monocyte recruitment, which can be attenuated by blocking the corresponding chemokine receptor CCR5. Atheroprotective and plaque stabilizing properties are attributed to CXCL12, which plays an important role in regenerative processes by attracting progenitor cells. Its release from luminal attached platelets accelerates endothelial healing after injury. Platelet surface molecules GPIIb/IIIa, GP1bα, P-selectin, JAM-A and the CD40/CD40L dyade are crucially involved in the interaction with endothelial cells, leukocytes and matrix molecules affecting atherogenesis. Beyond the effects on the arterial inflammatory infiltrate, platelets affect cholesterol metabolism by binding, modifying and endocytosing LDL particles via their scavenger receptors and contribute to the formation of lipid laden macrophages. Current medical therapies for the prevention of atherosclerotic therapies enable the elucidation of mechanisms linking platelets to inflammation

  2. Are cytokines and chemokines suitable biomarkers for Takayasu arteritis?

    Science.gov (United States)

    Savioli, Bruna; Abdulahad, Wayel H; Brouwer, Elisabeth; Kallenberg, Cees G M; de Souza, Alexandre Wagner Silva

    2017-10-01

    There is a growing need for disease related biomarkers in Takayasu arteritis (TA).The assessment of pro-inflammatory cytokines and chemokines in TA may provide a better understanding of its pathophysiology, and circulating levels of these mediators may act as biomarkers of disease activity. Serum level of interleukin 6 (IL-6) is a potential biomarker for TA, which is mostly associated with TA status and disease activity. Associations between TA and serum/plasma levels of other cytokines are less clear. mRNA expression of IL-4 and tumor necrosis factor α (TNFα) are constitutively increased in peripheral blood mononuclear cells (PBMC) from TA patients and the expression of both cytokines increases even more after PBMC stimulation in vitro, while the expression of IL-10 mRNA decreases. In addition, circulating T cells from TA patients produce increased levels of both Th1- and Th17-related cytokines upon in vitro stimulation. In the aorta from TA patients, an increased expression of interferon γ (IFNγ), IL-6, IL-12 and IL-17 has been described. Regarding circulating chemokines in TA, serum/plasma levels of IL-8 (CXCL8), CCL2 and CCL5 were shown to be elevated in TA patients compared with healthy controls as well as in TA patients with active disease compared with those in remission. Serum IL-6 seems to be the best biomarker for disease state and disease activity in TA and increased Th1 and Th17 responses are predominant in the pathophysiology of TA. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. 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

  4. Inhibition of chemokine-glycosaminoglycan interactions in donor tissue reduces mouse allograft vasculopathy and transplant rejection.

    Directory of Open Access Journals (Sweden)

    Erbin Dai

    2010-05-01

    Full Text Available Binding of chemokines to glycosaminoglycans (GAGs is classically described as initiating inflammatory cell migration and creating tissue chemokine gradients that direct local leukocyte chemotaxis into damaged or transplanted tissues. While chemokine-receptor binding has been extensively studied during allograft transplantation, effects of glycosaminoglycan (GAG interactions with chemokines on transplant longevity are less well known. Here we examine the impact of interrupting chemokine-GAG interactions and chemokine-receptor interactions, both locally and systemically, on vascular disease in allografts.Analysis of GAG or CC chemokine receptor 2 (CCR2 deficiency were coupled with the infusion of viral chemokine modulating proteins (CMPs in mouse aortic allograft transplants (n = 239 mice. Inflammatory cell invasion and neointimal hyperplasia were significantly reduced in N-deacetylase-N-sulfotransferase-1 (Ndst1(f/fTekCre(+ heparan sulfate (GAG-deficient (Ndst1(-/-, p<0.044 and CCR2-deficient (Ccr2(-/-, p<0.04 donor transplants. Donor tissue GAG or CCR2 deficiency markedly reduced inflammation and vasculopathy, whereas recipient deficiencies did not. Treatment with three CMPs was also investigated; Poxviral M-T1 blocks CC chemokine receptor binding, M-T7 blocks C, CC, and CXC GAG binding, and herpesviral M3 binds receptor and GAG binding for all classes. M-T7 reduced intimal hyperplasia in wild type (WT (Ccr2(+/+, p< or =0.003 and Ccr2(-/-, pchemokine-GAG interactions, even in the absence of chemokine-receptor blockade, is a highly effective approach to reduction of

  5. C-C chemokine receptor type 5 deficiency exacerbates alcoholic fatty liver disease through pro-inflammatory cytokines and chemokines-induced hepatic inflammation.

    Science.gov (United States)

    Park, Ju Ho; Lee, Dong Hun; Park, Mork Soon; Jung, Young Suk; Hong, Jin Tae

    2017-06-01

    Chemokines and chemokine receptors implicated with alcoholic liver disease. Studies have shown that inflammation and oxidative stress induce fat molecules aggregation in liver. We evaluated the relationship between alcoholic fatty liver disease and C-C chemokine receptor 5 (CCR5) and impact of inflammation and oxidative stress in fat molecule deposition. Lieber-DeCarli diet containing ethanol or isocaloric control diets were fed to wild-type and CCR5 knockout mice for 10 days and gavaged with a single dose of ethanol or isocaloric maltose dextrin at 11th day. Cytokine, chemokine, and reactive oxygen species levels were measured in liver tissues to study the role of CCR5 in alcoholic fatty liver disease. C-C chemokine receptor type 5 knockout mice exacerbated ethanol-induced liver injury. Serum levels of aspartate aminotransferase and alanine aminotransferase were higher in CCR5 knockout mice than wild-type mice, and CCR5 knockout mice showed more severe lipid accumulation in liver tissue than wild-type mice after ethanol feeding. Increased expressions of pro-inflammatory cytokines TNF-α and IL-6 and chemokines CCL2, CCL3, CCL4, and CCL5 result in exacerbation of hepatitis in CCR5 knockout mice after ethanol feeding. Oxidative stress induced by reactive oxygen species was more severe in CCR5 knockout mice, and increasing level of fatty acid import and decreasing level of lipid degradation resulted in lipid accumulation in ethanol-fed CCR5 knockout mice. Deficiency of CCR5 exacerbates alcoholic fatty liver disease by hepatic inflammation induced by pro-inflammatory cytokines and chemokines and oxidative stress. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  6. Structural Insights into the Interaction Between a Potent Anti-Inflammatory Protein, Viral CC Chemokine Inhibitor (vCCI), and the Human CC Chemokine, Eotaxin-1

    Energy Technology Data Exchange (ETDEWEB)

    Kuo, Nai-Wei; Gao, Yong; Schill, Megan S.; Isern, Nancy G.; Dupureur, Cynthia M.; Liwang, Patricia J.

    2014-01-30

    Chemokines play important roles in the immune system, not only recruiting leukocytes to the site of infection and inflammation but also guiding cell homing and cell development. The soluble poxvirusencoded protein vCCI, a CC chemokine inhibitor, can bind to human CC chemokines tightly to impair the host immune defense. This protein has no known homologs in eukaryotes, and may represent a potent method to stop inflammation. Previously, our structure of the vCCI:MIP-1β complex indicated that vCCI uses negatively charged residues in β-sheet II to interact with positively charged residues in the MIP-1βN-terminus, 20’s region and 40’s loop. However, the interactions between vCCI and other CC chemokines have not yet been fully explored. Here, we used NMR and fluorescence anisotropy to study the interaction between vCCI and eotaxin-1 (CCL11), another CC chemokine that is an important factor in the asthma response. NMR results reveal that the binding pattern is very similar to the vCCI:MIP-1βcomplex, and suggest that electrostatic interactions provide a major contribution to binding. Fluorescence anisotropy results on variants of eotaxin-1 further confirm the critical roles of the charged residues in eotaxin. Compared to wild-type eotaxin, single, double, or triple mutations at these critical charged residues weaken the binding. One exception is the K47A mutation that exhibits increased affinity for vCCI, which can be explained structurally. In addition, the binding affinity between vCCI and other wild type CC chemokines, MCP-1, MIP-1β and RANTES, were determined as 1.09 nM, 1.16 nM, and 0.22 nM, respectively. To our knowledge, this is the first work quantitatively measuring the binding affinity between vCCI and different CC chemokines.

  7. C-terminal engineering of CXCL12 and CCL5 chemokines: functional characterization by electrophysiological recordings.

    Directory of Open Access Journals (Sweden)

    Antoine Picciocchi

    Full Text Available Chemokines are chemotactic cytokines comprised of 70-100 amino acids. The chemokines CXCL12 and CCL5 are the endogenous ligands of the CXCR4 and CCR5 G protein-coupled receptors that are also HIV co-receptors. Biochemical, structural and functional studies of receptors are ligand-consuming and the cost of commercial chemokines hinders their use in such studies. Here, we describe methods for the expression, refolding, purification, and functional characterization of CXCL12 and CCL5 constructs incorporating C-terminal epitope tags. The model tags used were hexahistidines and Strep-Tag for affinity purification, and the double lanthanoid binding tag for fluorescence imaging and crystal structure resolution. The ability of modified and purified chemokines to bind and activate CXCR4 and CCR5 receptors was tested in Xenopus oocytes expressing the receptors, together with a Kir3 G-protein activated K(+ channel that served as a reporter of receptor activation. Results demonstrate that tags greatly influence the biochemical properties of the recombinant chemokines. Besides, despite the absence of any evidence for CXCL12 or CCL5 C-terminus involvement in receptor binding and activation, we demonstrated unpredictable effects of tag insertion on the ligand apparent affinity and efficacy or on the ligand dissociation. These tagged chemokines should constitute useful tools for the selective purification of properly-folded chemokines receptors and the study of their native quaternary structures.

  8. Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers

    Directory of Open Access Journals (Sweden)

    Jessica L Williams

    2014-05-01

    Full Text Available In the adult central nervous system (CNS, chemokines and their receptors are involved in developmental, physiological and pathological processes. Although most lines of investigation focus on their ability to induce the migration of cells, recent studies indicate that chemokines also promote cellular interactions and activate signaling pathways that maintain CNS homeostatic functions. Many homeostatic chemokines are expressed on the vasculature of the blood brain barrier including CXCL12, CCL19, CCL20, and CCL21. While endothelial cell expression of these chemokines is known to regulate the entry of leukocytes into the CNS during immunosurveillance, new data indicate that CXCL12 is also involved in diverse cellular activities including adult neurogenesis and neuronal survival, having an opposing role to the homeostatic chemokine, CXCL14, which appears to regulate synaptic inputs to neural precursors. Neuronal expression of CX3CL1, yet another homeostatic chemokine that promotes neuronal survival and communication with microglia, is partly regulated by CXCL12. Regulation of CXCL12 is unique in that it may regulate its own expression levels via binding to its scavenger receptor CXCR7/ACKR3. In this review, we explore the diverse roles of these and other homeostatic chemokines expressed within the CNS, including the possible implications of their dysfunction as a cause of neurologic disease.

  9. Immune response CC Chemokines, CCL2 and CCL5 are associated with Pulmonary Sarcoidosis

    LENUS (Irish Health Repository)

    Palchevskiy, Vyacheslav

    2011-04-04

    Abstract Background Pulmonary sarcoidosis involves an intense leukocyte infiltration of the lung with the formation of non-necrotizing granulomas. CC chemokines (chemokine (C-C motif) ligand 2 (CCL2)-CCL5) are chemoattractants of mononuclear cells and act through seven transmembrane G-coupled receptors. Previous studies have demonstrated conflicting results with regard to the associations of these chemokines with sarcoidosis. In an effort to clarify previous discrepancies, we performed the largest observational study to date of CC chemokines in bronchoalveolar lavage fluid (BALF) from patients with pulmonary sarcoidosis. Results BALF chemokine levels from 72 patients affected by pulmonary sarcoidosis were analyzed by enzyme-linked immunosorbent assay (ELISA) and compared to 8 healthy volunteers. BALF CCL3 and CCL4 levels from pulmonary sarcoidosis patients were not increased compared to controls. However, CCL2 and CCL5 levels were elevated, and subgroup analysis showed higher levels of both chemokines in all stages of pulmonary sarcoidosis. CCL2, CCL5, CC chemokine receptor type 1 (CCR1), CCR2 and CCR3 were expressed from mononuclear cells forming the lung granulomas, while CCR5 was only found on mast cells. Conclusions These data suggest that CCL2 and CCL5 are important mediators in recruiting CCR1, CCR2, and CCR3 expressing mononuclear cells as well as CCR5-expressing mast cells during all stages of pulmonary sarcoidosis.

  10. Flexible Programs of Chemokine Receptor Expression on Human Polarized T Helper 1 and 2 Lymphocytes

    Science.gov (United States)

    Sallusto, Federica; Lenig, Danielle; Mackay, Charles R.; Lanzavecchia, Antonio

    1998-01-01

    Chemokines and their receptors are important elements for the selective attraction of various subsets of leukocytes. To better understand the selective migration of functional subsets of T cells, chemokine receptor expression was analyzed using monoclonal antibodies, RNase protection assays, and the response to distinct chemokines. Naive T cells expressed only CXC chemokine receptor (CXCR)4, whereas the majority of memory/activated T cells expressed CXCR3, and a small proportion expressed CC chemokine receptor (CCR)3 and CCR5. When polarized T cell lines were analyzed, CXCR3 was found to be expressed at high levels on T helper cell (Th)0s and Th1s and at low levels on Th2s. In contrast, CCR3 and CCR4 were found on Th2s. This was confirmed by functional responses: only Th2s responded with an increase in [Ca2+]i to the CCR3 and CCR4 agonists eotaxin and thymus and activation regulated chemokine (TARC), whereas only Th0s and Th1s responded to low concentrations of the CXCR3 agonists IFN-γ–inducible protein 10 (IP-10) and monokine induced by IFN-γ (Mig). Although CCR5 was expressed on both Th1 and Th2 lines, it was absent in several Th2 clones and its expression was markedly influenced by interleukin 2. Chemokine receptor expression and association with Th1 and Th2 phenotypes was affected by other cytokines present during polarization. Transforming growth factor β inhibited CCR3, but enhanced CCR4 and CCR7 expression, whereas interferon α inhibited CCR3 but upregulated CXCR3 and CCR1. These results demonstrate that chemokine receptors are markers of naive and polarized T cell subsets and suggest that flexible programs of chemokine receptor gene expression may control tissue-specific migration of effector T cells. PMID:9500790

  11. [Circulating levels of Th1- and Th2-chemokines increase in patients with early syphilis].

    Science.gov (United States)

    Zhu, Anyou; Wang, Chenchen; Sun, Hong; Han, Hongfang; Wang, Fengchao; Zhang, Lunjun; Hu, Jianguo

    2017-03-01

    Objective To study the changes of plasma T helper type I (Th1)-and Th2-chemokine levels and analyze their roles in immune response and pathogenesis of early syphilis. Methods Heparin-anticoagulated peripheral blood was collected from 56 patients with early syphilis (primary syphilis, PS, n=22; secondary syphilis, SS, n=34) and healthy controls (HC, n=20). The levels of plasma Th1 chemokines including monokine induced by interferon-γ (MIG), interferon-γ inducible protein-10 (IP-10), interferon-inducible T-cell α chemoattractant (I-TAC) and Th2 chemokines including thymus-and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) were examined using ELISA. Meanwhile, the levels of plasma cytokines (IFN-γ, IL-4 and TNF-α) and C-reactive protein (CRP) were detected. Results The levels of plasma MIG, IP-10 and TARC, MDC in the patients with PS and SS were significantly higher than those in the healthy controls. Moreover, the level of I-TAC in the patients with SS was significantly higher than that in the healthy controls. In particular, the levels of plasma Th1 chemokines (MIG, IP-10 and I-TAC) in the patients with SS significantly increased compared with those with PS. However, no significant difference was observed in the levels of plasma Th2 chemokines (TARC and MDC) between the patients with PS and SS. The correlation analysis showed that there was an obvious positive correlation between IP-10 and MIG, I-TAC, IFN-γ, TNF-α levels in the patients with early syphilis. Furthermore, the levels of MIG and IP-10 were positively associated with plasma CRP in the patients with early syphilis. Conclusion Both Th1 chemokines and Th2 chemokines are involved in immune response of early syphilis.

  12. Antagonism of Bacillus spp. against Xanthomonas campestris pv. campestris

    Directory of Open Access Journals (Sweden)

    Leila Monteiro

    2005-01-01

    Full Text Available The antagonism of eight Bacillus isolates was investigated against nine strains of Xanthomonas campestris pv. campestris (causal agent of crucifers black rot to assess the role of lipopeptides in this process. Antimicrobial and hemolytic (surfactant activity tests were performed in vitro using agar diffusion methods. Antibiosis and hemolysis were positive for four Bacillus isolates against all X. campestris pv. campestris strains. The correlation observed between antimicrobial and hemolytic activities indicated that lipopeptides were involved in the antibiosis mechanism of the studied antagonists. Fermentation studies were carried out with the isolates that showed highest antimicrobial and hemolytic activities, to follow up growth and production of bioactive and surfactant compounds. Production of bioactive and surfactant compounds was observed during the late growth phase of the Bacillus isolates.Investigação sobre o antagonismo de oito isolados de Bacillus: B. subtilis R14, B. megaterium pv. cerealis RAB7, B. megaterium pv. cerealis C211, B. megaterium C116, Bacillus sp. RAB9, B. cereus C240, Bacillus sp. C11 e B. cereus C210, contra nove linhagens de X. campestris pv. campestris (bactéria responsável pela podridão negra das crucíferas foi realizada para se verificar a participação de lipopeptídeos neste mecanismo. Testes de atividades antimicrobiana e hemolítica (surfactante foram realizados, utilizando-se o método de difusão em ágar. Antibiose e hemólise foram positivas para quatro isolados de Bacillus: R14, RAB7, C116 e C210. A correlação observada entre as atividades antimicrobiana e a hemolítica indica que lipopeptídeos estão envolvidos no mecanismo de antibiose dos isolados investigados. As fermentações foram realizadas com os isolados que demonstraram melhores resultados nos testes de atividades antimicrobiana e hemolítica: R14, RAB7 e C116, para acompanhar o crescimento e a produção de compostos bioativos e

  13. Cytokine and chemokine tear levels in patients with uveitis.

    Science.gov (United States)

    Carreño, Ester; Portero, Alejandro; Herreras, José M; García-Vázquez, Carmen; Whitcup, Scott M; Stern, Michael E; Calonge, Margarita; Enríquez-de-Salamanca, Amalia

    2017-08-01

    To determine whether the levels of cytokines and chemokines in tears differ in uveitis patients and healthy subjects. Ninety-two uveitis patients (mean age 46.4 years) and 157 control healthy subjects (mean age 49.5 years) were recruited. Subjects with ocular surface diseases such as dry eye were excluded from the study. Using multiplex bead-based assays, tears (4 μl) were analysed for the concentration of interleukin (IL)-1β, IL-1RA, IL-2, IL-6, IL-7, IL-8/CXCL8, IL-10, IL-12p70, IL-15, IL-17A, IL-23, epidermal growth factor (EGF), fractalkine/CX3CL1, interferon-γ, IP-10/CXCL10, monocyte chemo-attractant protein (MCP)-1/CCL2, tumour necrosis factor-α, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, TGF-β2 and TGF-β3. Tear molecule levels were compared between the groups and among the different forms of uveitis and disease severity. Epidermal growth factor, IL-1RA, IL-7, IL-8/CXCL8, IP-10/CXCL10, MCP-1/CCL2, TGF-β2 and VEGF were detected in more than 75% of the samples in both groups. Statistically significant differences in percentage of detection between control and patient groups were found for IL-23, IL-1β, IL-15, EGF, fractalkine/CX3CL1 and MCP-1/CCL2. The concentrations of IL-1RA, IL-8/CXCL8, fractalkine/CX3CL1, IP-10/CXCL10, VEGF and TGF-β2 in uveitis tear samples were elevated compared to controls (p uveitis. There were significant differences in the levels of several cytokines and chemokines in tears of patients with uveitis compared with healthy subjects. These results can help understand the underlying pathophysiology of the uveitis and could potentially aid in diagnosis. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  14. Truncation of CXCL12 by CD26 reduces its CXC chemokine receptor 4- and atypical chemokine receptor 3-dependent activity on endothelial cells and lymphocytes

    DEFF Research Database (Denmark)

    Janssens, Rik; Mortier, Anneleen; Boff, Daiane

    2017-01-01

    The chemokine CXCL12 or stromal cell-derived factor 1/SDF-1 attracts hematopoietic progenitor cells and mature leukocytes through the G protein-coupled CXC chemokine receptor 4 (CXCR4). In addition, it interacts with atypical chemokine receptor 3 (ACKR3 or CXCR7) and glycosaminoglycans. CXCL12...... characterization. Compared to unmodified CXCL12, CXCL12(3-68) was no longer able to signal through CXCR4 via inositol trisphosphate (IP3), Akt or extracellular signal-regulated kinases 1 and 2 (ERK1/2). Interestingly, the recruitment of β-arrestin 2 to the cell membrane via CXCR4 by CXCL12(3-68) was abolished......, whereas a weakened but significant β-arrestin recruitment remained via ACKR3. CXCL12-induced endothelial cell migration and signal transduction was completely abrogated by CD26. Intact CXCL12 hardly induced lymphocyte migration upon intra-articular injection in mice. In contrast, oral treatment of mice...

  15. Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems

    Directory of Open Access Journals (Sweden)

    Veronica Dusi

    2016-01-01

    Full Text Available Among the chemokines discovered to date, nineteen are presently considered to be relevant in heart disease and are involved in all stages of cardiovascular response to injury. Chemokines are interesting as biomarkers to predict risk of cardiovascular events in apparently healthy people and as possible therapeutic targets. Moreover, they could have a role as mediators of crosstalk between immune and cardiovascular system, since they seem to act as a “working-network” in deep linkage with the autonomic nervous system. In this paper we will describe the single chemokines more involved in heart diseases; then we will present a comprehensive perspective of them as a complex network connecting the cardiovascular system to both the immune and the autonomic nervous systems. Finally, some recent evidences indicating chemokines as a possible new tool to predict cardiovascular risk will be described.

  16. Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes

    NARCIS (Netherlands)

    Berckmans, René J.; Nieuwland, Rienk; Kraan, Maarten C.; Schaap, Marianne C. L.; Pots, Desirée; Smeets, Tom J. M.; Sturk, Augueste; Tak, Paul P.

    2005-01-01

    Synovial fluid from patients with various arthritides contains procoagulant, cell-derived microparticles. Here we studied whether synovial microparticles modulate the release of chemokines and cytokines by fibroblast-like synoviocytes (FLS). Microparticles, isolated from the synovial fluid of

  17. submitter Emerging importance of chemokine receptor CXCR3 and its ligands in cardiovascular diseases

    CERN Document Server

    Altara, R; Brandao, R D; Zeidan, A; Booz, G W; Zouein, F A

    2016-01-01

    The CXC chemokines, CXCL4, -9, -10, -11, CXCL4L1, and the CC chemokine CCL21, activate CXC chemokine receptor 3 (CXCR3), a cell-surface G protein-coupled receptor expressed mainly by Th1 cells, cytotoxic T (Tc) cells and NK cells that have a key role in immunity and inflammation. However, CXCR3 is also expressed by vascular smooth muscle and endothelial cells, and appears to be important in controlling physiological vascular function. In the last decade, evidence from pre-clinical and clinical studies has revealed the participation of CXCR3 and its ligands in multiple cardiovascular diseases (CVDs) of different aetiologies including atherosclerosis, hypertension, cardiac hypertrophy and heart failure, as well as in heart transplant rejection and transplant coronary artery disease (CAD). CXCR3 ligands have also proven to be valid biomarkers for the development of heart failure and left ventricular dysfunction, suggesting an underlining pathophysiological relation between levels of these chemokines and the deve...

  18. Reduced IL-37 Production Increases Spontaneous Chemokine Expressions in Colon Epithelial Cells

    NARCIS (Netherlands)

    Günaltay, Sezin; Ghiboub, Mohammed; Hultgren, Olof; Hörnquist, Elisabeth Hultgren

    2017-01-01

    Microscopic colitis, comprising collagenous colitis and lymphocytic colitis, is a common cause of chronic diarrhea. Previously, we showed enhanced chemokine productions in microscopic colitis patients, indicating dysregulated immune cell chemotaxis in the immunopathogenesis. We also showed decreased

  19. Cytokine and chemokine levels in radicular and residual cyst fluids.

    Science.gov (United States)

    Muglali, Mehtap; Komerik, Nurgul; Bulut, Emel; Yarim, Gul Fatma; Celebi, Nukhet; Sumer, Mahmut

    2008-03-01

    Cytokines were thought to play an important role for the expansion of odontogenic cysts. The purpose of this study was to evaluate the cytokine and chemokine levels of radicular and residual cyst fluids. Cyst fluids were aspirated from 21 patients (11 radicular and 10 residual cysts) and the levels of interleukin-1 alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), and regulated upon activation normal T cell expressed and secreted (RANTES) were determined by ELISA using commercially available kits. Both radicular and residual cyst fluids contained IL-1alpha, TNF-alpha, MCP-1, and RANTES, concentrations of which were significantly higher in the radicular cyst fluids than those in the residual cysts (P cyst fluids. In addition, positive correlations were found between IL-1alpha, TNF-alpha, MCP-1, and RANTES in radicular and residual cyst fluids. If the radicular cyst is inadvertently left behind following tooth extraction, some degree of inflammation may carry on. Residual cysts, although to a lesser extend than radicular cysts, have the potential to expand.

  20. Follicular Proinflammatory Cytokines and Chemokines as Markers of IVF Success

    Directory of Open Access Journals (Sweden)

    Aili Sarapik

    2012-01-01

    Full Text Available Cytokines are key modulators of the immune system and also contribute to regulation of the ovarian cycle. In this study, Bender MedSystems FlowCytomix technology was used to analyze follicular cytokines (proinflammatory: IL-1β, IL-6, IL-18, IFN-γ, IFN-α, TNF-α, IL-12, and IL-23;, and anti-inflammatory: G-CSF, chemokines (MIP-1α, MIP-1β, MCP-1, RANTES, and IL-8, and other biomarkers (sAPO-1/Fas, CD44(v6 in 153 women undergoing in vitro fertilization (IVF. Cytokine origin was studied by mRNA analysis of granulosa cells. Higher follicular MIP-1α and CD44(v6 were found to correlate with polycystic ovary syndrome, IL-23, INF-γ, and TNF-α with endometriosis, higher CD44(v6 but lower IL-β and INF-α correlated with tubal factor infertility, and lower levels of IL-18 and CD44(v6 characterized unexplained infertility. IL-12 positively correlated with oocyte fertilization and embryo development, while increased IL-18, IL-8, and MIP-1β were associated with successful IVF-induced pregnancy.

  1. Chemokines: a new dendritic cell signal for T cell activation

    Directory of Open Access Journals (Sweden)

    Christoph A Thaiss

    2011-08-01

    Full Text Available Dendritic cells (DCs are the main inducers and regulators of cytotoxic T lymphocyte (CTL responses against viruses and tumors. One checkpoint to avoid misguided CTL activation, which might damage healthy cells of the body, is the necessity for multiple activation signals, involving both antigenic as well as additional signals that reflect the presence of pathogens. DCs provide both signals when activated by ligands of pattern recognition receptors and licensed by helper lymphocytes. Recently, it has been established that such T cell licensing can be facilitated by CD4+ T helper cells (classical licensing or by NKT cells (alternative licensing. Licensing regulates the DC/CTL cross-talk at multiple layers. Direct recruitment of CTLs through chemokines released by licensed DCs has recently emerged as a common theme and has a crucial impact on the efficiency of CTL responses. Here, we discuss recent advances in our understanding of DC licensing for cross-priming and implications for the temporal and spatial regulation underlying this process. Future vaccination strategies will benefit from a deeper insight into the mechanisms that govern CTL activation.

  2. One-step immunopurification and lectinochemical characterization of the Duffy atypical chemokine receptor from human erythrocytes

    OpenAIRE

    Grodecka, Magdalena; Bertrand, Olivier; Karolak, Ewa; Lisowski, Marek; Waśniowska, Kazimiera

    2012-01-01

    Duffy antigen/receptor for chemokines (DARC) is a glycosylated seven-transmembrane protein acting as a blood group antigen, a chemokine binding protein and a receptor for Plasmodium vivax malaria parasite. It is present on erythrocytes and endothelial cells of postcapillary venules. The N-terminal extracellular domain of the Duffy glycoprotein carries Fya/Fyb blood group antigens and Fy6 linear epitope recognized by monoclonal antibodies. Previously, we have shown that recombinant Duffy prote...

  3. Potential evidence for biotype-specific chemokine profile following BVDV infection of bovine macrophages

    OpenAIRE

    Burr, Stephen; Thomas, Carole; Brownlie, Joe; Offord, Victoria; Coffey, Tracey J.; Werling, Dirk

    2012-01-01

    Chemokines play a key role in initiating the innate and subsequently adaptive immune response by recruiting immune cells to the site of an infection. Monocytes/macrophages (M?) are part of the first line of defence against invading pathogens, and have been shown to release a variety of chemokines in response to infection. Here, we reveal the early transcriptional response of M? to infection with cytopathogenic (cp) and non-cytopathogenic (ncp) bovine viral diarrhoea strains (BVDV). We demonst...

  4. Chemokines and Cytokines as Salivary Biomarkers for the Early Diagnosis of Oral Cancer

    OpenAIRE

    Gareema Prasad; Michael McCullough

    2013-01-01

    Chemokines have been shown to be important in both inflammation and carcinogenesis and are able to be measured in saliva with relatively robust methods including enzyme-linked immunosorbent assays (ELISA). Thus it has been hypothesized that patients with oral cancer and oral potentially malignant lesions will have elevated levels of specific chemokines in oral fluids and that this may be used as a marker of both the early detection of malignant disease and progression to malignancy. The conce...

  5. Gene Expression Profiling of Chemokines and Their Receptors in Low and High Grade Astrocytoma

    Science.gov (United States)

    Sharma, Ira; Singh, Avninder; Sharma, Karam Chand; Saxena, Sunita

    2017-05-01

    Background: Despite intense interest in molecular characterization and searches for novel therapeutic targets, the glioblastoma remains a formidable clinical challenge. Among many contributors to gliomagenesis, chemokines have drawn special attention due to their involvement in a plethora of biological processes and pathological conditions. In the present study we aimed to elucidate any pro-gliomagenic chemokine axis and probable roles in development of glioblastoma multiforme (GBM). Method: An array of 84 chemokines, chemokine receptors and related genes were studied by real time PCR with comparison between low grade astrocytoma (diffuse astrocytoma – grade II) and high grade astrocytoma (glioblastoma multiforme – grade IV). Gene ontology analysis and database mining were performed to funnel down the important axis in GBM followed by validation at the protein level by immunohistochemistry on tissue microarrays. Results: Gene expression and gene ontology analysis identified CXCL8 as an important chemokine which was more frequently up-regulated in GBM as compared to diffuse astrocytoma. Further we demonstrated localization of CXCL8 and its receptors in glioblastoma possibly affecting autocrine and paracrine signalling that promotes tumor cell proliferation and neovascularisation with vascular mimicry. Conclusion: From these results CXCL8 appears to be an important gliomagenic chemokine which may be involved in GBM growth by promoting tumor cell proliferation and neovascularization via vascular mimicry. Further in vitro and in vivo investigations are required to explore its potential candidature in anti-GBM therapy. Creative Commons Attribution License

  6. Gene Expression Profiling of Chemokines and Their Receptors in Low and High Grade Astrocytoma

    Science.gov (United States)

    Sharma, Ira; Singh, Avninder; Sharma, Karam Chand; Saxena, Sunita

    2017-01-01

    Background: Despite intense interest in molecular characterization and searches for novel therapeutic targets, the glioblastoma remains a formidable clinical challenge. Among many contributors to gliomagenesis, chemokines have drawn special attention due to their involvement in a plethora of biological processes and pathological conditions. In the present study we aimed to elucidate any pro-gliomagenic chemokine axis and probable roles in development of glioblastoma multiforme (GBM). Method: An array of 84 chemokines, chemokine receptors and related genes were studied by real time PCR with comparison between low grade astrocytoma (diffuse astrocytoma – grade II) and high grade astrocytoma (glioblastoma multiforme – grade IV). Gene ontology analysis and database mining were performed to funnel down the important axis in GBM followed by validation at the protein level by immunohistochemistry on tissue microarrays. Results: Gene expression and gene ontology analysis identified CXCL8 as an important chemokine which was more frequently up-regulated in GBM as compared to diffuse astrocytoma. Further we demonstrated localization of CXCL8 and its receptors in glioblastoma possibly affecting autocrine and paracrine signalling that promotes tumor cell proliferation and neovascularisation with vascular mimicry. Conclusion: From these results CXCL8 appears to be an important gliomagenic chemokine which may be involved in GBM growth by promoting tumor cell proliferation and neovascularization via vascular mimicry. Further in vitro and in vivo investigations are required to explore its potential candidature in anti-GBM therapy. PMID:28610419

  7. CC and CXC chemokines are pivotal mediators of cerebral injury in ischaemic stroke.

    Science.gov (United States)

    Mirabelli-Badenier, Marisol; Braunersreuther, Vincent; Viviani, Giorgio Luciano; Dallegri, Franco; Quercioli, Alessandra; Veneselli, Edvige; Mach, François; Montecucco, Fabrizio

    2011-03-01

    The definition of ischaemic stroke has been recently updated as an acute episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischaemia in the presence of a cerebral infarction. This "tissular" definition has highlighted the importance of pathophysiological processes underlying cerebral damage. In particular, post- ischaemic inflammation in the brain and in the blood stream could influence crucial steps of the tissue injury/repair cascade. CC and CXC chemokines orchestrate the inflammatory response in atherosclerotic plaque vulnerability and cerebral infarction. These molecules exert their activities through the binding to selective transmembrane receptors. CC and CXC chemokines modulate crucial processes (such as inflammatory cell recruitment and activation, neuronal survival, neoangiogenesis). On the other hand, CXC chemokines could also modulate stem cell homing, thus favouring tissue repair. Given this evidence, both CC and CXC chemokines could represent promising therapeutic targets in primary and secondary prevention of ischaemic stroke. Only preliminary studies have been performed investigating treatments with selective chemokine agonists/antagonists. In this review, we will update evidence on the role and the potential therapeutic strategies targeting CC and CXC chemokines in the pathophysiology of ischaemic stroke.

  8. A chemokine-binding domain in the tumor necrosis factor receptor from variola (smallpox) virus.

    Science.gov (United States)

    Alejo, Alí; Ruiz-Argüello, M Begoña; Ho, Yin; Smith, Vincent P; Saraiva, Margarida; Alcami, Antonio

    2006-04-11

    Variola virus (VaV) is the causative agent of smallpox, one of the most devastating diseases encountered by man, that was eradicated in 1980. The deliberate release of VaV would have catastrophic consequences on global public health. However, the mechanisms that contribute to smallpox pathogenesis are poorly understood at the molecular level. The ability of viruses to evade the host defense mechanisms is an important determinant of viral pathogenesis. Here we show that the tumor necrosis factor receptor (TNFR) homologue CrmB encoded by VaV functions not only as a soluble decoy TNFR but also as a highly specific binding protein for several chemokines that mediate recruitment of immune cells to mucosal surfaces and the skin, sites of virus entry and viral replication at late stages of smallpox. CrmB binds chemokines through its C-terminal domain, which is unrelated to TNFRs, was named smallpox virus-encoded chemokine receptor (SECRET) domain and uncovers a family of poxvirus chemokine inhibitors. An active SECRET domain was found in another viral TNFR (CrmD) and three secreted proteins encoded by orthopoxviruses. These findings identify a previously undescribed chemokine-binding and inhibitory domain unrelated to host chemokine receptors and a mechanism of immune modulation in VaV that may influence smallpox pathogenesis.

  9. The role of CXC chemokine ligand (CXCL)12-CXC chemokine receptor (CXCR)4 signalling in the migration of neural stem cells towards a brain tumour

    NARCIS (Netherlands)

    van der Meulen, A. A. E.; Biber, K.; Lukovac, S.; Balasubramaniyan, V.; den Dunnen, W. F. A.; Boddeke, H. W. G. M.; Mooij, J. J. A.

    2009-01-01

    Aims: It has been shown that neural stem cells (NSCs) migrate towards areas of brain injury or brain tumours and that NSCs have the capacity to track infiltrating tumour cells. The possible mechanism behind the migratory behaviour of NSCs is not yet completely understood. As chemokines are involved

  10. Online Antagonism of the Alt-Right in the 2016 Election

    National Research Council Canada - National Science Library

    Heikkilä, Niko

    2017-01-01

    .... In particular, the alt-right’s unique style and internal jargon created notable confusion and also attracted interest by the media, while its promotional tactics included the use of social media and Internet memes, through which the movement came to epitomize online antagonism in the 2016 election.

  11. Design and development of benzoxazole derivatives with toll-like receptor 9 antagonism.

    Science.gov (United States)

    Roy, Swarnali; Mukherjee, Ayan; Paul, Barnali; Rahaman, Oindrila; Roy, Shounak; Maithri, Gundaram; Ramya, Bandaru; Pal, Sourav; Ganguly, Dipyaman; Talukdar, Arindam

    2017-07-07

    Toll-like receptor 9 (TLR9) is a major therapeutic target for numerous inflammatory disorders. Development of small molecule inhibitors for TLR9 remains largely empirical due to lack of structural understanding of potential TLR9 antagonism by small molecules and due to the unusual topology of the ligand binding surface of the receptor. To develop a structural model for rational design of small molecule TLR9 antagonists, an enhanced homology model of human TLR9 (hTLR9) was constructed. Binding mode analysis of a series of molecules having characteristic molecular geometry, flexibility and basicity was conducted based on crystal structure of the inhibitory DNA (iDNA) bound to horse and bovine TLR9. Interaction with specific amino acid residues in four leucine rich repeat (LRR) regions of TLR9 was identified to be critical for antagonism by small molecules. The biological validation of TLR9 antagonism and its correlation with probe-receptor interactions led to a reliable model that could be used for development of novel small molecules with potent TLR9 antagonism (IC 50 30-100 nM) with excellent selectivity against TLR7. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. The mechanism of the antagonism by naloxone of acute alcohol intoxication.

    OpenAIRE

    Badawy, A A; Evans, M

    1981-01-01

    Naloxone lowers blood-ethanol concentration and causes a simultaneous reversal of the disturbances in the redox states of the hepatic nicotinamide-adenine dinucleotide (phosphate) couples in acutely-ethanol-intoxicated rats. It is suggested that these effects of naloxone form the basis of its antagonism of acute alcohol intoxication.

  13. NO EVIDENCE FOR A ROLE OF MUSCARINIC M(2) RECEPTORS IN FUNCTIONAL ANTAGONISM IN BOVINE TRACHEA

    NARCIS (Netherlands)

    ROFFEL, AF; MEURS, H; ELZINGA, CRS; ZAAGSMA, J

    1 The functional antagonism between methacholine- or histamine-induced contraction and beta-adrenoceptor-mediated relaxation was evaluated in bovine tracheal smooth muscle in vitro. In addition, the putative contribution of muscarinic M(2) receptors mediating inhibition of beta-adrenoceptor-induced

  14. Mutualism and Antagonism: Ecological Interactions Among Bark Beetles, Mite and Fungi

    Science.gov (United States)

    K.D. Klepzig; J.C. Moser; M.J. Lombardero; M.P. Ayres; R.W. Hofstetter; C.J. Walkinshaw

    2001-01-01

    Insect-fungal complexes provide challenging and fascinating systems for the study of biotic interactions between plants. plant pathogens, insect vectors and other associated organisms. The types of interactions among these organisms (mutualism. antagonism. parasitism. phoresy. etc.) are as variable as the range of organisms involved (plants, fungi, insects. mites. etc...

  15. Functional antagonism of different angiotensin II type I receptor blockers in human arteries

    NARCIS (Netherlands)

    Voors, AA; Buikema, H; van Buiten, A; Lubeck, RH; Boonstra, PW; van Veldhuisen, DJ; van Gilst, WH

    Objectives. To evaluate and compare the functional type and the degree of antagonism of the selective angiotensin II type I receptor blockers (ARB) losartan, EXP 3174 (the active metabolite of losartan), valsartan and candesartan in human internal mammary arteries. Methods. Human internal mammary

  16. ORE1 balances leaf senescence against maintenance by antagonizing G2-like-mediated transcription

    OpenAIRE

    Rauf, Mamoona; Arif, Muhammad; Dortay, Hakan; Matallana-Ramírez, Lilian P; Waters, Mark T.; Gil Nam, Hong; Lim, Pyung-Ok; Mueller-Roeber, Bernd; Balazadeh, Salma

    2013-01-01

    Transcription factor ORE1 is a key regulator of senescence in Arabidopsis thaliana. Here, it is shown to also inhibit the function of Golden2-like transcription factors, which antagonize senescence, revealing a new mechanism of ORE1-mediated senescence control.

  17. Chemokine Ligand 5 (CCL5 and chemokine receptor (CCR5 genetic variants and prostate cancer risk among men of African Descent: a case-control study

    Directory of Open Access Journals (Sweden)

    Kidd LaCreis R

    2012-11-01

    Full Text Available Abstract Background Chemokine and chemokine receptors play an essential role in tumorigenesis. Although chemokine-associated single nucleotide polymorphisms (SNPs are associated with various cancers, their impact on prostate cancer (PCA among men of African descent is unknown. Consequently, this study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses. Methods Sequence variants were evaluated in germ-line DNA samples from 814 African-American and Jamaican men (279 PCA cases and 535 controls using Illumina’s Goldengate genotyping system. Results Inheritance of CCL5 rs2107538 (AA, GA+AA and rs3817655 (AA, AG, AG+AA genotypes were linked with a 34-48% reduction in PCA risk. Additionally, the recessive and dominant models for CCR5 rs1799988 and CCR7 rs3136685 were associated with a 1.52-1.73 fold increase in PCA risk. Upon stratification, only CCL5 rs3817655 and CCR7 rs3136685 remained significant for the Jamaican and U.S. subgroups, respectively. Conclusions In summary, CCL5 (rs2107538, rs3817655 and CCR5 (rs1799988 sequence variants significantly modified PCA susceptibility among men of African descent, even after adjusting for age and multiple comparisons. Our findings are only suggestive and require further evaluation and validation in relation to prostate cancer risk and ultimately disease progression, biochemical/disease recurrence and mortality in larger high-risk subgroups. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent.

  18. Enterovirus infection induces cytokine and chemokine expression in insulin-producing cells.

    Science.gov (United States)

    Nair, Sandhya; Leung, Kin-Chuen; Rawlinson, William D; Naing, Zin; Craig, Maria E

    2010-11-01

    Despite evidence supporting an association between enterovirus (EV) infection and type 1 diabetes, the etiological mechanism(s) for EV-induced beta cell destruction is(are) not well understood. In this study, the effects of Coxsackievirus B (CVB) 1-6 on cell lysis and cytokine/chemokine expression in the insulinoma-1 (INS-1) beta cell line were investigated. Cytolysis was assessed using tissue culture infectious dose 50 (TCID(50)). Quantitative RT-PCR was used to measure viral RNA and mRNA of cytokines interferon (IFN)-α, IFN-β, IFN-γ, tumor necrosis factor (TNF)-α, and chemokine (C-X-C motif) ligand 10 (CXCL10), chemokine (C-C motif) ligand 2 (CCL2), and chemokine (C-C motif) ligand 5 (CCL5) in infected INS-1 cells. CVB2, 4, 5, and 6 lysed and replicated in INS-1 cells; TCID(50) was lowest for CVB5 and highest for CVB6. IFN-γ, CXCL10, and CCL5 mRNA levels all increased significantly following infection with CVB2, 4, 5, and 6 (PCVB5 infection (P<0.05), while TNF-α mRNA and IFN-β mRNA (P<0.001) increased with CVB2 infection. Dose-dependent effects of infection on cytokine mRNA levels were observed for all (P<0.01) except IFN-γ. Following inoculation of INS-1 cells with CVB1 and 3, viral RNA was not detected and cytokine/chemokine mRNA levels were unchanged. In conclusion, CVB2, 4, 5, and 6 induce dose-dependent cytokine and chemokine mRNA production from INS-1 cells suggesting that pro-inflammatory cytokine and chemokine secretion by beta cells is a potential mechanism for EV-induced beta cell damage in type 1 diabetes. © 2010 Wiley-Liss, Inc.

  19. Identification of chemokines associated with the recruitment of decidual leukocytes in human labour: potential novel targets for preterm labour.

    Science.gov (United States)

    Hamilton, Sarah A; Tower, Clare L; Jones, Rebecca L

    2013-01-01

    Current therapies for preterm labour (PTL) focus on arresting myometrial contractions but are largely ineffective, thus alternative therapeutic targets need to be identified. Leukocytes infiltrate the uterus around the time of labour, and are in particularly abundant in decidua (maternal-fetal interface). Moreover, decidual inflammation precedes labour in rat pregnancies and thus may contribute to initiation of labour. We hypothesized that chemokines mediate decidual leukocyte trafficking during preterm labour (PTL) and term labour (TL), thus representing potential targets for preventing PTL. Women were recruited into 4 groups: TL, term not in labour (TNL), idiopathic PTL and PTL with infection (PTLI). Choriodecidual RNA was subjected to a pathway-specific PCR array for chemokines. Differential expression of 12 candidate chemokines was validated by real time RT-PCR and Bioplex assay, with immunohistochemistry to confirm cellular origin. 25 chemokines were upregulated in choriodecidua from TL compared to TNL. A similar pattern was detected in PTL, however a distinct profile was observed in PTLI consistent with differences in leukocyte infiltration. Upregulation of CCL2, CCL4, CCL5, CXCL8 and CXCL10 mRNA and protein was confirmed in TL, with CCL8 upregulated in PTL. Significant correlations were detected between these chemokines and decidual leukocyte abundance previously assessed by immunohistochemical and image analysis. Chemokines were primarily expressed by decidual stromal cells. In addition, CXCL8 and CCL5 were significantly elevated in maternal plasma during labour, suggesting chemokines contribute to peripheral inflammatory events during labour. Differences in chemokine expression patterns between TL and idiopathic PTL may be attributable to suppression of chemokine expression by betamethasone administered to women in PTL; this was supported by in vitro evidence of chemokine downregulation by clinically relevant concentrations of the steroid. The current

  20. Possible Roles of CC- and CXC-Chemokines in Regulating Bovine Endometrial Function during Early Pregnancy

    Directory of Open Access Journals (Sweden)

    Ryosuke Sakumoto

    2017-03-01

    Full Text Available The aim of the present study was to determine the possible roles of chemokines in regulating bovine endometrial function during early pregnancy. The expression of six chemokines, including CCL2, CCL8, CCL11, CCL14, CCL16, and CXCL10, was higher in the endometrium at 15 and 18 days of pregnancy than at the same days in non-pregnant animals. Immunohistochemical staining showed that chemokine receptors (CCR1, CCR2, CCR3, and CXCR3 were expressed in the epithelial cells and glandular epithelial cells of the bovine endometrium as well as in the fetal trophoblast obtained from a cow on day 18 of pregnancy. The addition of interferon-τ (IFNT to an endometrial tissue culture system increased CCL8 and CXCL10 expression in the tissues, but did not affect CCL2, CCL11, and CCL16 expression. CCL14 expression by these tissues was inhibited by IFNT. CCL16, but not other chemokines, clearly stimulated interferon-stimulated gene 15 (ISG15 and myxovirus-resistance gene 1 (MX1 expression in these tissues. Cyclooxygenase 2 (COX2 expression decreased after stimulation with CCL8 and CCL14, and oxytocin receptor (OTR expression was decreased by CCL2, CCL8, CCL14, and CXCL10. Collectively, the expression of chemokine genes is increased in the endometrium during early pregnancy. These genes may contribute to the regulation of endometrial function by inhibiting COX2 and OTR expression, subsequently decreasing prostaglandin production and preventing luteolysis in cows.

  1. Different Cytokine and Chemokine Expression Patterns in Malignant Compared to Those in Nonmalignant Renal Cells

    Directory of Open Access Journals (Sweden)

    Nadine Gelbrich

    2017-01-01

    Full Text Available Objective. Cytokines and chemokines are widely involved in cancer cell progression and thus represent promising candidate factors for new biomarkers. Methods. Four renal cell cancer (RCC cell lines (Caki-1, 786-O, RCC4, and A498 and a nonmalignant renal cell line (RC-124 were examined with respect to their proliferation. The cytokine and chemokine expression pattern was examined by a DNA array (Human Cytokines & Chemokines RT2 Profiler PCR Array; Qiagen, Hilden, Germany, and expression profiles were compared. Results. Caki-1 and 786-O cells exhibited significantly increased proliferation rates, whereas RCC4 and A498 cells demonstrated attenuated proliferation, compared to nonmalignant RC-124 cells. Expression analysis revealed 52 cytokines and chemokines primarily involved in proliferation and inflammation and differentially expressed not only in malignant and nonmalignant renal cells but also in the four RCC cell lines. Conclusion. This is the first study examining the expression of 84 cytokines and chemokines in four RCC cell lines compared to that in a nonmalignant renal cell line. VEGFA, NODAL, and BMP6 correlated with RCC cell line proliferation and, thus, may represent putative clinical biomarkers for RCC progression as well as for RCC diagnosis and prognosis.

  2. Inflammatory cytokines and chemokines, skeletal muscle and polycystic ovary syndrome: effects of pioglitazone and metformin treatment.

    Science.gov (United States)

    Ciaraldi, Theodore P; Aroda, Vanita; Mudaliar, Sunder R; Henry, Robert R

    2013-11-01

    Chronic low-grade inflammation is a common feature of insulin resistant states, including obesity and type 2 diabetes. Less is known about inflammation in Polycystic Ovary Syndrome (PCOS). Thus we evaluated the impact of PCOS on circulating cytokine levels and the effects of anti-diabetic therapies on insulin action, cytokine and chemokine levels and inflammatory signaling in skeletal muscle. Twenty subjects with PCOS and 12 healthy normal cycling (NC) subjects of similar body mass index were studied. PCOS subjects received oral placebo or pioglitazone, 45 mg/d, for 6 months. All PCOS subjects then had metformin, 2 g/day, added to their treatment. Circulating levels of cytokines, chemokines, and adiponectin, skeletal muscle markers of inflammation and phosphorylation of signaling proteins, insulin action evaluated by the hyperinsulinemic/euglycemic clamp procedure and Homeostasis Model Assessment of Insulin Resistance were measured. Circulating levels of a number of cytokines and chemokines were generally similar between PCOS and NC subjects. Levels in PCOS subjects were not altered by pioglitazone or metformin treatment, even though whole body insulin action and adiponectin levels increased with pioglitazone. In spite of the lack of change in levels of cytokines and chemokines, several markers of inflammation in skeletal muscle were improved with Pio treatment. PCOS may represent a state of elevated sensitivity of inflammatory cells in skeletal muscle to cytokines and chemokines, a property that could be reversed by pioglitazone treatment together with improved insulin action. © 2013.

  3. Potential evidence for biotype-specific chemokine profile following BVDV infection of bovine macrophages.

    Science.gov (United States)

    Burr, Stephen; Thomas, Carole; Brownlie, Joe; Offord, Victoria; Coffey, Tracey J; Werling, Dirk

    2012-11-15

    Chemokines play a key role in initiating the innate and subsequently adaptive immune response by recruiting immune cells to the site of an infection. Monocytes/macrophages (MØ) are part of the first line of defence against invading pathogens, and have been shown to release a variety of chemokines in response to infection. Here, we reveal the early transcriptional response of MØ to infection with cytopathogenic (cp) and non-cytopathogenic (ncp) bovine viral diarrhoea strains (BVDV). We demonstrate up-regulation of several key chemokines of the CCL and CXCL families in MØ exposed to cpBVDV, but not ncpBVDV. In contrast, infection of MØ with ncpBVDV led to down-regulation of chemokine mRNA expression compared to uninfected cells. Data suggest that ncpBVDV can shut down production of several key chemokines that play crucial roles in the immune response to infection. This study helps to further our understanding of the pathogenesis of BVDV infection, highlighting biotype-specific cellular responses. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Chemokines Referee Inflammation within the Central Nervous System during Infection and Disease

    Directory of Open Access Journals (Sweden)

    Douglas M. Durrant

    2014-01-01

    Full Text Available The discovery that chemokines and their receptors are expressed by a variety of cell types within the normal adult central nervous system (CNS has led to an expansion of their repertoire as molecular interfaces between the immune and nervous systems. Thus, CNS chemokines are now divided into those molecules that regulate inflammatory cell migration into the CNS and those that initiate CNS repair from inflammation-mediated tissue damage. Work in our laboratory throughout the past decade has sought to elucidate how chemokines coordinate leukocyte entry and interactions at CNS endothelial barriers, under both homeostatic and inflammatory conditions, and how they promote repair within the CNS parenchyma. These studies have identified several chemokines, including CXCL12 and CXCL10, as critical regulators of leukocyte migration from perivascular locations. CXCL12 additionally plays an essential role in promoting remyelination of injured white matter. In both scenarios we have shown that chemokines serve as molecular links between inflammatory mediators and other effector molecules involved in neuroprotective processes.

  5. Positive Relationship between Total Antioxidant Status and Chemokines Observed in Adults

    Directory of Open Access Journals (Sweden)

    Yanli Li

    2014-01-01

    Full Text Available Objective. Human evidence is limited regarding the interaction between oxidative stress biomarkers and chemokines, especially in a population of adults without overt clinical disease. The current study aims to examine the possible relationships of antioxidant and lipid peroxidation markers with several chemokines in adults. Methods. We assessed cross-sectional associations of total antioxidant status (TAS and two lipid peroxidation markers malondialdehyde (MDA and thiobarbituric acid reactive substances (TBARS with a suite of serum chemokines, including CXCL-1 (GRO-α, CXCL-8 (IL-8, CXCL-10 (IP-10, CCL-2 (MCP-1, CCL-5 (RANTES, CCL-8 (MCP-2, CCL-11 (Eotaxin-1, and CCL-17 (TARC, among 104 Chinese adults without serious preexisting clinical conditions in Beijing before 2008 Olympics. Results. TAS showed significantly positive correlations with MCP-1 (r=0.15751, P=0.0014, MCP-2 (r=0.3721, P=0.0001, Eotaxin-1 (r=0.39598, P<0.0001, and TARC (r=0.27149, P=0.0053. The positive correlations remained unchanged after controlling for age, sex, body mass index, smoking, and alcohol drinking status. No associations were found between any of the chemokines measured in this study and MDA or TBARS. Similar patterns were observed when the analyses were limited to nonsmokers. Conclusion. Total antioxidant status is positively associated with several chemokines in this adult population.

  6. CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: A systematic review.

    Science.gov (United States)

    Kothur, Kavitha; Wienholt, Louise; Brilot, Fabienne; Dale, Russell C

    2016-01-01

    Despite improved understanding of the pathogenesis of neuroinflammatory disorders of the brain and development of new diagnostic markers, our biomarker repertoire to demonstrate and monitor inflammation remains limited. Using PubMed database, we reviewed 83 studies on CSF cytokines and chemokines and describe the pattern of elevation and possible role of cytokines/chemokines as biomarkers in viral and autoimmune inflammatory neurological disorders of the CNS. Despite inconsistencies and overlap of cytokines and chemokines in different neuroinflammation syndromes, there are some trends regarding the pattern of cytokines/chemokine elevation. Namely B cell markers, such as CXCL13 and BAFF are predominantly investigated and found to be elevated in autoantibody-associated disorders, whereas interferon gamma (IFN-γ) is elevated mainly in viral encephalitis. Th2 and Th17 cytokines are frequently elevated in acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO), whereas Th1 and Th17 cytokines are more commonly elevated in multiple sclerosis (MS). Cytokine/chemokine profiling might provide new insights into disease pathogenesis, and improve our ability to monitor inflammation and response to treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Oxidative damage and chemokine production dominate days before immune cell infiltration and EAE disease debut

    DEFF Research Database (Denmark)

    Hasseldam, Henrik; Rasmussen, Rune Skovgaard; Johansen, Flemming Fryd

    2016-01-01

    of degenerative processes from mitochondrial membrane potentials, reactive oxidative species, cell death markers, chemokines, and inflammatory cell types in brain, spinal cord, and optic nerve tissue during the effector phase of the disease, before clinical disease was evident. METHODS: Sixty-two rats were placed...... as a consequence of immunization with complete Freund's adjuvant, whereas the encephalitogenic emulsion induced an upregulation of the chemokines Ccl2, Ccl20, and Cxcl1, specifically in brain tissue, 7 days after immunization. CONCLUSION: Five to seven days after immunization, subtle decreases in the mitochondrial...... membrane potential and an increased reactive oxygen species burden in brain tissue were observed. No cell death was detected at these time-points, but a specific expression pattern of chemokines indicates activity in the CNS, several days before clinical disease debut....

  8. The Role of Chemokines in Promoting Colorectal Cancer Invasion/Metastasis

    Directory of Open Access Journals (Sweden)

    Yoshiro Itatani

    2016-04-01

    Full Text Available Colorectal cancer (CRC is one of the leading causes of cancer-related death worldwide. Although most of the primary CRC can be removed by surgical resection, advanced tumors sometimes show recurrences in distant organs such as the liver, lung, lymph node, bone or peritoneum even after complete resection of the primary tumors. In these advanced and metastatic CRC, it is the tumor-stroma interaction in the tumor microenvironment that often promotes cancer invasion and/or metastasis through chemokine signaling. The tumor microenvironment contains numerous host cells that may suppress or promote cancer aggressiveness. Several types of host-derived myeloid cells reside in the tumor microenvironment, and the recruitment of them is under the control of chemokine signaling. In this review, we focus on the functions of chemokine signaling that may affect tumor immunity by recruiting several types of bone marrow-derived cells (BMDC to the tumor microenvironment of CRC.

  9. Structure of the CCR5 Chemokine Receptor-HIV Entry Inhibitor Maraviroc Complex

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Qiuxiang; Zhu, Ya; Li, Jian; Chen, Zhuxi; Han, Gye Won; Kufareva, Irina; Li, Tingting; Ma, Limin; Fenalti, Gustavo; Li, Jing; Zhang, Wenru; Xie, Xin; Yang, Huaiyu; Jiang, Hualiang; Cherezov, Vadim; Liu, Hong; Stevens, Raymond C.; Zhao, Qiang; Wu, Beili [Scripps; (Chinese Aca. Sci.); (UCSD)

    2013-10-21

    The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom–resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor–gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.

  10. Amniotic Fluid Chemokines and Autism Spectrum Disorders: An Exploratory Study Utilizing a Danish Historic Birth Cohort

    DEFF Research Database (Denmark)

    Abdallah, Morsi; Larsen, Nanna; Grove, Jakob

    2012-01-01

    Introduction: Elevated levels of chemokines have been reported in plasma and brain tissue of individuals with Autism Spectrum Disorders (ASD). The aim of this study was to examine chemokine levels in amniotic fluid (AF) samples of individuals diagnosed with ASD and their controls. Material...... controls was sufficient for Luminex analysis. Including all individuals in the cohort yielded no significant differences in chemokine levels in cases versus controls. Logistic regression analyses, performed on individuals diagnosed using ICD-10 only, showed increased risk for ASD with elevated MCP-1....... Case-control differences were assessed as dichotomized at below the 10th percentile or above the 90th percentile cut-off points derived from the control biomarker distributions (logistic regression) or continuous measures (tobit regression). Results and Conclusion AF volume for 331 cases and 698...

  11. Chemokines in Chronic Liver Allograft Dysfunction Pathogenesis and Potential Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Bin Liu

    2013-01-01

    Full Text Available Despite advances in immunosuppressive drugs, long-term success of liver transplantation is still limited by the development of chronic liver allograft dysfunction. Although the exact pathogenesis of chronic liver allograft dysfunction remains to be established, there is strong evidence that chemokines are involved in organ damage induced by inflammatory and immune responses after liver surgery. Chemokines are a group of low-molecular-weight molecules whose function includes angiogenesis, haematopoiesis, mitogenesis, organ fibrogenesis, tumour growth and metastasis, and participating in the development of the immune system and in inflammatory and immune responses. The purpose of this review is to collect all the research that has been done so far concerning chemokines and the pathogenesis of chronic liver allograft dysfunction and helpfully, to pave the way for designing therapeutic strategies and pharmaceutical agents to ameliorate chronic allograft dysfunction after liver transplantation.

  12. Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS

    DEFF Research Database (Denmark)

    Babcock, Alicia A; Kuziel, William A; Rivest, Serge

    2003-01-01

    Innate responses in the CNS are critical to first line defense against infection and injury. Leukocytes migrate to inflammatory sites in response to chemokines. We studied leukocyte migration and glial chemokine expression within the denervated hippocampus in response to axonal injury caused...... hr after axotomy, whereas MCP-1/CCL2 was significantly induced before leukocyte infiltration occurred. Neither T cells nor macrophages infiltrated the denervated hippocampus of CCR2-deficient mice, arguing for a critical role for the CCR2 ligand MCP-1/CCL2 in leukocyte migration. Both T cells......+ microglia and GFAP+ astrocytes as major sources of MCP-1/CCL2 within the lesion-reactive hippocampus. We conclude that leukocyte responses to CNS axonal injury are directed via innate glial production of chemokines....

  13. Dynamic T-lymphocyte chemokine receptor expression induced by interferon-beta therapy in multiple sclerosis

    DEFF Research Database (Denmark)

    Krakauer, M; Sorensen, P S; Khademi, M

    2006-01-01

    Treatment with interferon (IFN)-beta reduces clinical disease activity in multiple sclerosis (MS). Using flow cytometry, an enzyme-linked immunosorbent assay and a real-time polymerase chain reaction, we studied in vivo IFN-beta-induced effects on CD4(+) T-lymphocyte chemokine receptor expression...... and immunoregulatory genes. In conclusion, IFN-beta treatment caused 'steady-state' increases of several chemokine receptors relevant for CD4(+) T-lymphocyte trafficking and function, possibly facilitating lymphocyte migration into the CNS. An important therapeutic effect of IFN-beta treatment may be the normalization...... as these influence central nervous system (CNS) transmigration and inflammation. At 'steady state' (>/=1 day after the most recent IFN-beta injection), IFN-beta treatment increased CD4(+) T-cell surface expression of CC chemokine receptor (CCR)4, CCR5 and CCR7 after 3 months of treatment, whereas that of CXC...

  14. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL

    DEFF Research Database (Denmark)

    Staller, Peter; Sulitkova, Jitka; Lisztwan, Joanna

    2003-01-01

    Organ-specific metastasis is governed, in part, by interactions between chemokine receptors on cancer cells and matching chemokines in target organs. For example, malignant breast cancer cells express the chemokine receptor CXCR4 and commonly metastasize to organs that are an abundant source...... regulates CXCR4 expression owing to its capacity to target hypoxia-inducible factor (HIF) for degradation under normoxic conditions. This process is suppressed under hypoxic conditions, resulting in HIF-dependent CXCR4 activation. An analysis of clear cell renal carcinoma that manifests mutation of the VHL...... gene in most cases revealed an association of strong CXCR4 expression with poor tumour-specific survival. These results suggest a mechanism for CXCR4 activation during tumour cell evolution and imply that VHL inactivation acquired by incipient tumour cells early in tumorigenesis confers not only...

  15. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Yi; Qin, Ling; Ortiz Zacarías, Natalia V.; de Vries, Henk; Han, Gye Won; Gustavsson, Martin; Dabros, Marta; Zhao, Chunxia; Cherney, Robert J.; Carter, Percy; Stamos, Dean; Abagyan, Ruben; Cherezov, Vadim; Stevens, Raymond C.; IJzerman, Adriaan P.; Heitman, Laura H.; Tebben, Andrew; Kufareva, Irina; Handel , Tracy M. (Vertex Pharm); (Leiden-MC); (USC); (BMS); (UCSD)

    2016-12-07

    CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases2 including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer3. These disease associations have motivated numerous preclinical studies and clinical trials4 (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2–chemokine axis. To aid drug discovery efforts5, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]7) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein–protein interactions, receptor–chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.

  16. The role of chemokines in the recruitment of lymphocytes to the liver.

    Science.gov (United States)

    Oo, Ye H; Adams, David H

    2010-02-01

    Chemokines direct leukocyte trafficking and positioning within tissues. They thus play critical roles in regulating immune responses and inflammation. The chemokine system is complex involving interactions between multiple chemokines and their receptors that operate in combinatorial cascades with adhesion molecules. The involvement of multiple chemokines and chemokine receptors in these processes brings flexibility and specificity to recruitment. The hepatic vascular bed is a unique low flow environment through which leukocyte are recruited to the liver during homeostatic immune surveillance and in response to infection or injury. The rate of leukocyte recruitment and the nature of cells recruited through the sinusoids in response to inflammatory signals will shape the severity of disease. At one end of the spectrum fulminant liver failure results from a rapid recruitment of leukocytes that leads to hepatocyte destruction and liver failure at the other diseases such as chronic hepatitis C infection may progress over many years from hepatitis to fibrosis and cirrhosis. Chronic hepatitis is charactezised by a T lymphocyte rich infiltrate and the nature and outcome of hepatitis will depend on the T cell subsets recruited, their activation and function within the liver. Different subsets of effector T cells have been described based on their secretion of cytokines and specific functions. These include Th1 and Th2 cells and more recently Th17 and Th9 cells which are associated with different types of immune response and which express distinct patterns of chemokine receptors that promote their recruitment under particular conditions. The effector function of these cells is balanced by the recruitment of regulatory T cells that are able to suppress antigen-specific effectors to allow resolution of immune responses and restoration of immune homeostasis. Understanding the signals that are responsible for recruiting different lymphocyte subsets to the liver will elucidate

  17. Specific regulation of the chemokine response to viral hemorrhagic septicemia virus at the entry site.

    Science.gov (United States)

    Montero, Jana; Garcia, Jessica; Ordas, M Camino; Casanova, Isabel; Gonzalez, Antonia; Villena, Alberto; Coll, Julio; Tafalla, Carolina

    2011-05-01

    The fin bases constitute the main portal of rhabdovirus entry into rainbow trout (Oncorhynchus mykiss), and replication in this first site strongly conditions the outcome of the infection. In this context, we studied the chemokine response elicited in this area in response to viral hemorrhagic septicemia virus (VHSV), a rhabdovirus. Among all the rainbow trout chemokine genes studied, only the transcription levels of CK10 and CK12 were significantly upregulated in response to VHSV. As the virus had previously been shown to elicit a much stronger chemokine response in internal organs, we compared the effect of VHSV on the gills, another mucosal site which does not constitute the main site of viral entry or rhabdoviral replication. In this case, a significantly stronger chemokine response was triggered, with CK1, CK3, CK9, and CK11 being upregulated in response to VHSV and CK10 and CK12 being down-modulated by the virus. We then conducted further experiments to understand how these different chemokine responses of mucosal tissues could correlate with their capacity to support VHSV replication. No viral replication was detected in the gills, while at the fin bases, only the skin and the muscle were actively supporting viral replication. Within the skin, viral replication took place in the dermis, while viral replication was blocked within epidermal cells at some point before protein translation. The different susceptibilities of the different skin layers to VHSV correlated with the effect that VHSV has on their capacity to secrete chemotactic factors. Altogether, these results suggest a VHSV interference mechanism on the early chemokine response at its active replication sites within mucosal tissues, a possible key process that may facilitate viral entry.

  18. CC chemokine receptor 5 delta32 and CC chemokine receptor 2 64I polymorphisms do not influence the virologic and immunologic response to antiretroviral combination therapy in human immunodeficiency virus type 1-infected patients

    NARCIS (Netherlands)

    Wit, Ferdinand W. N. M.; van Rij, Ronald P.; Weverling, Gerrit Jan; Lange, Joep M. A.; Schuitemaker, Hanneke

    2002-01-01

    To investigate the influence of the CC chemokine receptor 2 64I and CC chemokine receptor 5 delta32 polymorphisms on the virologic and immunologic response of human immunodeficiency virus type 1 (HIV-1)-infected patients to highly active antiretroviral therapy, data from 4 clinical studies were

  19. Immunopathological Roles of Cytokines, Chemokines, Signaling Molecules, and Pattern-Recognition Receptors in Systemic Lupus Erythematosus

    Science.gov (United States)

    Yu, Shui-Lian; Kuan, Woon-Pang; Wong, Chun-Kwok; Li, Edmund K.; Tam, Lai-Shan

    2012-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease with unknown etiology affecting more than one million individuals each year. It is characterized by B- and T-cell hyperactivity and by defects in the clearance of apoptotic cells and immune complexes. Understanding the complex process involved and the interaction between various cytokines, chemokines, signaling molecules, and pattern-recognition receptors (PRRs) in the immune pathways will provide valuable information on the development of novel therapeutic targets for treating SLE. In this paper, we review the immunopathological roles of novel cytokines, chemokines, signaling molecules, PRRs, and their interactions in immunoregulatory networks and suggest how their disturbances may implicate pathological conditions in SLE. PMID:22312407

  20. Structure, function and physiological consequences of virally encoded chemokine seven transmembrane receptors

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Smit, M J; Waldhoer, M

    2008-01-01

    A number of human and animal herpes viruses encode G-protein coupled receptors with seven transmembrane (7TM) segments-most of which are clearly related to human chemokine receptors. It appears, that these receptors are used by the virus for immune evasion, cellular transformation, tissue targeting...... pathogenesis is still poorly understood. Here we focus on the current knowledge of structure, function and trafficking patterns of virally encoded chemokine receptors and further address the putative roles of these receptors in virus survival and host -cell and/or -immune system modulation. Finally, we...

  1. Cytokines and Chemokines as Regulators of Skeletal Muscle Inflammation: Presenting the Case of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Boel De Paepe

    2013-01-01

    Full Text Available Duchenne muscular dystrophy is a severe inherited muscle disease that affects 1 in 3500 boys worldwide. Infiltration of skeletal muscle by inflammatory cells is an important facet of disease pathophysiology and is strongly associated with disease severity in the individual patient. In the chronic inflammation that characterizes Duchenne muscle, cytokines and chemokines are considered essential activators and recruiters of inflammatory cells. In addition, they provide potential beneficiary effects on muscle fiber damage control and tissue regeneration. In this review, current knowledge of cytokine and chemokine expression in Duchenne muscular dystrophy and its relevant animal disease models is listed, and implications for future therapeutic avenues are discussed.

  2. International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors.

    OpenAIRE

    Bachelerie Francoise; Ben-Baruch Adit; Burkhardt Amanda M.; Combadiere Christophe; Farber Joshua M.; Graham Gerard J; Horuk Richard; Sparre-Ulrich Alexander Hovard; Locati Massimo; Luster Andrew D.; Mantovani Alberto; Matsushima Kouji; Murphy Philip M.; Nibbs Robert; Nomiyama Hisayuki

    2014-01-01

    Sixteen years ago the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven transmembrane (7TM) G protein coupled chemokine receptors the large family of leukocyte chemoattractant receptors that regulates immune system development and function in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM Baggiolini M Charo IF Héber...

  3. International Union of Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors

    OpenAIRE

    Bachelerie, Francoise; Ben-Baruch, Adit; Burkhardt, Amanda M.; Combadiere, Christophe; Farber, Joshua M.; Graham, Gerard J.; Horuk, Richard; Sparre-Ulrich, Alexander Hovard; Locati, Massimo; Luster, Andrew D.; Mantovani, Alberto; Matsushima, Kouji; Murphy, Philip M.; Nibbs, Robert; Nomiyama, Hisayuki

    2014-01-01

    Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large family of leukocyte chemoattractant receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF,...

  4. CX3CL1/CX3CR1 and CCL2/CCR2 Chemokine/Chemokine Receptor Complex in Patients with AMD

    DEFF Research Database (Denmark)

    Falk, Mads Krüger; Singh, Amardeep; Faber, Carsten

    2014-01-01

    . Chemokine plasma level and chemokine receptor expression were measured by flow-cytometry. RESULTS: A total of 150 participants were included. We found a significantly lower expression of CX3CR1 on CD8+ T cells in the neovascular AMD group compared to the control group (p = 0.04). We found a significant...... positive correlation between CCR2 and CX3CR1 expression on CD8+ cells (r = 0.727, p = 0.0001). We found no difference in plasma levels of CX3CL1 and CCL2 among the groups. CONCLUSIONS: Our results show a down regulation of CX3CR1 on CD8+ cells; this correlated to a low expression of CCR2 on CD8+ cells......PURPOSE: The chemokine receptors CX3CR1 and CCR2 have been implicated in the development of age-related macular degeneration (AMD). The evidence is mainly derived from experimental cell studies and murine models of AMD. The purpose of this study was to investigate the association between expression...

  5. Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

    DEFF Research Database (Denmark)

    Nijnik, Anastasia; Madera, Laurence; Ma, Shuhua

    2010-01-01

    and the PI3K, NF-κB, and MAPK signaling pathways. The protective activity of the peptide was associated with in vivo augmentation of chemokine production and recruitment of neutrophils and monocytes to the site of infection. These results highlight the importance of the chemokine induction activity of host...

  6. β-Endorphin Antagonizes the Effects of α-MSH on Food Intake and Body Weight

    OpenAIRE

    Dutia, Roxanne; Meece, Kana; Dighe, Shveta; Andrea J. Kim; Wardlaw, Sharon L.

    2012-01-01

    Proopiomelanocortin (POMC) is posttranslationally processed to several peptides including α-MSH, a primary regulator of energy balance that inhibits food intake and stimulates energy expenditure. However, another POMC-derived peptide, β-endorphin (β-EP), has been shown to stimulate food intake. In this study we examined the effects of intracerebroventricular (icv) β-EP on food intake and its ability to antagonize the negative effects of α-MSH on energy balance in male rats. A single icv injec...

  7. Antipsychotic agents antagonize non-competitive N-methyl-D-aspartate antagonist-induced behaviors.

    Science.gov (United States)

    Corbett, R; Camacho, F; Woods, A T; Kerman, L L; Fishkin, R J; Brooks, K; Dunn, R W

    1995-07-01

    Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitive N-methyl-D-aspartate (NMDA) antagonist-induced behaviors. All of the agents dose-dependently antagonized the apomorphine-induced climbing mouse assay (CMA) and dizocilpine (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CMA/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and 0.05 mg/kg) than the CMA (12.3 and 0.45 mg/kg) and as a result had a CMA/MK-801-LF ratio of 11.2 and 9, respectively. Furthermore, phencyclidine (PCP) (2 mg/kg) can selectively induce social withdrawal in naive rats that were housed in pairs (familiar) for 10 days prior to testing without affecting motor activity. SCH 23390, raclopride, haloperidol, chlorpromazine and risperidone failed to reverse the social withdrawal induced by PCP up to doses which produced significant motor impairment. However, clozapine (2.5 and 5.0 mg/kg) and olanzapine (0.25 and 0.5 mg/kg) significantly reversed this social withdrawal in rats. Therefore, the non-competitive NMDA antagonists PCP and MK-801 can induce behaviors in Rodents which are selectively antagonized by clozapine and olanzapine. Furthermore, assessment of the effects of antipsychotic agents in the CMA, MK-801-LF and PCP-induced social withdrawal assays may provide a preclinical approach to identify novel agents for negative symptoms and treatment resistant schizophrenia.

  8. Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction

    Science.gov (United States)

    Chang, Jennifer; Fedinec, Alexander L.; Kuntamallappanavar, Guruprasad; Leffler, Charles W.; Bukiya, Anna N.

    2016-01-01

    Despite preventive education, the combined consumption of alcohol and caffeine (particularly from “energy drinks”) continues to rise. Physiologic perturbations by separate intake of ethanol and caffeine have been widely documented. However, the biologic actions of the alcohol-caffeine combination and their underlying subcellular mechanisms have been scarcely studied. Using intravital microscopy on a closed-cranial window and isolated, pressurized vessels, we investigated the in vivo and in vitro action of ethanol-caffeine mixtures on cerebral arteries from rats and mice, widely recognized models to address cerebrovascular pathophysiology and pharmacology. Caffeine at concentrations found in human circulation after ingestion of one to two cups of coffee (10 µM) antagonized the endothelium-independent constriction of cerebral arteries evoked by ethanol concentrations found in blood during moderate-heavy alcohol intoxication (40–70 mM). Caffeine antagonism against alcohol was similar whether evaluated in vivo or in vitro, suggesting independence of systemic factors and drug metabolism, but required a functional endothelium. Moreover, caffeine protection against alcohol increased nitric oxide (NO•) levels over those found in the presence of ethanol alone, disappeared upon blocking NO• synthase, and could not be detected in pressurized cerebral arteries from endothelial nitric-oxide synthase knockout (eNOS−/−) mice. Finally, incubation of de-endothelialized cerebral arteries with the NO• donor sodium nitroprusside (10 µM) fully restored the protective effect of caffeine. This study demonstrates for the first time that caffeine antagonizes ethanol-induced cerebral artery constriction and identifies endothelial NO• as the critical caffeine effector on smooth muscle targets. Conceivably, situations that perturb endothelial function and/or NO• availability will critically alter caffeine antagonism of alcohol-induced cerebrovascular constriction without

  9. Caffeine intake antagonizes salt sensitive hypertension through improvement of renal sodium handling

    OpenAIRE

    Hao Yu; Tao Yang; Peng Gao; Xing Wei; Hexuan Zhang; Shiqiang Xiong; Zongshi Lu; Li Li; Xiao Wei; Jing Chen; Yu Zhao; Arendshorst, William J.; Qianhui Shang; Daoyan Liu; Zhiming Zhu

    2016-01-01

    High salt intake is a major risk factor for hypertension. Although acute caffeine intake produces moderate diuresis and natriuresis, caffeine increases the blood pressure (BP) through activating sympathetic activity. However, the long-term effects of caffeine on urinary sodium excretion and blood pressure are rarely investigated. Here, we investigated whether chronic caffeine administration antagonizes salt sensitive hypertension by promoting urinary sodium excretion. Dahl salt-sensitive (Dah...

  10. Parental antagonism and parent-offspring co-adaptation interact to shape family life.

    Science.gov (United States)

    Meunier, Joël; Kölliker, Mathias

    2012-10-07

    The family is an arena for conflicts between offspring, mothers and fathers that need resolving to promote the evolution of parental care and the maintenance of family life. Co-adaptation is known to contribute to the resolution of parent-offspring conflict over parental care by selecting for combinations of offspring demand and parental supply that match to maximize the fitness of family members. However, multiple paternity and differences in the level of care provided by mothers and fathers can generate antagonistic selection on offspring demand (mediated, for example, by genomic imprinting) and possibly hamper co-adaptation. While parent-offspring co-adaptation and parental antagonism are commonly considered two major processes in the evolution of family life, their co-occurrence and the evolutionary consequences of their joint action are poorly understood. Here, we demonstrate the simultaneous and entangled effects of these two processes on outcomes of family interactions, using a series of breeding experiments in the European earwig, Forficula auricularia, an insect species with uniparental female care. As predicted from parental antagonism, we show that paternally inherited effects expressed in offspring influence both maternal care and maternal investment in future reproduction. However, and as expected from the entangled effects of parental antagonism and co-adaptation, these effects critically depended on postnatal interactions with caring females and maternally inherited effects expressed in offspring. Our results demonstrate that parent-offspring co-adaptation and parental antagonism are entangled key drivers in the evolution of family life that cannot be fully understood in isolation.

  11. ACE2 Antagonizes VEGFa to Reduce Vascular Permeability During Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    Xiaobo Yu

    2016-03-01

    Full Text Available Background/Aims: Angiotensin converting enzyme 2 (ACE2 treatment suppresses the severity of acute lung injury (ALI, through antagonizing hydrolyzing angiotensin II (AngII and the ALI-induced apoptosis of pulmonary endothelial cells. Nevertheless, the effects of ACE2 on vessel permeability and its relationship with vascular endothelial growth factor a (VEGFa remain ill-defined. In the current study, we examined the relationship between ACE2 and VEGFa in ALI model in mice. Methods: Here, we used a previously published bleomycin method to induce ALI in mice, and treated the mice with ACE2. We analyzed the levels of VEGFa in these mice. The mouse lung vessel permeability was determined by a fluorescence pharmacokinetic assay following i.v. injection of 62.5µg/kg Visudyne. VEGFa pump or SU5416 pump was given to increase or decrease VEGFa effects, respectively. The long-term effects on lung function were determined by measurement of lung resistance using methacholine. Results: ACE2 treatment did not alter VEGFa levels in lung, but antagonized the effects of VEGFa on increases of lung vessel permeability. Ectogenic VEGFa abolished the antagonizing effects of ACE2 on the vessel permeability against VEGFa. On the other hand, suppression of VEGF signaling mimicked the effects of ACE2 on the vessel permeability against VEGFa. The suppression of vessel permeability resulted in improvement of lung function after ALI. Conclusion: ACE2 may antagonize the VEGFa-mediated increases in lung vessel permeability during ALI, resulting in improvement of lung function after ALI.

  12. Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction.

    Science.gov (United States)

    Chang, Jennifer; Fedinec, Alexander L; Kuntamallappanavar, Guruprasad; Leffler, Charles W; Bukiya, Anna N; Dopico, Alex M

    2016-01-01

    Despite preventive education, the combined consumption of alcohol and caffeine (particularly from "energy drinks") continues to rise. Physiologic perturbations by separate intake of ethanol and caffeine have been widely documented. However, the biologic actions of the alcohol-caffeine combination and their underlying subcellular mechanisms have been scarcely studied. Using intravital microscopy on a closed-cranial window and isolated, pressurized vessels, we investigated the in vivo and in vitro action of ethanol-caffeine mixtures on cerebral arteries from rats and mice, widely recognized models to address cerebrovascular pathophysiology and pharmacology. Caffeine at concentrations found in human circulation after ingestion of one to two cups of coffee (10 µM) antagonized the endothelium-independent constriction of cerebral arteries evoked by ethanol concentrations found in blood during moderate-heavy alcohol intoxication (40-70 mM). Caffeine antagonism against alcohol was similar whether evaluated in vivo or in vitro, suggesting independence of systemic factors and drug metabolism, but required a functional endothelium. Moreover, caffeine protection against alcohol increased nitric oxide (NO•) levels over those found in the presence of ethanol alone, disappeared upon blocking NO• synthase, and could not be detected in pressurized cerebral arteries from endothelial nitric-oxide synthase knockout (eNOS(-/-)) mice. Finally, incubation of de-endothelialized cerebral arteries with the NO• donor sodium nitroprusside (10 µM) fully restored the protective effect of caffeine. This study demonstrates for the first time that caffeine antagonizes ethanol-induced cerebral artery constriction and identifies endothelial NO• as the critical caffeine effector on smooth muscle targets. Conceivably, situations that perturb endothelial function and/or NO• availability will critically alter caffeine antagonism of alcohol-induced cerebrovascular constriction without

  13. H3K36 Methylation Antagonizes PRC2-mediated H3K27 Methylation*

    OpenAIRE

    Yuan, Wen; Xu, Mo; Huang, Chang; Liu, Nan; Chen, She; Zhu, Bing

    2011-01-01

    H3K27 methylation mediated by the histone methyltransferase complex PRC2 is critical for transcriptional regulation, Polycomb silencing, Drosophila segmentation, mammalian X chromosome inactivation, and cancer. PRC2-mediated H3K27 methylation can spread along the chromatin and propagate the repressive chromatin environment; thus, chromatin components that antagonize the activity of PRC2 are important for restraining Polycomb silencing. Here we report that in HeLa cells, H3 histones unmethylat...

  14. CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions

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    Vincent Vanheule

    2017-05-01

    Full Text Available Several acute and chronic inflammatory diseases are driven by accumulation of activated leukocytes due to enhanced chemokine expression. In addition to specific G protein-coupled receptor-dependent signaling, chemokine–glycosaminoglycan (GAG interactions are important for chemokine activity in vivo. Therefore, the GAG–chemokine interaction has been explored as target for inhibition of chemokine activity. It was demonstrated that CXCL9(74-103 binds with high affinity to GAGs, competed with active chemokines for GAG binding and thereby inhibited CXCL8- and monosodium urate (MSU crystal-induced neutrophil migration to joints. To evaluate the affinity and specificity of the COOH-terminal part of CXCL9 toward different GAGs in detail, we chemically synthesized several COOH-terminal CXCL9 peptides including the shorter CXCL9(74-93. Compared to CXCL9(74-103, CXCL9(74-93 showed equally high affinity for heparin and heparan sulfate (HS, but lower affinity for binding to chondroitin sulfate (CS and cellular GAGs. Correspondingly, both peptides competed with equal efficiency for CXCL8 binding to heparin and HS but not to cellular GAGs. In addition, differences in anti-inflammatory activity between both peptides were detected in vivo. CXCL8-induced neutrophil migration to the peritoneal cavity and to the knee joint were inhibited with similar potency by intravenous or intraperitoneal injection of CXCL9(74-103 or CXCL9(74-93, but not by CXCL9(86-103. In contrast, neutrophil extravasation in the MSU crystal-induced gout model, in which multiple chemoattractants are induced, was not affected by CXCL9(74-93. This could be explained by (1 the lower affinity of CXCL9(74-93 for CS, the most abundant GAG in joints, and (2 by reduced competition with GAG binding of CXCL1, the most abundant ELR+ CXC chemokine in this gout model. Mechanistically we showed by intravital microscopy that fluorescent CXCL9(74-103 coats the vessel wall in vivo and that CXCL9

  15. Arctigenin antagonizes mineralocorticoid receptor to inhibit the transcription of Na/K-ATPase.

    Science.gov (United States)

    Cheng, Ye; Zhou, Meili; Wang, Yan

    2016-01-01

    Hypertension is one of the most important risk factors in cardiovascular disease and is the most common chronic disease. Mineralocorticoid receptor (MR) antagonists have been successfully used in clinic for the treatment of hypertension. Our study aims to investigate whether Arctigenin can antagonize MR and inhibit the transcription of Na/K-ATPase. The yeast two-hybrid assay was used to screen natural products and Arctigenin was identified as an MR antagonist. The direct binding of Arctigenin to MR was determined using assays based on surface plasmon resonance, differential scanning calorimetry and fluorescence quenching. Furthermore, results from mammalian one-hybrid and transcriptional activation experiments also confirmed that Arctigenin can potently antagonize MR in cells. We demonstrated that Arctigenin can decrease the level of Na/K-ATPase mRNA by antagonizing MR in HK-2 cells. Our findings show that Arctigenin can effectively decrease Na/K-ATPase transcription; thus highlight its potential as an anti-hypertensive drug lead compound. Our current findings demonstrate that Arctigenin is an antagonist of MR and effectively decreases the Na/K-ATPase 1 gene expression. Our work provides a hint for the drug discovery against cardiovascular disease.

  16. In vitro antagonism of Trichoderma harzianum Rifai against Mycosphaerella fijiensis Morelet

    Directory of Open Access Journals (Sweden)

    Mayra Acosta-Suárez

    2013-10-01

    Full Text Available The in vitro antagonism of Trichoderma harzianum against Mycosphaerella fijiensis, foliar pathogen of banana and plantain, was evaluated. The assays were performed using the dual culture method. Competition for space and nutrients, the antagonistic capacity and forms and intensity of antagonism were determined considering the invasion of the surface of the colony, colonization and sporulation of T. harzianum on M. fijiensis after seven days of inoculation. Finally, the effect of volatile metabolites of T. harzianum was evaluated. The results showed in vitro antagonism of T. harzianum against M. fijiensis by competition for space and nutrients of the culture medium. Trichoderma grew over the pathogen colony with hyperparasitism and high intensity. Also, it completely covered the surface of the culture medium. T. harzianum not inhibited the growth of M. fijiensis by volatile metabolites. Damage was observed in the integrity of the cell wall of M. fijiensis hyphae and the cell content exit. The use of antagonistic fungi, could contribute to the design of strategies for integrated management of this disease. Key words: banana and plantain, biocontrol, mechanisms of action

  17. Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes.

    Science.gov (United States)

    Gazzara, Matthew R; Mallory, Michael J; Roytenberg, Renat; Lindberg, John P; Jha, Anupama; Lynch, Kristen W; Barash, Yoseph

    2017-08-01

    Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors. We validate this functional antagonism through knockdown and overexpression experiments in human cells and find CELF2 represses RBFOX2 mRNA and protein levels. Because both families of proteins have been implicated in the development and maintenance of neuronal, muscle, and heart tissues, we analyzed publicly available data in these systems. Our analysis suggests global, antagonistic coregulation of splicing by the CELF and RBFOX proteins in mouse muscle and heart in several physiologically relevant targets, including proteins involved in calcium signaling and members of the MEF2 family of transcription factors. Importantly, a number of these coregulated events are aberrantly spliced in mouse models and human patients with diseases that affect these tissues, including heart failure, diabetes, or myotonic dystrophy. Finally, analysis of exons regulated by ancient CELF family homologs in chicken, Drosophila, and Caenorhabditis elegans suggests this antagonism is conserved throughout evolution. © 2017 Gazzara et al.; Published by Cold Spring Harbor Laboratory Press.

  18. The Modulatory Properties of Chronic Antidepressant Drugs Treatment on the Brain ChemokineChemokine Receptor Network: A Molecular Study in an Animal Model of Depression

    Directory of Open Access Journals (Sweden)

    Ewa Trojan

    2017-11-01

    Full Text Available An increasing number of studies indicate that the chemokine system may be the third major communication system of the brain. Therefore, the role of the chemokine system in the development of brain disorders, including depression, has been recently proposed. However, little is known about the impact of the administration of various antidepressant drugs on the brain chemokinechemokine receptor axis. In the present study, we used an animal model of depression based on the prenatal stress procedure. We determined whether chronic treatment with tianeptine, venlafaxine, or fluoxetine influenced the evoked by prenatal stress procedure changes in the mRNA and protein levels of the homeostatic chemokines, CXCL12 (SDF-1α, CX3CL1 (fractalkine and their receptors, in the hippocampus and frontal cortex. Moreover, the impact of mentioned antidepressants on the TGF-β, a molecular pathway related to fractalkine receptor (CX3CR1, was explored. We found that prenatal stress caused anxiety and depressive-like disturbances in adult offspring rats, which were normalized by chronic antidepressant treatment. Furthermore, we showed the stress-evoked CXCL12 upregulation while CXCR4 downregulation in hippocampus and frontal cortex. CXCR7 expression was enhanced in frontal cortex but not hippocampus. Furthermore, the levels of CX3CL1 and CX3CR1 were diminished by prenatal stress in the both examined brain areas. The mentioned changes were normalized with various potency by chronic administration of tested antidepressants. All drugs in hippocampus, while tianeptine and venlafaxine in frontal cortex normalized the CXCL12 level in prenatally stressed offspring. Moreover, in hippocampus only fluoxetine enhanced CXCR4 level, while fluoxetine and tianeptine diminished CXCR7 level in frontal cortex. Additionally, the diminished by prenatal stress levels of CX3CL1 and CX3CR1 in the both examined brain areas were normalized by chronic tianeptine and partially fluoxetine

  19. Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection

    Science.gov (United States)

    Larrubia, Juan R; Benito-Martínez, Selma; Calvino, Miryam; Sanz-de-Villalobos, Eduardo; Parra-Cid, Trinidad

    2008-01-01

    Chemokines produced in the liver during hepatitis C virus (HCV) infection induce migration of activated T cells from the periphery to infected parenchyma. The milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper/T-cytotoxic type-1 cell (Th1/Tc1) response. These chemokines consist of CCL3 (macrophage inflammatory protein-1α; MIP-1α), CCL4 (MIP-1β), CCL5 (regulated on activation normal T cell expressed and secreted; RANTES), CXCL10 (interferon-γ−inducible protein-10; IP-10), CXCL11 (interferon-inducible T-cell α chemoattractant; I-TAC), and CXCL9 (monokine induced by interferon γ; Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine receptors. Intrahepatic and peripheral blood levels of these chemokines are increased during chronic hepatitis C. The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection. When the adaptive immune response fails in this task, non-specific T cells without the capacity to control the infection are also recruited to the liver, and these are ultimately responsible for the persistent hepatic damage. The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection, and to maintain liver viability during the chronic phase, by impairing non-specific T cell migration. Some chemokines and their receptors correlate with liver damage, and CXCL10 (IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome. The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver. PMID:19084927

  20. Biased agonism as a mechanism for differential signaling by chemokine receptors.

    Science.gov (United States)

    Rajagopal, Sudarshan; Bassoni, Daniel L; Campbell, James J; Gerard, Norma P; Gerard, Craig; Wehrman, Tom S

    2013-12-06

    Chemokines display considerable promiscuity with multiple ligands and receptors shared in common, a phenomenon that is thought to underlie their biochemical "redundancy." Their receptors are part of a larger seven-transmembrane receptor superfamily, commonly referred to as G protein-coupled receptors, which have been demonstrated to be able to signal with different efficacies to their multiple downstream signaling pathways, a phenomenon referred to as biased agonism. Biased agonism has been primarily reported as a phenomenon of synthetic ligands, and the biologic prevalence and importance of such signaling are unclear. Here, to assess the presence of biased agonism that may underlie differential signaling by chemokines targeting the same receptor, we performed a detailed pharmacologic analysis of a set of chemokine receptors with multiple endogenous ligands using assays for G protein signaling, β-arrestin recruitment, and receptor internalization. We found that chemokines targeting the same receptor can display marked differences in their efficacies for G protein- or β-arrestin-mediated signaling or receptor internalization. This ligand bias correlates with changes in leukocyte migration, consistent with different mechanisms underlying the signaling downstream of these receptors induced by their ligands. These findings demonstrate that biased agonism is a common and likely evolutionarily conserved biological mechanism for generating qualitatively distinct patterns of signaling via the same receptor in response to different endogenous ligands.

  1. A Combinatorial Approach to Biophysically Characterise Chemokine-Glycan Binding Affinities for Drug Development

    Directory of Open Access Journals (Sweden)

    Tanja Gerlza

    2014-07-01

    Full Text Available Chemokine binding to glycosaminoglycans (GAGs is recognised to be an important step in inflammation and other pathological disorders like tumor growth and metastasis. Although different ways and strategies to interfere with these interactions are being pursued, no major breakthrough in the development of glycan-targeting drugs has been reported so far. We have engineered CXCL8 towards a dominant-negative form of this chemokine (dnCXCL8 which was shown to be highly active in various inflammatory animal models due to its inability to bind/activate the cognate CXCL8 GPC receptors on neutrophils in combination with its significantly increased GAG-binding affinity [1]. For the development of GAG-targeting chemokine-based biopharmaceuticals, we have established a repertoire of methods which allow the quantification of protein-GAG interactions. Isothermal fluorescence titration (IFT, surface plasmon resonance (SPR, isothermal titration calorimetry (ITC, and a novel ELISA-like competition assay (ELICO have been used to determine Kd and IC50 values for CXCL8 and dnCXCL8 interacting with heparin and heparan sulfate (HS, the proto-typical members of the GAG family. Although the different methods gave different absolute affinities for the four protein-ligand pairs, the relative increase in GAG-binding affinity of dnCXCL8 compared to the wild type chemokine was found by all methods. In combination, these biophysical methods allow to discriminate between unspecific and specific protein-GAG interactions.

  2. Design, synthesis, and functionalization of dimeric peptides targeting chemokine receptor CXCR4.

    NARCIS (Netherlands)

    Demmer, O.; Dijkgraaf, I.; Schumacher, U.; Marinelli, L.; Cosconati, S.; Gourni, E.; Wester, H.J.; Kessler, H.

    2011-01-01

    The chemokine receptor CXCR4 is a critical regulator of inflammation and immune surveillance, and it is specifically implicated in cancer metastasis and HIV-1 infection. On the basis of the observation that several of the known antagonists remarkably share a C(2) symmetry element, we constructed

  3. Admission chemokine (C-C motif) ligand 4 levels predict survival in pediatric septic shock.

    Science.gov (United States)

    Nowak, Jeffrey E; Wheeler, Derek S; Harmon, Kelli K; Wong, Hector R

    2010-03-01

    Stratification with an effective outcome biomarker could improve the design of interventional trials in pediatric septic shock. The objective of this study was to test the usefulness of chemokine (C-C motif) ligand 4 as an outcome biomarker for mortality in pediatric septic shock. A cross-sectional, observational study. Eighteen pediatric intensive care units in the United States. One hundred fifty-six pediatric patients with septic shock. Serum samples were obtained within 24 hrs of admission to the pediatric intensive care unit. Serum levels of chemokine (C-C motif) ligand 4 were measured by enzyme-linked immunosorbent assay and compared with mortality in a training set of 34 patients. These data were used to generate a cutoff value whose usefulness was evaluated through prospective application-without post hoc modification-to a larger validation set of 122 patients. On inspection of the training set data, a cutoff value of 140 pg/mL was chosen. When applied to the validation set, serum chemokine (C-C motif) ligand 4 levels >140 pg/mL yielded a sensitivity of 92% and a specificity of 40% for mortality. A serum level of pediatric septic shock. Exclusion of patients with a chemokine (C-C motif) ligand 4 level of pediatric septic shock could create a study population in which survival benefit from the study agent could be more readily demonstrated.

  4. CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens

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    Matthew A. Crawford

    2017-11-01

    Full Text Available The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobial-resistant pathogens requires a multifaceted effort that includes the discovery of novel therapeutic approaches. Here, we establish the capacity of the human CXC chemokines CXCL9 and CXCL10 to kill multidrug-resistant Gram-negative bacteria, including New Delhi metallo-beta-lactamase-1-producing Klebsiella pneumoniae and colistin-resistant members of the family Enterobacteriaceae that harbor the mobile colistin resistance protein MCR-1 and thus possess phosphoethanolamine-modified lipid A. Colistin-resistant K. pneumoniae isolates affected by genetic mutation of the PmrA/PmrB two-component system, a chromosomally encoded regulator of lipopolysaccharide modification, and containing 4-amino-4-deoxy-l-arabinose-modified lipid A were also found to be susceptible to chemokine-mediated antimicrobial activity. However, loss of PhoP/PhoQ autoregulatory control, caused by disruption of the gene encoding the negative regulator MgrB, limited the bactericidal effects of CXCL9 and CXCL10 in a variable, strain-specific manner. Cumulatively, these findings provide mechanistic insight into chemokine-mediated antimicrobial activity, highlight disparities amongst determinants of colistin resistance, and suggest that chemokine-mediated bactericidal effects merit additional investigation as a therapeutic avenue for treating infections caused by multidrug-resistant pathogens.

  5. Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors

    DEFF Research Database (Denmark)

    Thiele, Stefanie; Malmgaard-Clausen, Mikkel; Engel-Andreasen, Jens

    2012-01-01

    Among 18 human chemokine receptors, CCR1, CCR4, CCR5, and CCR8 were activated by metal ion Zn(II) or Cu(II) in complex with 2,2'-bipyridine or 1,10-phenanthroline with similar potencies (EC(50) from 3.9 to 172 μM). Besides being agonists, they acted as selective allosteric enhancers of CCL3...

  6. Chemokine receptor 2 (CCR2) G190A polymorphism in chronic ...

    African Journals Online (AJOL)

    End-stage renal disease is associated with the inflammatory state characterized by infiltrating macrophages/lymphocytes, a major source of chemokines. The aim of this study was to determine the association of CCR2 G190A polymorphism in patients with chronic renal failure (CRF) requiring hemodialysis. Seventy CRF ...

  7. Tumor Necrosis Factor (TNF) and Chemokines in Colitis-Associated Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mukaida, Naofumi, E-mail: naofumim@kenroku.kanazawa-u.ac.jp; Sasakki, So-ichiro [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Popivanova, Boryana K. [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Present Address, Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan)

    2011-06-27

    The connection between inflammation and tumorigenesis has been well established, based on a great deal of supporting evidence obtained from epidemiological, pharmacological, and genetic studies. One representative example is inflammatory bowel disease, because it is an important risk factor for the development of colon cancer. Moreover, intratumoral infiltration of inflammatory cells suggests the involvement of inflammatory responses also in other forms of sporadic as well as heritable colon cancer. Inflammatory responses and tumorigenesis activate similar sets of transcription factors such as NF-κB, Stat3, and hypoxia inducible factor and eventually enhances the expression of inflammatory cytokines including tumor necrosis factor (TNF) and chemokines. The expression of TNF and chemokines is aberrantly expressed in a mouse model of colitis-associated carcinogenesis as well as in inflammatory bowel disease and colon cancer in humans. Here, after summarizing the presumed actions of TNF and chemokines in tumor biology, we will discuss the potential roles of TNF and chemokines in chronic inflammation-associated colon cancer in mice.

  8. The role of redox status on chemokine expression in acute pancreatitis

    OpenAIRE

    Yubero, S.; Ramudo, L.; Manso, M.A.; De Dios, I.

    2009-01-01

    The role of redox status on chemokine expression in acute pancreatitis correspondance: Corresponding author. Departamento Fisiologia y Farmacologia. Edificio Departamental Campus Miguel de Unamuno 37007 Salamanca Spain. Fax: +34 923 294673. (De Dios, I.) (De Dios, I.) Department of Physiology and Pharmacology. University of Salamanca. 37007 Salamanca. Spain--> - (Yubero, S.) Department of Physiology and Pharmacology. ...

  9. Differential CCR7 Targeting in Dendritic Cells by Three Naturally Occurring CC-Chemokines

    DEFF Research Database (Denmark)

    Hjorto, Gertrud M.; Larsen, Olav; Steen, Anne

    2016-01-01

    identify a molecular switch in the top of TM7 important for keeping CCR7 in an inactive conformation (Tyr312), as introduction of the chemokine receptor-conserved Glu (or Ala) induces high constitutive activity. Summarized, we show that the interaction of the tail of CCL21 with polysialic acid is needed...

  10. Extracellular Disulfide Bridges Serve Different Purposes in Two Homologous Chemokine Receptors, CCR1 and CCR5

    DEFF Research Database (Denmark)

    Rummel, Pia Cwarzko; Thiele, Stefanie; Hansen, Lærke Smidt

    2013-01-01

    In addition to the 7 transmembrane receptor (7TM)-conserved disulfide bridge between transmembrane (TM) helix 3 and extracellular loop (ECL)-2, chemokine receptors (CCR) contain a disulfide bridge between the N terminus and what previously was believed to be ECL-3. Recent crystal and NMR structur...

  11. Cytokines and Chemokines at the Crossroads of Neuroinflammation, Neurodegeneration, and Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Geeta Ramesh

    2013-01-01

    Full Text Available Cytokines and chemokines are proteins that coordinate the immune response throughout the body. The dysregulation of cytokines and chemokines is a central feature in the development of neuroinflammation, neurodegeneration, and demyelination both in the central and peripheral nervous systems and in conditions of neuropathic pain. Pathological states within the nervous system can lead to activation of microglia. The latter may mediate neuronal and glial cell injury and death through production of proinflammatory factors such as cytokines and chemokines. These then help to mobilize the adaptive immune response. Although inflammation may induce beneficial effects such as pathogen clearance and phagocytosis of apoptotic cells, uncontrolled inflammation can result in detrimental outcomes via the production of neurotoxic factors that exacerbate neurodegenerative pathology. In states of prolonged inflammation, continual activation and recruitment of effector cells can establish a feedback loop that perpetuates inflammation and ultimately results in neuronal injury. A critical balance between repair and proinflammatory factors determines the outcome of a neurodegenerative process. This review will focus on how cytokines and chemokines affect neuroinflammation and disease pathogenesis in bacterial meningitis and brain abscesses, Lyme neuroborreliosis, human immunodeficiency virus encephalitis, and neuropathic pain.

  12. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice

    DEFF Research Database (Denmark)

    Koenen, RR; Hundelshausen, P; Nesmelova, IV

    2009-01-01

    ) and RANTES (CCL5), triggering monocyte arrest on inflamed endothelium. Homo-oligomerization is required for the recruitment functions of CCL5, and chemokine heteromerization has more recently emerged as an additional regulatory mechanism, as evidenced by a mutual modulation of CXCL8 and CXCL4 activities...

  13. Molecular determinants of receptor binding and signaling by the CX3C chemokine fractalkine

    DEFF Research Database (Denmark)

    Mizoue, L S; Sullivan, S K; King, D S

    2001-01-01

    , but not all, pathways required for migration. Fractalkine also binds the human cytomegalovirus receptor US28, and analysis of the mutants indicates that US28 recognizes many of the same epitopes of fractalkine as CX3CR1. Comparison of the binding surfaces of fractalkine and the CC chemokine MCP-1 reveals...

  14. Partial functional complementation between human and mouse cytomegalovirus chemokine receptor homologues

    DEFF Research Database (Denmark)

    Farrell, Helen E; Abraham, Alexander M; Cardin, Rhonda D

    2011-01-01

    The human cytomegalovirus (CMV) proteins US28 and UL33 are homologous to chemokine receptors (CKRs). Knockout of the mouse CMV M33 protein (UL33 homologue) results in substantial attenuation of salivary gland infection/replication and reduced efficiency of reactivation from tissue explants. M33...

  15. Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment

    NARCIS (Netherlands)

    Drechsler, Maik; de Jong, Renske; Rossaint, Jan; Viola, Joana R.; Leoni, Giovanna; Wang, Ji Ming; Grommes, Jochen; Hinkel, Rabea; Kupatt, Christian; Weber, Christian; Döring, Yvonne; Zarbock, Alexander; Soehnlein, Oliver

    2015-01-01

    Chemokine-controlled arterial leukocyte recruitment is a crucial process in atherosclerosis. Formyl peptide receptor 2 (FPR2) is a chemoattractant receptor that recognizes proinflammatory and proresolving ligands. The contribution of FPR2 and its proresolving ligand annexin A1 to atherosclerotic

  16. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment

    NARCIS (Netherlands)

    Bernhagen, J.; Krohn, R.; Lue, H.; Gregory, J.L.; Zernecke, A.; Koenen, R.R.; Dewor, M.; Georgiev, I.; Schober, A.; Leng, L.; Kooistra, T.; Fingerle-Rowson, G.; Ghezzi, P.; Kleemann, R.; McColl, S.R.; Bucala, R.; Hickey, M.J.; Weber, C.

    2007-01-01

    The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G αi- and integrin-dependent arrest and chemotaxis of monocytes and T cells,

  17. The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice

    NARCIS (Netherlands)

    Bongers, G.; Maussang, D.; Muniz, L.R.; Noriega, V.M.; Fraile-Ramos, A.; Barker, N.; Marchesi, F.; Thirunarayanan, N.; Vischer, H.F.; Qin, L.; Mayer, L.; Harpaz, N.; Leurs, R.; Furtado, G.C.; Clevers, H.; Tortorella, D.; Smit, M.J.; Lira, S.A.

    2010-01-01

    US28 is a constitutively active chemokine receptor encoded by CMV (also referred to as human herpesvirus 5), a highly prevalent human virus that infects a broad spectrum of cells, including intestinal epithelial cells (IECs). To study the role of US28 in vivo, we created transgenic mice (VS28 mice)

  18. Chemokine receptor CCR5 and CXCR4 might influence virus replication during IBDV infection.

    Science.gov (United States)

    Ou, Changbo; Wang, Qiuxia; Yu, Yan; Zhang, Yanhong; Ma, Jinyou; Kong, Xianghui; Liu, Xingyou

    2017-06-01

    Both CCR5 and CXCR4 are important chemokine receptors and take vital role in migration, development and distribution of T cells, however, whether they will influence the process of T cell infiltration into bursa of Fabricius during infectious bursal disease virus (IBDV) infection is unclear. In the current study, CCR5 and CXCR4 antagonists, Maraviroc and AMD3100, were administrated into chickens inoculated with IBDV, and the gene levels of IBDV VP2, CCR5, CXCR4 and related cytokines were determined by real-time PCR. The results showed that large number of T cells began to migrate into the bursae on Day 3 post infection with IBDV and the mRNA of chemokine receptors CCR5 and CXCR4 began to increase on Day 1. Moreover, antagonist treatments have increased the VP2, CCR5 and CXCR4 gene transcriptions and influenced on the gene levels of IL-2, IL-6, IL-8, IFN-γ, TGF-β4, MHC-I and MDA5. In conclusion, the chemokine receptors CCR5 and CXCR4 might influence virus replication during IBDV infection and further study would focus on the interaction between chemokine receptors and their ligands. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. 77 FR 10598 - BIOTECH Holdings Ltd., California Oil & Gas Corp., Central Minera Corp., Chemokine Therapeutics...

    Science.gov (United States)

    2012-02-22

    ... From the Federal Register Online via the Government Publishing Office SECURITIES AND EXCHANGE COMMISSION BIOTECH Holdings Ltd., California Oil & Gas Corp., Central Minera Corp., Chemokine Therapeutics... current and accurate information concerning the securities of California Oil & Gas Corp. because it has...

  20. The cre-inducer doxycycline lowers cytokine and chemokine transcript levels in the gut of mice

    DEFF Research Database (Denmark)

    Hansen, Axel Kornerup; Malm, Sara Astrup; Metzdorff, Stine B.

    2017-01-01

    a strong impact on the immune system. Here we show that in C57BL/6 mice, the most commonly applied strain for genetic modification, doxycycline treatment lowered transcription of the genes Il1b, Il10, Il18, Tnf, Cxcl1, and Cxcl2 in the ileum, and of the gene Il18 in colon. Cytokines and chemokines encoded...

  1. Chemokine expression of oral fibroblasts and epithelial cells in response to artificial saliva.

    Science.gov (United States)

    Müller, Heinz-Dieter; Cvikl, Barbara; Lussi, Adrian; Gruber, Reinhard

    2016-06-01

    Artificial saliva is widely used to overcome reduced natural salivary flow. Natural saliva provokes the expression of chemokines in oral fibroblasts in vitro. However, if artificial saliva changes the expression of chemokines remains unknown. Here, we investigated the ability of Saliva Orthana®, Aldiamed®, Glandosane®, and Saliva Natura® to change the expression of chemokines in human oral fibroblasts and the human oral epithelial cell line HSC-2 by means of reverse transcription polymerase chain reaction and immunoassays. Mucins isolated from bovine submaxillary glands and recombinant human mucin 1 were included in the bioassay. Formazan formation and LIVE/DEAD® staining determined the impact of artificial saliva on cell viability. The involvement of signaling pathways was determined by pharmacologic inhibitors and Western blotting. In gingival fibroblasts, Saliva Orthana®-containing mucins provoked a significantly increased expression of CXC ligand 8 (CXCL8, or interleukin 8), CXCL1, and CXCL2. Immunoassays for CXCL8 and CXCL1 confirmed the translation at the protein level. The respective dilution of artificial saliva had no impact on formazan formation and LIVE/DEAD® staining. Mucins isolated from bovine submaxillary glands also increased the panel of chemokine expression in gingival fibroblasts. BAY 11-7082, a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor, but also TAK-242, an inhibitor of toll-like receptor 4 signaling, blocked chemokine expression of Saliva Orthana® and bovine mucins. In HSC-2 cells, Glandosane® significantly increased CXCL8 expression. Saliva Orthana® stimulated chemokine expression in gingival fibroblasts. Mammalian mucins, but also possible contaminations with endotoxins, might contribute to the respective changes in gene expression. Epithelial cells have a differential response to artificial saliva with Glandosane® changing CXCL8 expression. Artificial saliva can incite a cellular response

  2. Cell recruiting chemokine-loaded sprayable gelatin hydrogel dressings for diabetic wound healing.

    Science.gov (United States)

    Yoon, Dong Suk; Lee, Yunki; Ryu, Hyun Aae; Jang, Yeonsue; Lee, Kyoung-Mi; Choi, Yoorim; Choi, Woo Jin; Lee, Moses; Park, Kyung Min; Park, Ki Dong; Lee, Jin Woo

    2016-07-01

    In this study, we developed horseradish peroxidase (HRP)-catalyzed sprayable gelatin hydrogels (GH) as a bioactive wound dressing that can deliver cell-attracting chemotactic cytokines to the injured tissues for diabetic wound healing. We hypothesized that topical administration of chemokines using GH hydrogels might improve wound healing by inducing recruitment of the endogenous cells. Two types of chemokines (interleukin-8; IL-8, macrophage inflammatory protein-3α; MIP-3α) were simply loaded into GH hydrogels during in situ cross-linking, and then their wound-healing effects were evaluated in streptozotocin-induced diabetic mice. The incorporation of chemokines did not affect hydrogels properties including swelling ratio and mechanical stiffness, and the bioactivities of IL-8 and MIP-3α released from hydrogel matrices were stably maintained. In vivo transplantation of chemokine-loaded GH hydrogels facilitated cell infiltration into the wound area, and promoted wound healing with enhanced re-epithelialization/neovascularization and increased collagen deposition, compared with no treatment or the GH hydrogel alone. Based on our results, we suggest that cell-recruiting chemokine-loaded GH hydrogel dressing can serve as a delivery platform of various therapeutic proteins for wound healing applications. Despite development of materials combined with therapeutic agents for diabetic wound treatment, impaired wound healing by insufficient chemotactic responses still remain as a significant problem. In this study, we have developed enzyme-catalyzed gelatin (GH) hydrogels as a sprayable dressing material that can deliver cell-attracting chemokines for diabetic wound healing. The chemotactic cytokines (IL-8 and MIP-3α) were simply loaded within hydrogel during in situ gelling, and wound healing efficacy of chemokine-loaded GH hydrogels was investigated in STZ-induced diabetic mouse model. These hydrogels significantly promoted wound-healing efficacy with faster wound

  3. The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis.

    Science.gov (United States)

    Tutunea-Fatan, Elena; Majumder, Mousumi; Xin, Xiping; Lala, Peeyush K

    2015-02-10

    Tumor-induced lymphangiogenesis facilitates breast cancer progression by generating new lymphatic vessels that serve as conduits for tumor dissemination to lymph nodes and beyond. Given the recent evidence suggesting the implication of C-C chemokine ligand 21/chemokine receptor 7 (CCL21/CCR7) in lymph node metastasis, the aim of our study was to define the role of this chemokine pair in breast cancer-associated lymphangiogenesis. The expression analysis of CCL21/CCR7 pair and lymphatic endothelial cell (LEC) markers in breast cancer specimens was performed by means of quantitative real-time PCR. By utilizing CCR7 and CCL21 gene manipulated breast cancer cell implants into orthotopic sites of nude mice, lymphatic vessel formation was assessed through quantitative real-time PCR, immunohistochemistry and immunofluorescence assays. Finally, the lymphangiogenic potential of CCL21/CCR7 was assessed in vitro with primary LECs through separate functional assays, each attempting to mimic different stages of the lymphangiogenic process. We found that CCR7 mRNA expression in human breast cancer tissues positively correlates with the expression of lymphatic endothelial markers LYVE-1, podoplanin, Prox-1, and vascular endothelial growth factor-C (VEGF-C). We demonstrated that the expression of CCL21/CCR7 by breast cancer cells has the ability to promote tumor-induced lymph-vascular recruitment in vivo. In vitro, CCL21/CCR7 chemokine axis regulates the expression and secretion of lymphangiogenic factor VEGF-C and thereby promotes proliferation, migration, as well as tube formation of the primary human LECs. Finally, we showed that protein kinase B (AKT) signaling pathway is the intracellular mechanism of CCR7-mediated VEGF-C secretion by human breast cancer cells. These results reveal that CCR7 and VEGF-C display a significant crosstalk and suggest a novel role of the CCL21/CCR7 chemokine axis in the promotion of breast cancer-induced lymphangiogenesis.

  4. Chemokines and cytokines in patients with an occult Onchocerca volvulus infection.

    Science.gov (United States)

    Lechner, Christian J; Gantin, Richard G; Seeger, Tanja; Sarnecka, Alicja; Portillo, Jennifer; Schulz-Key, Hartwig; Karabou, Potochoziou K; Helling-Giese, Gertrud; Heuschkel, Christoph; Banla, Meba; Soboslay, Peter T

    2012-05-01

    Repeated ivermectin treatment will clear microfilaria (Mf) of Onchocerca volvulus from skin and eyes of onchocerciasis patients while adult filaria remains alive and reproductive, and such occult O. volvulus infection may persist for years. To investigate the effect of residual adult filaria on the immune response profile, chemokines and cytokines were quantified 1) in onchocerciasis patients who developed an occult O. volvulus infection (Mf-negative) due to repeated ivermectin treatments, 2) patients who became Mf-negative without ivermectin treatments due to missing re-infection, and 3) endemic and non-endemic O. volvulus Mf-negative controls. With occult O. volvulus infection, serum levels of pro-inflammatory chemokines MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, MPIF-1/CCL23 and CXCL8/IL-8 enhanced and approached higher concentrations as determined in infection-free controls, whilst regulatory and Th2-type cytokines and chemokines MCP-4/CCL13, MIP-1δ/CCL15, TARC/CCL17 and IL-13 lessened. Levels of Eotaxin-2/CCL24, MCP-3/CCL7 and BCA-1/CXCL13 remained unchanged. At 3 days post-initial ivermectin treatment, MCP-1/CCL2, MCP-4/CCL13, MPIF-1/CCL23 and Eotaxin-2/CCL24 were strongly enhanced, suggesting that monocytes and eosinophil granulocytes have mediated Mf clearance. In summary, with occult and expiring O. volvulus infections the serum levels of inflammatory chemokines enhanced over time while regulatory and Th2-type-promoting cytokines and chemokines lessened; these changes may reflect a decreasing effector cell activation against Mf of O. volvulus, and in parallel, an enhancing inflammatory immune responsiveness. Copyright © 2011 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  5. Environmental mold and mycotoxin exposures elicit specific cytokine and chemokine responses.

    Science.gov (United States)

    Rosenblum Lichtenstein, Jamie H; Hsu, Yi-Hsiang; Gavin, Igor M; Donaghey, Thomas C; Molina, Ramon M; Thompson, Khristy J; Chi, Chih-Lin; Gillis, Bruce S; Brain, Joseph D

    2015-01-01

    Molds can cause respiratory symptoms and asthma. We sought to use isolated peripheral blood mononuclear cells (PBMCs) to understand changes in cytokine and chemokine levels in response to mold and mycotoxin exposures and to link these levels with respiratory symptoms in humans. We did this by utilizing an ex vivo assay approach to differentiate mold-exposed patients and unexposed controls. While circulating plasma chemokine and cytokine levels from these two groups might be similar, we hypothesized that by challenging their isolated white blood cells with mold or mold extracts, we would see a differential chemokine and cytokine release. Peripheral blood mononuclear cells (PBMCs) were isolated from blood from 33 patients with a history of mold exposures and from 17 controls. Cultured PBMCs were incubated with the most prominent Stachybotrys chartarum mycotoxin, satratoxin G, or with aqueous mold extract, ionomycin, or media, each with or without PMA. Additional PBMCs were exposed to spores of Aspergillus niger, Cladosporium herbarum and Penicillium chrysogenum. After 18 hours, cytokines and chemokines released into the culture medium were measured by multiplex assay. Clinical histories, physical examinations and pulmonary function tests were also conducted. After ex vivo PBMC exposures to molds or mycotoxins, the chemokine and cytokine profiles from patients with a history of mold exposure were significantly different from those of unexposed controls. In contrast, biomarker profiles from cells exposed to media alone showed no difference between the patients and controls. These findings demonstrate that chronic mold exposures induced changes in inflammatory and immune system responses to specific mold and mycotoxin challenges. These responses can differentiate mold-exposed patients from unexposed controls. This strategy may be a powerful approach to document immune system responsiveness to molds and other inflammation-inducing environmental agents.

  6. Broad-Spectrum Inhibition of the CC-Chemokine Class Improves Wound Healing and Wound Angiogenesis.

    Science.gov (United States)

    Ridiandries, Anisyah; Bursill, Christina; Tan, Joanne

    2017-01-13

    Angiogenesis is involved in the inflammation and proliferation stages of wound healing, to bring inflammatory cells to the wound and provide a microvascular network to maintain new tissue formation. An excess of inflammation, however, leads to prolonged wound healing and scar formation, often resulting in unfavourable outcomes such as amputation. CC-chemokines play key roles in the promotion of inflammation and inflammatory-driven angiogenesis. Therefore, inhibition of the CC-chemokine class may improve wound healing. We aimed to determine if the broad-spectrum CC-chemokine inhibitor "35K" could accelerate wound healing in vivo in mice. In a murine wound healing model, 35K protein or phosphate buffered saline (PBS, control) were added topically daily to wounds. Cohorts of mice were assessed in the early stages (four days post-wounding) and in the later stages of wound repair (10 and 21 days post-wounding). Topical application of the 35K protein inhibited CC-chemokine expression (CCL5, CCL2) in wounds and caused enhanced blood flow recovery and wound closure in early-mid stage wounds. In addition, 35K promoted neovascularisation in the early stages of wound repair. Furthermore, 35K treated wounds had significantly lower expression of the p65 subunit of NF-κB, a key inflammatory transcription factor, and augmented wound expression of the pro-angiogenic and pro-repair cytokine TGF-β. These findings show that broad-spectrum CC-chemokine inhibition may be beneficial for the promotion of wound healing.

  7. LEVELS OF ANGIOGENESIS-REGULATORY CHEMOKINES IN THE SYNOVIAL FLUID OF PATIENTS WITH RHEUMATOID ARTHRITIS

    Directory of Open Access Journals (Sweden)

    D. A. Zhebrun

    2015-01-01

    Full Text Available The role of chemokines in the immunopathogenesis of rheumatoid arthritis (RA has been actively investigated in recent years. Angiogenic and angiostatic chemokines are important mediators of angiogenesis in the development and extent of pannus. Peripheral blood and synovial fluid (SF is a major biomaterial in clinical and immunological studies. At the same time, it is the SF test that may yield the most informative results since that gives an idea of the processes that occur locally within a joint. Objective: to perform a comparative analysis of the levels of a number of CXC, CC, and CX3C chemokines in the SF of patients with RA, osteoarthritis (OA, and joint injuries. Subjects and methods. The multiplex analysis using xMAP technology (Luminex, USA was used to analyze levels of CXC, CC, and CX3C chemokines in SF and serum of patients with RA (n = 20, OA (n = 9 and controls (n = 9. Results and discussion. The SF levels of CCL24/eotaxin-2, as well as those of the angiostatic chemokines CXCL9/MIG, CXCL10/IP10, CXCL11/ITAC, and CXCL13/BCA-1 were higher in the RA group than in the control and OA groups. There was a direct correlation between SF levels of CCL5/RANTES and DAS28, as well as patient global disease activity assessment on visual analogue scale, and that between the level of CCL2/MCP-1 in the SF and that of anticyclic citrullinated peptide (anti-CCP antibodies in the serum. The SF concentrations of CXCL5/ENA78 and CXCL7/NAP-2 were shown to depend on the presence of serum anti-CCP. Serum CXCL13/BCA-1 levels were higher in RA than those in OA, as that of CXCL7/NAP-2 than in the control group.

  8. CCR9 antagonism: potential in the treatment of Inflammatory Bowel Disease

    Directory of Open Access Journals (Sweden)

    Wendt E

    2015-04-01

    Full Text Available Emily Wendt, Satish Keshav Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK Abstract: Inflammatory Bowel Disease (IBD, mainly comprising Crohn's disease (CD and ulcerative colitis (UC, is a chronic condition that primarily affects the intestine and is characterized by leukocytic infiltration. Blocking the migration of leukocytes from the circulation is therefore a reasonable therapeutic goal. Recent clinical trials using this approach have shown promise, with the monoclonal antibody to α4β7 integrin, vedolizumab, and previously with the monoclonal antibody to the α4 subunit, natalizumab. Directly targeting the subset of α4β7 expressing cells that co-express CC chemokine receptor 9 (CCR9, using the orally administered antagonist, CCX282-B, also known as vercirnon, has also been evaluated in Phase II and III trials that have produced mixed results. Although CCX282-B showed efficacy in inducing response in active CD in early studies, this was not confirmed in a Phase III study. CCX282-B was also more effective than placebo in maintaining remission, and this result has yet to be confirmed in Phase III. The efficacy of blocking CCR9 in UC, where vedolizumab was effective, has not been tested. The prospect of targeting CCR9 in IBD remains attractive. Much of the local accumulation of inflammatory cells in the intestine arises from migration rather than local proliferation and genetic and pharmacological targeting of CCR9 or its ligand in preclinical models that mimic UC and CD ameliorate inflammation in some cases. Furthermore, binding of chemokine ligands to receptor is a critical step in activating integrin binding, so there is a potential for synergistic action between integrin and chemokine antagonists. CCR9 is expressed on a smaller proportion of circulating cells than α4β7 integrin, which may offer greater specificity of effect, particularly in long term use. Furthermore, while α4

  9. Chemokine polyreactivity of IL7Rα+CSF-1R+ lympho-myeloid progenitors in the developing fetal liver.

    Science.gov (United States)

    Kajikhina, Katja; Melchers, Fritz; Tsuneto, Motokazu

    2015-08-03

    In murine ontogeny, fetal liver is the major hemato- and B-lymphopoietic site until birth. Hematopoiesis develops in largely non-hematopoietic niches, which provide contacts, chemokines and cytokines that induce migration, residence, proliferation and differentiation of progenitors. Within early multipotent progenitors an IL7Rα(+)CSF-1R(+) subset expressed a mixture of lymphoid- and myeloid-specific genes and differentiated to lymphoid and myeloid lineages in vitro. By contrast, IL7Rα(+) cells were lymphoid-committed, and CSF-1R(+) cells were erythro-myeloid-restricted. To respond to a multitude of chemokines single biphenotypic cells expressed CXCR4 and as many as five other chemokine receptors. The monopotent IL7Rα(+) and CSF-1R(+)progenitors all expressed CXCR4, and mutually exclusive, more restricted sets of the analysed five chemokine receptors. This study proposes that chemokine polyreactive, cytokine-bipotent and monopotent progenitors transmigrate through LYVE-1(high) endothelium, attracted by selected chemokines, and reach the IL7- and CSF-1-producing ALCAM(high) mesenchymal niche, attracted by other sets of chemokines, to differentiate to B-lymphoid respectively myeloid cells.

  10. Antagonism of the 5-HT6 receptor - Preclinical rationale for the treatment of Alzheimer's disease.

    Science.gov (United States)

    de Jong, Inge E M; Mørk, Arne

    2017-10-01

    Antagonism of the 5-HT6 receptor is a promising approach for the symptomatic treatment of Alzheimer's disease (AD). There is compelling preclinical evidence for the procognitive potential of 5-HT6 receptor antagonists and several compounds are in clinical development, as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). This manuscript summarizes the scientific rationale for the use of 5-HT6 receptor antagonists as AD treatment, with some focus on the selective and high-affinity 5-HT6 receptor antagonist idalopirdine (Lu AE58054). The 5-HT6 receptor is enriched in brain regions that mediate cognition, where expression predominates on glutamatergic and GABAergic neurons and subsets of GABAergic interneurons. It is proposed that 5-HT6 receptor antagonism modulates the balance between neuronal excitation (glutamate) and inhibition (GABA), which may have widespread implications for neurotransmission and neuronal activity. This is supported by preclinical studies showing that 5-HT6 receptor antagonists increase concentrations of multiple neurotransmitters, and strengthened by recent evidence that idalopirdine facilitates neuronal oscillations and contributes to the recruitment of several neuronal networks relevant in cognition. Some of these effects are observed with idalopirdine monotherapy, whereas others require concomitant treatment with an AChEI. Several hypotheses for the mechanism underlying the synergistic actions between 5-HT6 receptor antagonists and AChEIs are discussed. Collectively, the current evidence suggests that 5-HT6 receptor antagonism adds a unique, complementary mechanism of action to that of AChEIs. The facilitation of multiple neurotransmitters and neuronal activity in brain regions that mediate cognition, and the synergy with AChEIs, are proposed to mediate the procognitive effects of 5-HT6 receptor antagonists in AD patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Azithromycin May Antagonize Inhaled Tobramycin When Targeting Pseudomonas aeruginosa in Cystic Fibrosis

    Science.gov (United States)

    Nick, Jerry A.; Moskowitz, Samuel M.; Chmiel, James F.; Forssén, Anna V.; Kim, Sun Ho; Saavedra, Milene T.; Saiman, Lisa; Taylor-Cousar, Jennifer L.

    2014-01-01

    Rationale: Recent studies of inhaled tobramycin in subjects with cystic fibrosis (CF) find less clinical improvement than previously observed. Nonhuman data suggest that in some strains of Pseudomonas aeruginosa, azithromycin can antagonize tobramycin. Objectives: We tested the hypothesis that concomitant azithromycin use correlates with less improvement in key outcome measures in subjects receiving inhaled tobramycin while not affecting those receiving a comparative, nonaminoglycoside inhaled antibiotic. Methods: We studied a cohort of 263 subjects with CF enrolled in a recent clinical trial comparing inhaled tobramycin with aztreonam lysine. We performed a secondary analysis to examine key clinical and microbiologic outcomes based on concomitant, chronic azithromycin use at enrollment. Measurements and Main Results: The cohort randomized to inhaled tobramycin and reporting azithromycin use showed a significant decrease in the percent predicted FEV1 after one and three courses of inhaled tobramycin when compared with those not reporting azithromycin use (28 d: −0.51 vs. 3.43%, P azithromycin and inhaled tobramycin use was also associated with earlier need for additional antibiotics, lesser improvement in disease-related quality of life, and a trend toward less reduction in sputum P. aeruginosa density. Subjects randomized to inhaled aztreonam lysine had significantly greater improvement in these outcome measures, which were unaffected by concomitant azithromycin use. Outcomes in those not using azithromycin who received inhaled tobramycin were not significantly different from subjects receiving aztreonam lysine. Azithromycin also antagonized tobramycin but not aztreonam lysine in 40% of P. aeruginosa clinical isolates tested in vitro. Conclusions: Oral azithromycin may antagonize the therapeutic benefits of inhaled tobramycin in subjects with CF with P. aeruginosa airway infection. PMID:24476418

  12. Alcohol-Induced Impairment of Balance is Antagonized by Energy Drinks.

    Science.gov (United States)

    Marczinski, Cecile A; Fillmore, Mark T; Stamates, Amy L; Maloney, Sarah F

    2018-01-01

    The acute administration of alcohol reliably impairs balance and motor coordination. While it is common for consumers to ingest alcohol with other stimulant drugs (e.g., caffeine, nicotine), little is known whether prototypical alcohol-induced balance impairments are altered by stimulant drugs. The purpose of this study was to examine whether the coadministration of a high-caffeine energy drink with alcohol can antagonize expected alcohol-induced increases in body sway. Sixteen social drinkers (of equal gender) participated in 4 separate double-blind dose administration sessions that involved consumption of alcohol and energy drinks, alone and in combination. Following dose administration, participants completed automated assessments of balance stability (both eyes open and eyes closed) measured using the Biosway Portable Balance System. Participants completed several subjective measures including self-reported ratings of sedation, stimulation, fatigue, and impairment. Blood pressure and pulse rate were recorded repeatedly. The acute administration of alcohol increased body sway, and the coadministration of energy drinks antagonized this impairment. When participants closed their eyes, alcohol-induced body sway was similar whether or not energy drinks were ingested. While alcohol administration increased ratings of sedation and fatigue, energy drink administration increased ratings of stimulation and reduced ratings of fatigue. Modest increases in systolic and diastolic blood pressure following energy drink administration were also observed. Visual assessment of balance impairment is frequently used to indicate that an individual has consumed too much alcohol (e.g., as part of police-standardized field sobriety testing or by a bartender assessing when someone should no longer be served more alcohol). The current findings suggest that energy drinks can antagonize alcohol-induced increases in body sway, indicating that future work is needed to determine whether this

  13. Naltrexone antagonizes the analgesic and immunosuppressive effects of morphine in mice.

    Science.gov (United States)

    Carr, D J; Gerak, L R; France, C P

    1994-05-01

    A study was undertaken to investigate the relationship between morphine-induced analgesia and immunosuppression after acute administration. In male CD1 mice, morphine (10.0-100.0 mg/kg s.c.) produced a U-shaped immunosuppressive dose-effect curve on splenic natural killer (NK) activity. Morphine also induced dose-related analgesia, as measured by an increase in tail-flick latency during thermal application; these analgesic effects were antagonized by naltrexone (1.0-10.0 mg/kg). In addition, morphine-induced suppression of splenic NK activity was antagonized in a dose-dependent manner and, at one dose of naltrexone (10.0 mg/kg), splenic NK activity was augmented. To investigate further the relationship between naltrexone antagonism of morphine-induced analgesia and immunomodulation, single doses of morphine (10.0-100.0 mg/kg) were administered to mice pretreated with naltrexone (0.01-10.0 mg/kg) or saline. A dose of 10.0 mg/kg of morphine produced 35% of the maximal possible effect in the analgesia study and no immunosuppression, whereas a dose of 32.0 mg/kg produced a maximal analgesic effect and significant suppression of NK activity. Naltrexone blocked morphine-induced analgesia and immunosuppression in a dose-dependent fashion. Moreover, the combination of 1.0 mg/kg of naltrexone and 32.0 mg/kg of morphine elevated splenic NK activity. A large dose of morphine (100.0 mg/kg) elicited full analgesia and had no effect on splenic NK activity in saline- or naltrexone-pretreated mice. Collectively, these results support the view that, in mice, morphine-induced analgesia and immunosuppression are mediated through a common opioid receptor type.

  14. What rules of thumb do clinicians use to decide whether to antagonize nondepolarizing neuromuscular blocking drugs?

    Science.gov (United States)

    Videira, Rogerio L R; Vieira, Joaquim E

    2011-11-01

    In anesthesia practice, inadequate antagonism of neuromuscular blocking drugs (NMBD) may lead to frequent prevalence of residual neuromuscular block that is associated with morbidity and death. In this study we analyzed the clinical decision on antagonizing NMBD to generate hypotheses about barriers to the introduction of experts' recommendations into clinical practice. Sequential surveys were conducted among 108 clinical anesthesiologists to elicit the rules of thumb (heuristics) that support their decisions and provide a measurement of the confidence the clinicians have in their own decisions in comparison with their peers' decisions. The 2 most frequently used heuristics for administering reversal were "the interval since the last NMBD dose was short" and "the breathing pattern is inadequate," chosen by 73% and 71% of the clinicians, respectively. Clinicians considered that the prevalence of clinically significant residual block is higher in their colleagues' practices than in their own practice (60% vs 16%, odds ratio=7.8, 95% confidence interval, 3.8 to 16.2, P=0.0001). The clinicians were less likely to use antagonists if >60 minutes had elapsed after a single dose of atracurium (0.5 mg/kg) (31%) in comparison with after rocuronium 0.6 mg/kg (53%) (P=0.0035). In our institution, the clinical decision to antagonize NMBD is mainly based on the pharmacological forecast and a qualitative judgment of the adequacy of the breathing pattern. Clinicians judge themselves as better skilled at avoiding residual block than they do their colleagues, making them overconfident in their capacity to estimate the duration of action of intermediate-acting NMBD. Awareness of these systematic errors related to clinical intuition may facilitate the adoption of experts' recommendations into clinical practice.

  15. Antagonism of Bacillus subtilis strain AG1 against vine wood fungal pathogens

    Directory of Open Access Journals (Sweden)

    A. Alfonzo

    2009-05-01

    Full Text Available Antagonistic substances produced by a Bacillus subtilis strain (AG1, which were previously found to slow down the growth of esca fungi in vitro, were produced in an artificial medium, isolated from the cell-free medium by precipitation and acidification (to less than pH 2.5 and extracted from the precipitate with 96% ethanol. The crude extract employed in antibiotic assays confirmed, in vitro, the antagonism of B. subtilis against Phaeoacremonium aleophilum and Phaeomoniella chlamydospora, and also showed an antifungal activity toward Verticillium dahliae and Botryosphaeria rhodina.

  16. Chronic mucocutaneous candidiasis: what can we conclude about IL-17 antagonism?

    Science.gov (United States)

    Veverka, Kevin K; Feldman, Steven R

    2017-11-21

    IL-17 antagonists are effective for psoriasis in clinical trials, but long-term safety is not fully characterized. Since chronic mucocutaneous candidiasis (CMC) is caused by defects in the IL-17 pathway, CMC risk data have been touted as providing reassurance about the safety of IL-17 antagonism. We performed a literature review to identify patients with CMC and compared the prevalence of cancer in these patients to the reported 5-year prevalence. There was a higher prevalence of oropharyngeal (2.5% vs. 0.028%; p esophageal cancer (1.9% vs. 0.013%; p candidiasis in patients taking these medications.

  17. An effector of the Irish potato famine pathogen antagonizes a host autophagy cargo receptor

    Science.gov (United States)

    Dagdas, Yasin F; Belhaj, Khaoula; Maqbool, Abbas; Chaparro-Garcia, Angela; Pandey, Pooja; Petre, Benjamin; Tabassum, Nadra; Cruz-Mireles, Neftaly; Hughes, Richard K; Sklenar, Jan; Win, Joe; Menke, Frank; Findlay, Kim; Banfield, Mark J; Kamoun, Sophien; Bozkurt, Tolga O

    2016-01-01

    Plants use autophagy to safeguard against infectious diseases. However, how plant pathogens interfere with autophagy-related processes is unknown. Here, we show that PexRD54, an effector from the Irish potato famine pathogen Phytophthora infestans, binds host autophagy protein ATG8CL to stimulate autophagosome formation. PexRD54 depletes the autophagy cargo receptor Joka2 out of ATG8CL complexes and interferes with Joka2's positive effect on pathogen defense. Thus, a plant pathogen effector has evolved to antagonize a host autophagy cargo receptor to counteract host defenses. DOI: http://dx.doi.org/10.7554/eLife.10856.001 PMID:26765567

  18. Bacterial Seed Endophytes of Domesticated Cucurbits Antagonize Fungal and Oomycete Pathogens Including Powdery Mildew

    Directory of Open Access Journals (Sweden)

    Eman M. Khalaf

    2018-02-01

    Full Text Available The cucurbit vegetables, including cucumbers, melons and pumpkins, have been cultivated for thousands of years without fungicides. However, their seed germination stage is prone to be infected by soil-borne fungal and oomycete pathogens. Endophytes are symbionts that reside inside plant tissues including seeds. Seed endophytes are founders of the juvenile plant microbiome and can promote host defense at seed germination and later stages. We previously isolated 169 bacterial endophytes associated with seeds of diverse cultivated cucurbits. We hypothesized that these endophytes can antagonize major fungal and oomycete pathogens. Here we tested the endophytes for in vitro antagonism (dual culture assays against important soil-borne pathogens (Rhizoctonia solani, Fusarium graminearum, Phytophthora capsici, Pythium aphanideratum. The endophytes were also assayed in planta (leaf disk and detached leaf bioassays for antagonism against a foliar pathogen of global importance, Podosphaera fuliginea, the causative agent of cucurbit powdery mildew. The endophytes were further tested in vitro for secretion of volatile organic compounds (VOCs known to induce plant defense. Extracellular ribonuclease activity was also tested, as a subset of pathogenesis-related (PR proteins of plant hosts implicated in suppression of fungal pathogens, displays ribonuclease activity. An unexpected majority of the endophytes (70%, 118/169 exhibited antagonism to the five phytopathogens, of which 68% (50/73 of in vitro antagonists belong to the genera Bacillus and Paenibacillus. All Lactococcus and Pantoea endophytes exhibited anti-oomycete activity. However, amongst the most effective inoculants against Podosphaera fuliginea were Pediococcus and Pantoea endophytes. Interestingly, 67% (113/169 of endophytes emitted host defense inducing VOCs (acetoin/diacetyl and 62% (104/169 secreted extracellular ribonucleases in vitro, respectively. These results show that seeds of cultivated

  19. Disruption of Cell-to-Cell Signaling Does Not Abolish the Antagonism of Phaeobacter gallaeciensis toward the Fish Pathogen Vibrio anguillarum in Algal Systems

    DEFF Research Database (Denmark)

    Prol García, María Jesús; D'Alvise, Paul; Gram, Lone

    2013-01-01

    Quorum sensing (QS) regulates Phaeobacter gallaeciensis antagonism in broth systems; however, we demonstrate here that QS is not important for antagonism in algal cultures. QS mutants reduced Vibrio anguillarum to the same extent as the wild type. Consequently, a combination of probiotic Phaeobac......Quorum sensing (QS) regulates Phaeobacter gallaeciensis antagonism in broth systems; however, we demonstrate here that QS is not important for antagonism in algal cultures. QS mutants reduced Vibrio anguillarum to the same extent as the wild type. Consequently, a combination of probiotic...

  20. Chemokines (RANTES and MCP-1) and chemokine-receptors (CCR2 and CCR5) gene polymorphisms in Alzheimer's and Parkinson's disease.

    Science.gov (United States)

    Huerta, Cecilia; Alvarez, Victoria; Mata, Ignacio F; Coto, Eliecer; Ribacoba, René; Martínez, Carmen; Blázquez, Marta; Guisasola, Luis M; Salvador, Carlos; Lahoz, Carlos H; Peña, Joaquín

    2004-11-11

    Parkinson's disease (PD) is a complex disorder characterized by the progressive degeneration of dopaminergic neurons in the midbrain. Late-onset Alzheimer's disease (LOAD) is the most common cause of dementia in the elderly, affecting about 5% of the population older than 65 years. Several works have demonstrated the involvement of inflammation in the pathogenesis of both, PD and LOAD. Genetic susceptibility to develop PD and LOAD has also been widely recognised. Thus, functional polymorphisms at the genes encoding inflammatory proteins could influence the overall risk of developing these neurodegenerative disorders. We examined whether DNA-polymorphisms at the genes encoding chemokines MCP-1 (-2518 A/G) and RANTES (-403 A/G), and chemokine receptors 5 (CCR5, Delta32) and 2 (CCR2,V64I), were associated with the risk and/or the clinical outcome of LOAD and PD. A total of 200 PD, 326 LOAD, and 370 healthy controls were genotyped for the four polymorphisms, and genotype frequencies statistically compared. We did not find significant differences in the frequencies of the different genotypes between both groups of patients and controls. We conclude that the four DNA polymorphisms, which have been associated with several immuno-modulated diseases, did not contribute to the risk of PD or LOAD.

  1. Growth factors and chemokines: a comparative functional approach between invertebrates and vertebrates.

    Science.gov (United States)

    Tettamanti, G; Malagoli, D; Benelli, R; Albini, A; Grimaldi, A; Perletti, G; Noonan, D M; de Eguileor, M; Ottaviani, E

    2006-01-01

    Growth factors and cytokines control and coordinate a broad spectrum of fundamental cellular functions, and are evolutionarily conserved both in vertebrates and invertebrates. In this review, we focus our attention on the functional phylogenetic aspects of growth factors/cytokines like the Transforming Growth Factor-beta (TGF-beta), the Connective Tissue Growth Factor (CTGF), and the Vascular Endothelial Growth Factor (VEGF). We will also delve into the activites of two chemokine families, interleukin (IL)-8 (or CXCL8) and CC chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2). These molecules have been selected for their involvement in immune responses and wound healing processes, where they mediate and finely regulate various regeneration processes like angiogenesis or fibroplasia, not only in vertebrates, but also in invertebrates.

  2. Evasins: therapeutic potential of a new family of chemokine binding proteins from ticks

    Directory of Open Access Journals (Sweden)

    Amanda E.I. Proudfoot

    2016-06-01

    Full Text Available Blood sucking parasites such as ticks remain attached to their hosts for relatively long periods of time in order to obtain their blood meal without eliciting an immune response. One mechanism used to avoid rejection is the inhibition of the recruitment of immune cells, which can be achieved by a class of chemokine binding proteins (CKBPs known as Evasins. We have identified three distinct Evasins produced by the salivary glands of the common brown dog tick, Rhipicephalus sanguineus. They display different selectivities for chemokines, the first two identified show a narrow selectivity profile, whilst the third has a broader binding spectrum. The Evasins showed efficacy in several animal models of inflammatory disease. Here we will discuss the potential of their development for therapeutic use, addressing both the advantages and disadvantages that this entails.

  3. Immunopathological Roles of Cytokines, Chemokines, Signaling Molecules, and Pattern-Recognition Receptors in Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Shui-Lian Yu

    2012-01-01

    Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disease with unknown etiology affecting more than one million individuals each year. It is characterized by B- and T-cell hyperactivity and by defects in the clearance of apoptotic cells and immune complexes. Understanding the complex process involved and the interaction between various cytokines, chemokines, signaling molecules, and pattern-recognition receptors (PRRs in the immune pathways will provide valuable information on the development of novel therapeutic targets for treating SLE. In this paper, we review the immunopathological roles of novel cytokines, chemokines, signaling molecules, PRRs, and their interactions in immunoregulatory networks and suggest how their disturbances may implicate pathological conditions in SLE.

  4. Roles of the chemokine system in development of obesity, insulin resistance, and cardiovascular disease.

    Science.gov (United States)

    Yao, Longbiao; Herlea-Pana, Oana; Heuser-Baker, Janet; Chen, Yitong; Barlic-Dicen, Jana

    2014-01-01

    The escalating epidemic of obesity has increased the incidence of obesity-induced complications to historically high levels. Adipose tissue is a dynamic energy depot, which stores energy and mobilizes it during nutrient deficiency. Excess nutrient intake resulting in adipose tissue expansion triggers lipid release and aberrant adipokine, cytokine and chemokine production, and signaling that ultimately lead to adipose tissue inflammation, a hallmark of obesity. This low-grade chronic inflammation is thought to link obesity to insulin resistance and the associated comorbidities of metabolic syndrome such as dyslipidemia and hypertension, which increase risk of type 2 diabetes and cardiovascular disease. In this review, we focus on and discuss members of the chemokine system for which there is clear evidence of participation in the development of obesity and obesity-induced pathologies.

  5. Intravenous infusion of erythromycin inhibits CXC chemokine production, but augments neutrophil degranulation in whole blood stimulated with Streptococcus pneumoniae

    NARCIS (Netherlands)

    Schultz, M. J.; Speelman, P.; Hack, C. E.; Buurman, W. A.; van Deventer, S. J.; van der Poll, T.

    2000-01-01

    Macrolides may influence the inflammatory response to an infection by mechanisms that are unrelated to their antimicrobial effect. Indeed, erythromycin and other macrolides inhibit cytokine production and induce degranulation of neutrophils in vitro. CXC chemokines are small chemotactic cytokines

  6. Synergistic enhancement of chemokine generation and lung injury by C5a or the membrane attack complex of complement

    DEFF Research Database (Denmark)

    Czermak, B J; Lentsch, A B; Bless, N M

    1999-01-01

    Complement plays an important role in many acute inflammatory responses. In the current studies it was demonstrated that, in the presence of either C5a or sublytic forms of the complement-derived membrane attack complex (MAC), rat alveolar macrophages costimulated with IgG immune complexes...... demonstrated synergistic production of C-X-C (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant) and C-C (macrophage inflammatory protein-1alpha and monocyte chemoattractant-1) chemokines. In the absence of the costimulus, C5a or MAC did not induce chemokine generation....... In in vivo studies, C5a and MAC alone caused limited or no intrapulmonary generation of chemokines, but in the presence of a costimulus (IgG immune complexes) C5a and MAC caused synergistic intrapulmonary generation of C-X-C and C-C chemokines but not of tumor necrosis factor alpha. Under these conditions...

  7. Codeine induces human mast cell chemokine and cytokine production: involvement of G-protein activation

    Science.gov (United States)

    Sheen, C. H.; Schleimer, R. P.; Kulka, M.

    2007-01-01

    Background Activation of mast cells and the systemic release of histamine are common side effects of opiates such as codeine and morphine. In some individuals, codeine not only elicits a sizable early response due to mast cell degranulation, but can also lead to late cutaneous allergic inflammation possibly through the production of chemokines. However, individuals who exhibit a late phase reaction to codeine often do not react to its synthetic analog, meperidine. The goal of this study was to test whether codeine and meperidine induce secretion of inflammatory mediators in human mast cells. Methods To characterize opiate activation of human mast cells, we stimulated cultured human (LAD2 cell line and CD34+-derived) mast cells with codeine and meperidine and measured degranulation and chemokine production. Results Codeine, but not meperidine, activated human mast cell degranulation within 30 min in a dose-dependent manner. Degranulation was blocked by the phosphoinositol-3 kinase (PI3K) inhibitor, wortmannin, and pertussis toxin but not by Ro-31-8220, a PKC inhibitor or forskolin, a cyclic adenylyl cyclase activator. After 3 and 8 h of stimulation, codeine, but not meperidine, activated human mast cells to release monocyte chemoattractant protein-1 (CCL2), regulated on activation, normal T expressed and secreted (RANTES, CCL5) and interleukin-8 (CXCL 8) but not inducible protein-10 (CXCL10). Conclusions Codeine activates human mast cell degranulation and chemokine production by activating protein kinase A and PI3 kinase, possibly leading to NF-κB activation. Therefore, opiates may regulate late phase allergic inflammation by activating chemokine production by human mast cells. PMID:17441793

  8. Oligonucleotide fishing for STAT6: cross-talk between IL-4 and chemokines

    DEFF Research Database (Denmark)

    Eriksen, K W; Nielsen, M; Kaltoft, K

    2001-01-01

    -stranded oligonucleotide probes containing a STAT6-binding gene-sequence from the promotor of the immunoglobulin heavy chain germline epsilon transcript to study the IL-4-induced DNA binding of STAT6. Using these probes, we show that repeated adjacent STAT6-binding sites result in enhanced STAT6-DNA binding. Moreover...... activation, whereas other chemokines and cytokines do not. In conclusion, our data show that oligonucleotide fishing is a supplementary tool for studying cytokine cross-talk at a genomic level....

  9. C-C chemokine receptor-7 mediated endocytosis of antibody cargoes into intact cells

    OpenAIRE

    Charest-Morin, Xavier; P?pin, R?my; Gagn?-Henley, Ang?lique; Morissette, Guillaume; Lodge, Robert; Marceau, Fran?ois

    2013-01-01

    The C–C chemokine receptor-7 (CCR7) is a G protein coupled receptor that has a role in leukocyte homing, but that is also expressed in aggressive tumor cells. Preclinical research supports that CCR7 is a valid target in oncology. In view of the increasing availability of therapeutic monoclonal antibodies that carry cytotoxic cargoes, we studied the feasibility of forcing intact cells to internalize known monoclonal antibodies by exploiting the cycle of endocytosis and recycling triggered by t...

  10. Melanoma brain metastasis globally reconfigures chemokine and cytokine profiles in patient cerebrospinal fluid.

    Science.gov (United States)

    Lok, Edwin; Chung, Amy S; Swanson, Kenneth D; Wong, Eric T

    2014-04-01

    The aggressiveness of melanoma is believed to be correlated with tumor-stroma-associated immune cells. Cytokines and chemokines act to recruit and then modulate the activities of these cells, ultimately affecting disease progression. Because melanoma frequently metastasizes to the brain, we asked whether global differences in immunokine profiles could be detected in the cerebrospinal fluid (CSF) of melanoma patients and reveal aspects of tumor biology that correlate with patient outcomes. We therefore measured the levels of 12 cytokines and 12 chemokines in melanoma patient CSF and the resulting data were analyzed to develop unsupervised hierarchical clustergrams and heat maps. Unexpectedly, the overall profiles of immunokines found in these samples showed a generalized reconfiguration of their expression in melanoma patient CSF, resulting in the segregation of individuals with melanoma brain metastasis from nondisease controls. Chemokine CCL22 and cytokines IL1α, IL4, and IL5 were reduced in most samples, whereas a subset including CXCL10, CCL4, CCL17, and IL8 showed increased expression. Further, analysis of clusters identified within the melanoma patient set comparing patient outcome suggests that suppression of IL1α, IL4, IL5, and CCL22, with concomitant elevation of CXCL10, CCL4, and CCL17, may correlate with more aggressive development of brain metastasis. These results suggest that global immunokine suppression in the host, together with a selective increase in specific chemokines, constitute a predominant immunomodulatory feature of melanoma brain metastasis. These alterations likely drive the course of this disease in the brain and variations in the immune profiles of individual patients may predict outcomes.

  11. Chemokines and inflammation in osteoarthritis: Insights from patients and animal models.

    Science.gov (United States)

    Scanzello, Carla R

    2017-04-01

    Evidence has been building that the pathologic drive for development of osteoarthritis (OA) involves more than simple mechanical "wear and tear." Inflammatory mechanisms play an important role in the tissue response to joint injury, and are involved in development of post-traumatic OA. Inflammation also appears integral to the progression of OA, whether post-traumatic or spontaneous, contributing to the evolution of joint tissue degradation and remodeling as well as joint pain. Both patient-based studies and in vivo models of disease have shed light on a number of inflammatory pathways and mediators that impact various aspects of this disease, both structurally and symptomatically. Recent work in this field has implicated inflammatory chemokines in osteoarthritis pathogenesis. Expression of multiple chemokines and their receptors is modulated during disease in both patients and animal models. Although best known for their effects on leukocyte migration and trafficking within the immune system, chemokines can have a wide variety of effects on both motile and non-motile cell types, impacting proliferation, differentiation, and activation of cellular responses. Their role in OA models has also demonstrated diverse effects on disease that exemplify their wide-ranging effects. Understanding how these important mediators of inflammation impact joint disease, and whether they can be targeted therapeutically, is actively being investigated by many groups in this field. This narrative review focuses on evidence published within the last 5 years highlighting chemokine-mediated pathways with mechanistic involvement in osteoarthritis and joint tissue repair. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:735-739, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  12. Type-I interferons suppress microglial production of the lymphoid chemokine, CXCL13.

    Science.gov (United States)

    Esen, Nilufer; Rainey-Barger, Emily K; Huber, Amanda K; Blakely, Pennelope K; Irani, David N

    2014-09-01

    Lymphoid chemokines are crucial for the development and maintenance of lymphoid organs, but their ectopic expression in non-lymphoid tissues is implicated in both local response to infection and chronic organ-specific autoimmunity. Production of one such chemokine, C-X-C motif ligand 13 (CXCL13), within the central nervous system (CNS) has been linked to the pathogenesis of multiple sclerosis (MS), although little is known about factors controlling its expression in different neural cell types and across a range of disease states. We provoked acute neuroinflammation in experimental animals without causing any associated demyelination using neuroadapted Sindbis virus (NSV) to better understand the sources and regulators of this chemokine in the CNS. We found that mice genetically deficient in the transcription factor, interferon (IFN) regulatory factor-7 (IRF7), made significantly higher CXCL13 protein levels in the CNS compared with wild-type (WT) controls. Microglia proved to be the main producer of CXCL13 in the brain during infection of both WT and IRF7(-/-) mice, and primary microglia cultured in vitro generated CXCL13 following stimulation with either virus particles or synthetic Toll-like receptor (TLR) ligands. Microglia cultured from IRF7(-/-) mice selectively overproduced CXCL13, and manipulation of extracellular type-I IFN levels demonstrated the existence of a negative feedback loop whereby type-I IFN receptor signaling specifically suppressed microglial CXCL13 release. Since IFN-β is used to treat patients with relapsing-remitting MS and yet acts through unknown mechanisms, we speculate that suppressed lymphoid chemokine production by microglia could contribute to its therapeutic effects. © 2014 The Authors. Glia Published by Wiley Periodicals, Inc.

  13. A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues

    OpenAIRE

    Hidalgo-Grass, Carlos; Mishalian, Inbal; Dan-Goor, Mary; Belotserkovsky, Ilia; Eran, Yoni; Nizet, Victor; Peled, Amnon; Hanski, Emanuel

    2006-01-01

    Group A Streptococcus (GAS) causes the life-threatening infection in humans known as necrotizing fasciitis (NF). Infected subcutaneous tissues from an NF patient and mice challenged with the same GAS strain possessed high bacterial loads but a striking paucity of infiltrating polymorphonuclear leukocytes (PMNs). Impaired PMN recruitment was attributed to degradation of the chemokine IL-8 by a GAS serine peptidase. Here, we use bioinformatics approach coupled with target mutagenesis to identif...

  14. Circulating chemokines accurately identify individuals with clinically significant atherosclerotic heart disease.

    Science.gov (United States)

    Ardigo, Diego; Assimes, Themistocles L; Fortmann, Stephen P; Go, Alan S; Hlatky, Mark; Hytopoulos, Evangelos; Iribarren, Carlos; Tsao, Philip S; Tabibiazar, Raymond; Quertermous, Thomas

    2007-11-14

    Serum inflammatory markers correlate with outcome and response to therapy in subjects with cardiovascular disease. However, current individual markers lack specificity for the diagnosis of coronary artery disease (CAD). We hypothesize that a multimarker proteomic approach measuring serum levels of vascular derived inflammatory biomarkers could reveal a "signature of disease" that can serve as a highly accurate method to assess for the presence of coronary atherosclerosis. We simultaneously measured serum levels of seven chemokines [CXCL10 (IP-10), CCL11 (eotaxin), CCL3 (MIP1 alpha), CCL2 (MCP1), CCL8 (MCP2), CCL7 (MCP3), and CCL13 (MCP4)] in 48 subjects with clinically significant CAD ("cases") and 44 controls from the ADVANCE Study. We applied three classification algorithms to identify the combination of variables that would best predict case-control status and assessed the diagnostic performance of these models with receiver operating characteristic (ROC) curves. The serum levels of six chemokines were significantly higher in cases compared with controls (P algorithms entered three chemokines in their final model, and only logistic regression selected clinical variables. Logistic regression produced the highest ROC of the three algorithms (AUC = 0.95; SE = 0.03), which was markedly better than the AUC for the logistic regression model of traditional risk factors of CAD without (AUC = 0.67; SE = 0.06) or with CRP (AUC = 0.68; SE = 0.06). A combination of serum levels of multiple chemokines identifies subjects with clinically significant atherosclerotic heart disease with a very high degree of accuracy. These results need to be replicated in larger cross-sectional studies and their prognostic value explored.

  15. CONTENTS OF CHEMOKINES AND CYTOKINES IN PERITONEAL FLUID FROM THE PATIENTS WITH ENDOMETRIOSIS OF VARIOUS SEVERITY

    Directory of Open Access Journals (Sweden)

    D. I. Sokolov

    2007-01-01

    Full Text Available Abstract. Endometriosis is a disease accompanied by development of heterotopic endometrial foci at the peritoneum, proliferation of endothelial cells, and inflammatory reaction. Aiming to specify the dynamics of inflammatory process in endometriosis of different severity, as well as significance of chemokines and cytokines in angiogenesis and inflammation, we determined concentrations of RANTES, IL-8, IP-10, MIG, MCP-1 chemokines, as well as IL-4, IL-6 and IL-10 cytokines in peritoneal fluid from patients by endometriosis. Forty women at reproductive age with an endometriosis have been observed. Among them, endometriosis grade I-II was registered in 20 cases, whereas grade III-IV has been confirmed in 20 women. Twenty-two women without evidence of endometriosis referred to diagnostic laparoscopy for pregnancy planning, comprised a control group. Diagnosis of endometriosis was based upon endoscopic findings and results of histological research. Severity grade of endometriosis was estimated according to R-AFS classification. Sampling of peritoneal fluid was carried out when performing surgical laparoscopies. Concentrations of chemokines and cytokines were determined by flow cytometry techniques, using BD Cytometric Bead Array test kits and FACStrack flow cytometer. The amounts of RANTES in peritoneal fluid were higher in grade I-II endometriosis, in comparison with grade III-IV endometriosis and control samples. Concentrations of IP-10, IL-8, МСР-1, MIG, IL-6, and IL-4 were higher than in control group and correlated with severity of the disease. IL-10 was not detectable in peritoneal fluid of the patients with endometriosis. These results suggest a significant role of the mentioned cytokines and chemokines that may promote invasion of endometrial cells, growth of heterotopic endometrioid locuses, development of vascular bed and induction of inflammatory processes, in development and progression of endometriosis.

  16. Chemokine regulation in response to beryllium exposure in human peripheral blood mononuclear and dendritic cells.

    Science.gov (United States)

    Hong-Geller, Elizabeth; Pardington, Paige E; Cary, Robert B; Sauer, Nancy N; Gupta, Goutam

    2006-02-01

    Exposure to beryllium (Be) induces a delayed-type hypersensitivity immune reaction in the lungs of susceptible individuals, which leads to the onset of Be sensitivity and Chronic Beryllium Disease (CBD). Although some mechanistic aspects of CBD have begun to be characterized, very little is known about the molecular mechanisms by which Be activates the host immune response. To gain insight into the cellular response to Be exposure, we have performed global microarray analysis using a mixture of peripheral blood mononuclear and dendritic cells (PBMC/DCs) from a non-CBD source to identify genes that are specifically upregulated in response to BeSO(4) stimulation, compared to a control metal salt, Al(2)(SO(4))(3). We identified a number of upregulated immunomodulatory genes, including several chemokines in the MIP-1 and GRO families. Using PBMC/DCs from three different donors, we demonstrate that BeSO(4) stimulation generally exhibits an increased rate of both chemokine mRNA transcription and release compared to Al(2)(SO(4))(3) exposure, although variations among the individual donors do exist. We show that MIP-1 alpha and MIP-1 beta neutralizing antibodies can partially inhibit the ability of BeSO(4) to stimulate cell migration of PBMC/DCs in vitro. Finally, incubation of PBMC/DCs with BeSO(4) altered the binding of the transcription factor RUNX to the MIP-1 alpha promoter consensus sequence, indicating that Be can regulate chemokine gene activation. Taken together, these results suggest a model in which Be stimulation of PBMC/DCs can modulate the expression and release of different chemokines, leading to the migration of lymphocytes to the lung and the formation of a localized environment for development of Be disease in susceptible individuals.

  17. The DRF motif of CXCR6 as chemokine receptor adaptation to adhesion.

    Directory of Open Access Journals (Sweden)

    Andrea Koenen

    Full Text Available The CXC-chemokine receptor 6 (CXCR6 is a class A GTP-binding protein-coupled receptor (GPCRs that mediates adhesion of leukocytes by interacting with the transmembrane cell surface-expressed chemokine ligand 16 (CXCL16, and also regulates leukocyte migration by interacting with the soluble shed variant of CXCL16. In contrast to virtually all other chemokine receptors with chemotactic activity, CXCR6 carries a DRF motif instead of the typical DRY motif as a key element in receptor activation and G protein coupling. In this work, modeling analyses revealed that the phenylalanine F3.51 in CXCR6 might have impact on intramolecular interactions including hydrogen bonds by this possibly changing receptor function. Initial investigations with embryonic kidney HEK293 cells and further studies with monocytic THP-1 cells showed that mutation of DRF into DRY does not influence ligand binding, receptor internalization, receptor recycling, and protein kinase B (AKT signaling. Adhesion was slightly decreased in a time-dependent manner. However, CXCL16-induced calcium signaling and migration were increased. Vice versa, when the DRY motif of the related receptor CX3CR1 was mutated into DRF the migratory response towards CX3CL1 was diminished, indicating that the presence of a DRF motif generally impairs chemotaxis in chemokine receptors. Transmembrane and soluble CXCL16 play divergent roles in homeostasis, inflammation, and cancer, which can be beneficial or detrimental. Therefore, the DRF motif of CXCR6 may display a receptor adaptation allowing adhesion and cell retention by transmembrane CXCL16 but reducing the chemotactic response to soluble CXCL16. This adaptation may avoid permanent or uncontrolled recruitment of inflammatory cells as well as cancer metastasis.

  18. Cytokines and chemokines as regulators of skeletal muscle inflammation: presenting the case of Duchenne muscular dystrophy

    OpenAIRE

    De Paepe, Boel; De Bleecker, Jan

    2013-01-01

    Duchenne muscular dystrophy is a severe inherited muscle disease that affects 1 in 3500 boys worldwide. Infiltration of skeletal muscle by inflammatory cells is an important facet of disease pathophysiology and is strongly associated with disease severity in the individual patient. In the chronic inflammation that characterizes Duchenne muscle, cytokines and chemokines are considered essential activators and recruiters of inflammatory cells. In addition, they provide potential beneficiary eff...

  19. Chemokine receptors expression on CD3+ blood cells in bronchial asthma.

    Science.gov (United States)

    Glück, Joanna; Rymarczyk, Barbara; Rogala, Barbara

    2016-03-01

    Chemokines and their receptors participate in pathomechanism of bronchial asthma. The aim of the study was to analyze the pattern of chemokine receptor expression on T cells in severe asthmatics and to compare to mild-to-moderate patients and controls. Flow cytometric analysis of CXCR1, CXCR2, CXCR3, CCR3, CCR4, CCR5, CCR7, CCR8 expression on CD3(+)CD8(-) and CD3(+)CD8(+) cells was performed in patients with different severity of chronic asthma and in controls. Percentages of CD3(+)CD8(+) cells expressing CXCR1 were significantly lower in severe asthmatic than in mild-to-moderate asthmatics and in controls. Percentages of CD3(+)CD8(+) cells expressing CCR7 were significantly lower in the severe asthma group than in control group. Percentages of CD3(+)CD8(-) cells expressing CXCR1, CXCR2 and CCR8 were significantly lower in the severe asthma group than in mild-to-moderate asthmatics and in controls. The number of cells CD3(+)CD8(-) and CD3(+)CD8(+) expressing of CXCR1 was significantly lower in the group of patients using more than 800μg of budesonide daily than in the group of patients using less than 400μg of budesonide. Percentages of CD3(+)CD8(-) cells expressing CXCR3, CCR4 and CCR5 were visibly higher (not significantly) in chronic mild-to-moderate asthma than in healthy controls and severe asthmatics. These results may indicate impairment of some chemokine expression on T cells in severe asthma patients. Moreover participation of both chemokine receptors related to Th1 and Th2 responses in mild-to-moderate asthma and attenuation of these responses in severe asthma has been suggested. Copyright © 2015 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  20. ETV5 Regulates Sertoli Cell Chemokines Involved in Mouse Stem/Progenitor Spermatogonia Maintenance

    Science.gov (United States)

    Simon, Liz; Ekman, Gail C; Garcia, Thomas; Carnes, Kay; Zhang, Zhen; Murphy, Theresa; Murphy, Kenneth M; Hess, Rex A; Cooke, Paul S; Hofmann, Marie–Claude

    2010-01-01

    Spermatogonial stem cells are the only stem cells in the body that transmit genetic information to offspring. Although growth factors responsible for self–renewal of these cells are known, the factors and mechanisms that attract and physically maintain these cells within their microenvironment are poorly understood. Mice with targeted disruption of Ets variant gene 5 (Etv5) show total loss of stem/progenitor spermatogonia following the first wave of spermatogenesis, resulting in a Sertoli cell–only phenotype and aspermia. Microarray analysis of primary Sertoli cells from Etv5 knockout (Etv5−/−) versus wild–type (WT) mice revealed significant decreases in expression of several chemokines. Chemotaxis assays demonstrated that migration of stem/progenitor spermatogonia toward Etv5−/− Sertoli cells was significantly decreased compared to migration toward WT Sertoli cells. Interestingly, differentiating spermatogonia, spermatocytes, and round spermatids were not chemoattracted by WT Sertoli cells, whereas stem/progenitor spermatogonia showed a high and significant chemotactic index. Rescue assays using recombinant chemokines indicated that C-C-motif ligand 9 (CCL9) facilitates Sertoli cell chemoattraction of stem/progenitor spermatogonia, which express C-C-receptor type 1 (CCR1). In addition, there is protein–DNA interaction between ETV5 and Ccl9, suggesting that ETV5 might be a direct regulator of Ccl9 expression. Taken together, our data show for the first time that Sertoli cells are chemoattractive for stem/progenitor spermatogonia, and that production of specific chemokines is regulated by ETV5. Therefore, changes in chemokine production and consequent decreases in chemoattraction by Etv5−/− Sertoli cells helps to explain stem/progenitor spermatogonia loss in Etv5−/− mice. PMID:20799334

  1. CpG-ODNs induces up-regulated expression of chemokine CCL9 in mouse macrophages and microglia

    Digital Repository Service at National Institute of Oceanography (India)

    Ravindran, C.; Cheng, Y.-C.; Liang, S.-M.

    with allergic diseases like inflammation. However, the mechanisms involved are not fully understood. Here we demonstrate for the first time that the CpG-ODN stimulates the chemokine CCL9. The gene CCL9, is responsible for activation of osteoclasts through its... in microglial (Bv2) cells was also observed and discussed, which may further contribute in understanding the mechanism that link in clearing the amyloid plaques in Alzheimer disease. Key words: Chemokine; Bacterial; machrophages; Neuroimmunology; Molecular...

  2. Interferon-inducible CXC chemokines directly contribute to host defense against inhalational anthrax in a murine model of infection.

    Directory of Open Access Journals (Sweden)

    Matthew A Crawford

    2010-11-01

    Full Text Available Chemokines have been found to exert direct, defensin-like antimicrobial activity in vitro, suggesting that, in addition to orchestrating cellular accumulation and activation, chemokines may contribute directly to the innate host response against infection. No observations have been made, however, demonstrating direct chemokine-mediated promotion of host defense in vivo. Here, we show that the murine interferon-inducible CXC chemokines CXCL9, CXCL10, and CXCL11 each exert direct antimicrobial effects in vitro against Bacillus anthracis Sterne strain spores and bacilli including disruptions in spore germination and marked reductions in spore and bacilli viability as assessed using CFU determination and a fluorometric assay of metabolic activity. Similar chemokine-mediated antimicrobial activity was also observed against fully virulent Ames strain spores and encapsulated bacilli. Moreover, antibody-mediated neutralization of these CXC chemokines in vivo was found to significantly increase host susceptibility to pulmonary B. anthracis infection in a murine model of inhalational anthrax with disease progression characterized by systemic bacterial dissemination, toxemia, and host death. Neutralization of the shared chemokine receptor CXCR3, responsible for mediating cellular recruitment in response to CXCL9, CXCL10, and CXCL11, was not found to increase host susceptibility to inhalational anthrax. Taken together, our data demonstrate a novel, receptor-independent antimicrobial role for the interferon-inducible CXC chemokines in pulmonary innate immunity in vivo. These data also support an immunomodulatory approach for effectively treating and/or preventing pulmonary B. anthracis infection, as well as infections caused by pathogenic and potentially, multi-drug resistant bacteria including other spore-forming organisms.

  3. B Cell, Th17, and Neutrophil Related Cerebrospinal Fluid Cytokine/Chemokines Are Elevated in MOG Antibody Associated Demyelination.

    Directory of Open Access Journals (Sweden)

    Kavitha Kothur

    Full Text Available Myelin oligodendrocyte glycoprotein antibody (MOG Ab associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination.To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS and -negative (NEG groups.We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM = 8, transverse myelitis (TM = 2 n = 10] and serum MOG Ab NEG (ADEM = 5, TM = 4, n = 9 demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls.The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19 as well as some of Th17 related cytokines (IL-6 AND G-CSF compared to MOG Ab NEG group (all p<0.01. In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies.Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.

  4. CCR11 is a functional receptor for the monocyte chemoattractant protein family of chemokines.

    Science.gov (United States)

    Schweickart, V L; Epp, A; Raport, C J; Gray, P W

    2000-03-31

    Chemokines mediate their diverse activities through G protein-coupled receptors. The human homolog of the bovine orphan receptor PPR1 shares significant similarity to chemokine receptors. Transfection of this receptor into murine L1.2 cells resulted in responsiveness to monocyte chemoattractant protein (MCP)-4, MCP-2, and MCP-1 in chemotaxis assays. Binding studies with radiolabeled MCP-4 demonstrated a single high affinity binding site with an IC(50) of 0.14 nM. As shown by competition binding, other members of the MCP family also recognized this receptor. MCP-2 was the next most potent ligand, with an IC(50) of 0.45 nM. Surprisingly, eotaxin (IC(50) = 6.7 nM) and MCP-3 (IC(50) = 4.1 nM) bind with greater affinity than MCP-1 (IC(50) = 10.7 nM) but only act as agonists in chemotaxis assays at 100-fold higher concentrations. Because of high affinity binding and functional chemotactic responses, we have termed this receptor CCR11. The gene for CCR11 was localized to human chromosome 3q22, which is distinct from most CC chemokine receptor genes at 3p21. Northern blot hybridization was used to identify CCR11 expression in heart, small intestine, and lung. Thus CCR11 shares functional similarity to CCR2 because it recognizes members of the MCP family, but CCR11 has a distinct expression pattern.

  5. Profile of human macrophage transcripts: insights into macrophage biology and identification of novel chemokines.

    Science.gov (United States)

    Chantry, D; DeMaggio, A J; Brammer, H; Raport, C J; Wood, C L; Schweickart, V L; Epp, A; Smith, A; Stine, J T; Walton, K; Tjoelker, L; Godiska, R; Gray, P W

    1998-07-01

    High throughput partial sequencing of randomly selected cDNA clones has proven to be a powerful tool for examining the relative abundance of mRNAs and for the identification of novel gene products. Because of the important role played by macrophages in immune and inflammatory responses, we sequenced over 3000 randomly selected cDNA clones from a human macrophage library. These sequences represent a molecular inventory of mRNAs from macrophages and provide a catalog of highly expressed transcripts. Two of the most abundant clones encode recently identified CC chemokines. Macrophage-derived chemokine (MDC) plays a complex role in immunoregulation and is a potent chemoattractant for dendritic cells, T cells, and natural killer cells. The chemokine receptor CCR4 binds MDC with high affinity and also responds by calcium flux and chemotaxis. CCR4 has been shown to be expressed by Th2 type T cells. Recent studies also implicate MDC as a major component of the host defense against human immunodeficiency virus.

  6. Monocyte chemotactic protein-4: tissue-specific expression and signaling through CC chemokine receptor-2.

    Science.gov (United States)

    Godiska, R; Chantry, D; Raport, C J; Schweickart, V L; Trong, H L; Gray, P W

    1997-03-01

    Chemokines constitute a family of low-molecular-weight proteins that attract or activate a variety of cell types, including leukocytes, endothelial cells, and fibroblasts. An electronic search of the GenBank Expressed Sequence Tags database uncovered a partial cDNA sequence with homology to the chemokine monocyte chemotactic protein-1 (MCP-1). Isolation of the full-length clone revealed that it encodes the chemokine MCP-4, an eosinophil chemoattractant recently described by Uguccioni et al. [J. Exp. Med. 183, 2379-2384]. Recombinant MCP-4 was expressed in mammalian cells and purified by heparin-Sepharose chromatography. Sequencing the amino terminus of this protein corroborated the reported sequence of recombinant MCP-4 produced in insect cells. As shown by calcium flux assays, MCP-4 activated the cloned G protein-coupled receptor CCR-2, which also recognizes MCP-1 and MCP-3. Northern hybridization indicated that MCP-4 is constitutively expressed at high levels in the small intestine, colon, and lung. This expression profile is consistent with its role as a chemoattractant for eosinophils, which can be rapidly mobilized to the lung or intestine in response to invading pathogens. In marked contrast to MCP-1, MCP-4 was not induced in cell lines treated with pro-inflammatory stimuli such as lipopolysaccharide or tumor necrosis factor alpha.

  7. Lonchocarpus sericeus lectin decreases leukocyte migration and mechanical hypernociception by inhibiting cytokine and chemokines production.

    Science.gov (United States)

    Napimoga, Marcelo H; Cavada, Benildo S; Alencar, Nylane M N; Mota, Mário L; Bittencourt, Flávio S; Alves-Filho, José C; Grespan, Renata; Gonçalves, Reginaldo B; Clemente-Napimoga, Juliana T; de Freitas, Andressa; Parada, Carlos A; Ferreira, Sérgio H; Cunha, Fernando Q

    2007-06-01

    In this study, we tested the potential use of a lectin from Lonchocarpus sericeus seeds (LSL), to control neutrophil migration and inflammatory hypernociception (decrease of nociceptive threshold). Pretreatment of the animals intravenously (15 min before) with LSL inhibited neutrophil migration to the peritoneal cavity in a dose-dependent fashion confirmed by an inhibition of rolling and adhesion of leukocytes by intravital microscopy. We also tested the ability of the pretreatment with LSL to inhibit neutrophil migration on immunised mice, and it was observed that a strong inhibition of neutrophil migration induced by ovoalbumin in immunized mice. Another set of experiments showed that pretreatment of the animals with LSL, inhibited the mechanical hypernociception in mice induced by the i.pl. injection of OVA in immunized mice and of carrageenan in naïve mice, but not that induced by prostaglandin E(2) (PGE(2)) or formalin. This anti-nociceptive effect correlated with an effective blockade of neutrophil influx, as assessed by the hind paw tissue myeloperoxidase levels. In addition, we measured cytokines (TNF-alpha and IL-1beta) and chemokines (MIP-1alpha [CCL3] and KC [CXCL1]) from the peritoneal exudates and i.pl. tissue. Animals treated with LSL showed inhibition of cytokines and chemokines release in a dose-dependent manner. In conclusion, we demonstrated that the inhibitory effects of LSL on neutrophil migration and mechanical inflammatory hypernocicepetion are associated with the inhibition of the production of cytokines and chemokines.

  8. [The role of CC-chemokine ligand 2 in the development of psychic dependence on methamphetamine].

    Science.gov (United States)

    Saika, Fumihiro; Kiguchi, Norikazu; Kishioka, Shiroh

    2015-10-01

    Addiction is described as a chronic neurological disorder associated with plasticity in the mesolimbic system. Recently, it has been suggested that neuroinflammation plays an important role in the induction of neuronal plasticity and the formation of pathogenesis in chronic neurological disorders. Therefore, we examined the role of CC-chemokine ligand 2 (CCL2), a proinflammatory chemokine, in the development of psychic dependence on methamphetamine. In mice treated with methamphetamine, CCL2 mRNA was significantly increased in prefrontal cortex and nucleus accumbens. Moreover, phosphorylated tyrosine hydroxylase serine40 (pTH Ser40) levels in the ventral tegmental area (VTA) were increased by methamphetamine. Similarly, pTH Ser40 levels in the VTA were also increased by the intracerebroventricular administration of recombinant CCL2. The increment of pTH Ser40 levels in the VTA by methamphetamine was attenuated by RS504393, a selective CC-chemokine receptor 2 (CCR2) antagonist, indicating that the increased CCL2 activates the brain reward system via CCR2 activation. In the conditioned place preference test, methamphetamine produced place preference in a dose-dependent manner, which was attenuated by RS504393. These results suggest that the activation of the brain reward system via CCL2-CCR2 pathway plays an important role in the development of psychic dependence on methamphetamine.

  9. Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults

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    Trautwein Christian

    2010-06-01

    Full Text Available Abstract Background Recent experimental approaches have unraveled essential migratory and functional differences of monocyte subpopulations in mice. In order to possibly translate these findings into human physiology and pathophysiology, human monocyte subsets need to be carefully revisited in health and disease. In analogy to murine studies, we hypothesized that human monocyte subsets dynamically change during ageing, potentially influencing their functionality and contributing to immunosenescence. Results Circulating monocyte subsets, surface marker and chemokine receptor expression were analyzed in 181 healthy volunteers (median age 42, range 18-88. Unlike the unaffected total leukocyte or total monocyte counts, non-classical CD14+CD16+ monocytes significantly increased with age, but displayed reduced HLA-DR and CX3CR1 surface expression in the elderly. Classical CD14++CD16- monocyte counts did not vary dependent on age. Serum MCP-1 (CCL2, but not MIP1α (CCL3, MIP1β (CCL4 or fractalkine (CX3CL1 concentrations increased with age. Monocyte-derived macrophages from old or young individuals did not differ with respect to cytokine release in vitro at steady state or upon LPS stimulation. Conclusions Our study demonstrates dynamic changes of circulating monocytes during ageing in humans. The expansion of the non-classical CD14+CD16+ subtype, alterations of surface protein and chemokine receptor expression as well as circulating monocyte-related chemokines possibly contribute to the preserved functionality of the monocyte pool throughout adulthood.

  10. The Role of Cytokines, Chemokines, and Growth Factors in the Pathogenesis of Pityriasis Rosea

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    Francesco Drago

    2015-01-01

    Full Text Available Introduction. Pityriasis rosea (PR is an exanthematous disease related to human herpesvirus- (HHV- 6/7 reactivation. The network of mediators involved in recruiting the infiltrating inflammatory cells has never been studied. Object. To investigate the levels of serum cytokines, growth factors, and chemokines in PR and healthy controls in order to elucidate the PR pathogenesis. Materials and Methods. Interleukin- (IL- 1, IL-6, IL-17, interferon- (IFN- γ, tumor necrosis factor- (TNF- α, vascular endothelial growth factor (VEGF, granulocyte colony stimulating factor (G-CSF, and chemokines, CXCL8 (IL-8 and CXCL10 (IP-10, were measured simultaneously by a multiplex assay in early acute PR patients’ sera and healthy controls. Subsequently, sera from PR patients were analysed at 3 different times (0, 15, and 30 days. Results and discussion. Serum levels of IL-17, IFN-γ, VEGF, and IP-10 resulted to be upregulated in PR patients compared to controls. IL-17 has a key role in host defense against pathogens stimulating the release of proinflammatory cytokines/chemokines. IFN-γ has a direct antiviral activity promoting NK cells and virus specific T cells cytotoxicity. VEGF stimulates vasculogenesis and angiogenesis. IP-10 can induce chemotaxis, apoptosis, cell growth, and angiogenesis. Conclusions. Our findings suggest that these inflammatory mediators may modulate PR pathogenesis in synergistic manner.

  11. Spread of Psoriasiform Inflammation to Remote Tissues Is Restricted by the Atypical Chemokine Receptor ACKR2.

    Science.gov (United States)

    Shams, Kave; Wilson, Gillian J; Singh, Mark; van den Bogaard, Ellen H; Le Brocq, Michelle L; Holmes, Susan; Schalkwijk, Joost; Burden, A David; McKimmie, Clive S; Graham, Gerard J

    2017-01-01

    Elucidating the poorly defined mechanisms by which inflammatory lesions are spatially restricted in vivo is of critical importance in understanding skin disease. Chemokines are the principal regulators of leukocyte migration and are essential in the initiation and maintenance of inflammation. The membrane-bound psoriasis-associated atypical chemokine receptor 2 (ACKR2) binds, internalizes and degrades most proinflammatory CC-chemokines. Here we investigate the role of ACKR2 in limiting the spread of cutaneous psoriasiform inflammation to sites that are remote from the primary lesion. Circulating factors capable of regulating ACKR2 function at remote sites were identified and examined using a combination of clinical samples, relevant primary human cell cultures, in vitro migration assays, and the imiquimod-induced model of psoriasiform skin inflammation. Localized inflammation and IFN-γ together up-regulate ACKR2 in remote tissues, protecting them from the spread of inflammation. ACKR2 controls inflammatory T-cell chemotaxis and positioning within the skin, preventing an epidermal influx that is associated with lesion development. Our results have important implications for our understanding of how spatial restriction is imposed on the spread of inflammatory lesions and highlight systemic ACKR2 induction as a therapeutic strategy in the treatment and prevention of psoriasis and potentially a broad range of other immune-mediated diseases. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Reduced local immunity in HPV-related VIN: expression of chemokines and involvement of immunocompetent cells.

    Science.gov (United States)

    Santegoets, Lindy A M; van Seters, Manon; Heijmans-Antonissen, Claudia; Kleinjan, Alex; van Beurden, Marc; Ewing, Patricia C; Kühne, Liesbeth C M; Beckmann, Ilse; Burger, Curt W; Helmerhorst, Theo J M; Blok, Leen J

    2008-08-01

    Usual type VIN is a premalignant disorder caused by persistent HPV infection. High prevalence of VIN in immuno-suppressed women suggests that a good innate and adaptive immune response is important for defense against HPV. Here, we explored expression levels of chemokines and related these to the presence or absence of immuno-competent cells (dendritic and T-cells) in affected (HPV-positive VIN) and non-affected (HPV-negative) vulvar tissues from the same patients. Combining microarray data with quantitative real-time RT-PCR, it was observed that several important chemokines were differentially expressed between VIN and control samples (up-regulation of IL8, CXCL10, CCL20 and CCL22 and down-regulation of CXCL12, CCL21 and CCL14). Furthermore, an increased number of mature dendritic cells (CD208+) seemed to be bottled up in the dermis, and although a T-cell response (increased CD4+ and CD8+ cells) was observed in VIN, a much larger response is required to clear the infection. In summary, it seems that most mature dendritic cells do not receive the proper chemokine signal for migration and will stay in the dermis, not able to present viral antigen to naive T-cells in the lymph node. Consequently the adaptive immune response diminishes, resulting in a persistent HPV infection with increased risk for neoplasia.

  13. Inhibition of murine neutrophil recruitment in vivo by CXC chemokine receptor antagonists.

    Science.gov (United States)

    McColl, S R; Clark-Lewis, I

    1999-09-01

    In this study, we have examined the ability of chemokine receptor antagonists to prevent neutrophil extravasation in the mouse. Two murine CXC chemokines, macrophage-inflammatory protein (MIP)-2 and KC, stimulated the accumulation of leukocytes into s.c. air pouches, although MIP-2 was considerably more potent. The leukocyte infiltrate was almost exclusively neutrophilic in nature. A human CXC chemokine antagonist, growth-related oncogene (GRO)-alpha(8-73), inhibited calcium mobilization induced by MIP-2, but not by platelet-activating factor in leukocytes isolated from the bone marrow, indicating that this antagonist inhibits MIP-2 activity toward murine leukocytes. Pretreatment of mice with GROalpha(8-73) inhibited, in a dose-dependent manner, the MIP-2-induced influx of neutrophils to levels that were not significantly different from control values. Moreover, this antagonist was also effective in inhibiting the leukocyte recruitment induced by TNF-alpha, LPS, and IL-1beta. Leukocyte infiltration into the peritoneal cavity in response to MIP-2 was also inhibited by prior treatment of mice with GROalpha(8-73) or the analogue of platelet factor 4, PF4(9-70). The results of this study indicate 1) that the murine receptor for MIP-2 and KC, muCXCR2, plays a major role in neutrophil recruitment to s.c. tissue and the peritoneal cavity in response to proinflammatory agents and 2) that CXCR2 receptor antagonists prevent acute inflammation in vivo.

  14. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis.

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    Ishan Roy

    Full Text Available Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

  15. IL-27 Modulates Chemokine Production in TNF-α -Stimulated Human Oral Epithelial Cells.

    Science.gov (United States)

    Hosokawa, Yoshitaka; Hosokawa, Ikuko; Ozaki, Kazumi; Matsuo, Takashi

    2017-10-05

    Interleukin-27 (IL-27) is a cytokine which belongs to the IL-12 family. However, the role of IL-27 in the pathogenesis of periodontal disease is uncertain. The aim of this study was to examine the effect of IL-27 on chemokine production in TNF-α-stimulated human oral epithelial cells (TR146). We measured chemokine production in TR146 by ELISA. We used western blot analysis to detect the phosphorylation levels of signal transduction molecules, including STAT1 and STAT3 in TR146. We used inhibitors to examine the role of STAT1 and STAT3 activation. IL-27 increased CXCR3 ligands production in TNF-α-stimulated TR146. Meanwhile, IL-27 suppressed IL-8 and CCL20 production induced by TNF-α. STAT1 phosphorylation level in IL-27 and TNF-α-stimulated TR146 was enhanced in comparison to TNF-α-stimulated TR146. STAT3 phosphorylation level in IL-27-treated TR146 did not change by TNF-α. Both STAT1 inhibitor and STAT3 inhibitor decreased CXCR3 ligands production. STAT1 inhibitor overrode the inhibitory effect of IL-27 on IL-8 and CCL20 production in TNF-α-stimulated TR146. Meanwhile, STAT3 inhibitor did not modulate IL-8 and CCL20 production. IL-27 might control leukocyte migration in periodontal lesion by modulating chemokine production from epithelial cells. © 2017 The Author(s). Published by S. Karger AG, Basel.

  16. Enhanced Chemokine Receptor Expression on Leukocytes of Patients with Alzheimer's Disease.

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    David Goldeck

    Full Text Available Although primarily a neurological complaint, systemic inflammation is present in Alzheimer's Disease, with higher than normal levels of proinflammatory cytokines and chemokines in the periphery as well as the brain. A gradient of these factors may enhance recruitment of activated immune cells into the brain via chemotaxis. Here, we investigated the phenotypes of circulating immune cells in AD patients with multi-colour flow cytometry to determine whether their expression of chemokine receptors is consistent with this hypothesis. In this study, we confirmed our previously reported data on the shift of early- to late-differentiated CD4+ T-cells in AD patients. The percentage of cells expressing CD25, a marker of acute T-cell activation, was higher in patients than in age-matched controls, and percentages of CCR6+ cells were elevated. This chemokine receptor is primarily expressed on pro-inflammatory memory cells and Th17 cells. The proportion of cells expressing CCR4 (expressed on Th2 cells and CCR5 (Th1 cells and dendritic cells was also greater in patients, and was more pronounced on CD4+ than CD8+ T-cells. These findings allow a more detailed insight into the systemic immune status of patients with Alzheimer's disease and suggest possible novel targets for immune therapy.

  17. Inactivation of HIV-1 chemokine co-receptor CXCR-4 by a novel intrakine strategy.

    Science.gov (United States)

    Chen, J D; Bai, X; Yang, A G; Cong, Y; Chen, S Y

    1997-10-01

    CXC-chemokine receptor (CXCR)-4/fusin, a newly discovered co-receptor for T-cell line (T)-tropic HIV-1 virus, plays a critical role in T-tropic virus fusion and entry into permissive cells. The occurrence of T-tropic HIV viruses is associated with CD4-positive cell decline and progression to AIDS, suggesting that the T-tropic HIV-1 contributes to AIDS pathogenesis. In this study, we used a novel strategy to inactivate CXCR-4 by targeting a modified CXC-chemokine to the endoplasmic reticulum (ER) to block the surface expression of newly synthesized CXCR-4. The genetically modified lymphocytes expressing this intracellular chemokine, termed "intrakine", are immune to T-tropic virus infection and appear to retain normal biological features. Thus, this genetic intrakine strategy is uniquely targeted at the conserved cellular receptor for the prevention of HIV-1 entry and may be developed into an effective treatment for HIV-1 infection and AIDS.

  18. Analysis of Chemokines and Receptors Expression Profile in the Myelin Mutant Taiep Rat

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    Guadalupe Soto-Rodriguez

    2015-01-01

    Full Text Available Taiep rat has a failure in myelination and remyelination processes leading to a state of hypomyelination throughout its life. Chemokines, which are known to play a role in inflammation, are also involved in the remyelination process. We aimed to demonstrate that remyelination-stimulating factors are altered in the brainstem of 1- and 6-month-old taiep rats. We used a Rat RT2 Profiler PCR Array to assess mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors. We also evaluated protein levels of CCL2, CCR1, CCR2, CCL5, CCR5, CCR8, CXCL1, CXCR2, CXCR4, FGF2, and VEGFA by ELISA. Sprague-Dawley rats were used as a control. PCR Array procedure showed that proinflammatory cytokines were not upregulated in the taiep rat. In contrast, some mRNA levels of beta and alpha chemokines were upregulated in 1-month-old rats, but CXCR4 was downregulated at their 6 months of age. ELISA results showed that CXCL1, CCL2, CCR2, CCR5, CCR8, and CXCR4 protein levels were decreased in brainstem at the age of 6 months. These results suggest the presence of a chronic neuroinflammation process with deficiency of remyelination-stimulating factors (CXCL1, CXCR2, and CXCR4, which might account for the demyelination in the taiep rat.

  19. Evolutionary strata on young mating-type chromosomes despite the lack of sexual antagonism.

    Science.gov (United States)

    Branco, Sara; Badouin, Hélène; Rodríguez de la Vega, Ricardo C; Gouzy, Jérôme; Carpentier, Fantin; Aguileta, Gabriela; Siguenza, Sophie; Brandenburg, Jean-Tristan; Coelho, Marco A; Hood, Michael E; Giraud, Tatiana

    2017-07-03

    Sex chromosomes can display successive steps of recombination suppression known as "evolutionary strata," which are thought to result from the successive linkage of sexually antagonistic genes to sex-determining genes. However, there is little evidence to support this explanation. Here we investigate whether evolutionary strata can evolve without sexual antagonism using fungi that display suppressed recombination extending beyond loci determining mating compatibility despite lack of male/female roles associated with their mating types. By comparing full-length chromosome assemblies from five anther-smut fungi with or without recombination suppression in their mating-type chromosomes, we inferred the ancestral gene order and derived chromosomal arrangements in this group. This approach shed light on the chromosomal fusion underlying the linkage of mating-type loci in fungi and provided evidence for multiple clearly resolved evolutionary strata over a range of ages (0.9-2.1 million years) in mating-type chromosomes. Several evolutionary strata did not include genes involved in mating-type determination. The existence of strata devoid of mating-type genes, despite the lack of sexual antagonism, calls for a unified theory of sex-related chromosome evolution, incorporating, for example, the influence of partially linked deleterious mutations and the maintenance of neutral rearrangement polymorphism due to balancing selection on sexes and mating types.

  20. Astaxanthin from psychrotrophic Sphingomonas faeni exhibits antagonism against food-spoilage bacteria at low temperatures.

    Science.gov (United States)

    Mageswari, Anbazhagan; Subramanian, Parthiban; Srinivasan, Ramachandran; Karthikeyan, Sivashanmugam; Gothandam, Kodiveri Muthukaliannan

    2015-10-01

    Food production and processing industry holds a perpetual relationship with microorganisms and their by-products. In the present study, we aimed to identify beneficial cold-adapted bacteria devoid of any food spoilage properties and study their antagonism against common food-borne pathogens at low temperature conditions. Ten isolates were obtained on selective isolation at 5 °C, which were spread across genera Pseudomonas, Sphingomonas, Psychrobacter, Leuconostoc, Rhodococcus, and Arthrobacter. Methanol extracts of strains were found to contain several bioactive metabolites. Among the studied isolates, methanol extracts of S. faeni ISY and Rhodococcus fascians CS4 were found to show antagonism against growth of Escherichia coli, Proteus mirabilis, Enterobacter aerogenes, Listeria monocytogenes and Vibrio fischeri at refrigeration temperatures. Characterization of the abundant yellow pigment in methanol extracts of S. faeni ISY through UV-Vis spectrophotometry, high performance liquid chromatography (HPLC) and mass spectrometry (LC-MS) revealed the presence of astaxanthin, which, owing to its presence in very large amounts and evidenced to be responsible for antagonistic activity of the solvent extract. Copyright © 2015 Elsevier GmbH. All rights reserved.

  1. Insecticidal Bacillus thuringiensis Silences Erwinia carotovora Virulence by a New Form of Microbial Antagonism, Signal Interference

    Science.gov (United States)

    Dong, Yi-Hu; Zhang, Xi-Fen; Xu, Jin-Ling; Zhang, Lian-Hui

    2004-01-01

    It is commonly known that bacteria may produce antibiotics to interfere with the normal biological functions of their competitors in order to gain competitive advantages. Here we report that Bacillus thuringiensis suppressed the quorum-sensing-dependent virulence of plant pathogen Erwinia carotovora through a new form of microbial antagonism, signal interference. E. carotovora produces and responds to acyl-homoserine lactone (AHL) quorum-sensing signals to regulate antibiotic production and expression of virulence genes, whereas B. thuringiensis strains possess AHL-lactonase, which is a potent AHL-degrading enzyme. B. thuringiensis did not seem to interfere with the normal growth of E. carotovora; rather, it abolished the accumulation of AHL signal when they were cocultured. In planta, B. thuringiensis significantly decreased the incidence of E. carotovora infection and symptom development of potato soft rot caused by the pathogen. The biocontrol efficiency is correlated with the ability of bacterial strains to produce AHL-lactonase. While all the seven AHL-lactonase-producing B. thuringiensis strains provided significant protection against E. carotovora infection, Bacillus fusiformis and Escherichia coli strains that do not process AHL-degradation enzyme showed little effect in biocontrol. Mutation of aiiA, the gene encoding AHL-lactonase in B. thuringiensis, resulted in a substantial decrease in biocontrol efficacy. These results suggest that signal interference mechanisms existing in natural ecosystems could be explored as a new version of antagonism for prevention of bacterial infections. PMID:14766576

  2. FCJ-156 Hacking the Social: Internet Memes, Identity Antagonism, and the Logic of Lulz.

    Directory of Open Access Journals (Sweden)

    Ryan M. Milner

    2013-12-01

    Full Text Available 4chan and reddit are participatory media collectives undergirded by a “logic of lulz” that favours distanced irony and critique. It often works at the expense of core identity categories like race and gender. However, the logic need not be entirely counterproductive to public discourse. Provided that diverse identities find voice instead of exclusion, these sites may facilitate vibrant, agonistic discussion instead of disenfranchising antagonism. In order to assess this potential for productive agonism, I undertook a critical discourse analysis of these collectives. Emphasising the image memes they produce, I evaluated discourses on race and gender. Both race and gender representations were dominated by familiar stereotypes and partial representations. However, while dissenting perspectives on race were repressed or excluded, dissenting perspectives on gender were vocalised and contested. The ‘logic of lulz’ facilitated both dominance and counter, each articulated with heavy reliance on irony and critique. This logic ambiguously balanced agonism and antagonism, but contestation provided sharper engagement than repression.

  3. Cotinine antagonizes the behavioral effects of nicotine exposure in the planarian Girardia tigrina.

    Science.gov (United States)

    Bach, Daniel J; Tenaglia, Matthew; Baker, Debra L; Deats, Sean; Montgomery, Erica; Pagán, Oné R

    2016-10-06

    Nicotine is one of the most addictive drugs abused by humans. Our laboratory and others have demonstrated that nicotine decreases motility and induces seizure-like behavior in planarians (pSLM, which are vigorous writhing and bending of the body) in a concentration-dependent manner. Nicotine also induces withdrawal-like behaviors in these worms. Cotinine is the major nicotine metabolite in humans, although it is not the final product of nicotine metabolism. Cotinine is mostly inactive in vertebrate nervous systems and is currently being explored as a molecule which possess most of nicotine's beneficial effects and few of its undesirable ones. It is not known whether cotinine is a product of nicotine metabolism in planarians. We found that cotinine by itself does not seem to elicit any behavioral effects in planarians up to a concentration of 1mM. We also show that cotinine antagonizes the aforementioned nicotine-induced motility decrease and also decreases the expression of nicotine-induced pSLMs in a concentration-dependent manner. Also cotinine prevents the manifestation of some of the withdrawal-like behaviors induced by nicotine in our experimental organism. Thus, we obtained evidence supporting that cotinine antagonizes nicotine in this planarian species. Possible explanations include competitive binding of both compounds at overlapping binding sites, at different nicotinic receptor subtypes, or maybe allosteric interactions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Dynamical transitions in a pollination-herbivory interaction: a conflict between mutualism and antagonism.

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    Tomás A Revilla

    Full Text Available Plant-pollinator associations are often seen as purely mutualistic, while in reality they can be more complex. Indeed they may also display a diverse array of antagonistic interactions, such as competition and victim-exploiter interactions. In some cases mutualistic and antagonistic interactions are carried-out by the same species but at different life-stages. As a consequence, population structure affects the balance of inter-specific associations, a topic that is receiving increased attention. In this paper, we developed a model that captures the basic features of the interaction between a flowering plant and an insect with a larval stage that feeds on the plant's vegetative tissues (e.g. leaves and an adult pollinator stage. Our model is able to display a rich set of dynamics, the most remarkable of which involves victim-exploiter oscillations that allow plants to attain abundances above their carrying capacities and the periodic alternation between states dominated by mutualism or antagonism. Our study indicates that changes in the insect's life cycle can modify the balance between mutualism and antagonism, causing important qualitative changes in the interaction dynamics. These changes in the life cycle could be caused by a variety of external drivers, such as temperature, plant nutrients, pesticides and changes in the diet of adult pollinators.

  5. IFITM Proteins Restrict HIV-1 Infection by Antagonizing the Envelope Glycoprotein

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    Jingyou Yu

    2015-10-01

    Full Text Available The interferon-induced transmembrane (IFITM proteins have been recently shown to restrict HIV-1 and other viruses. Here, we provide evidence that IFITM proteins, particularly IFITM2 and IFITM3, specifically antagonize the HIV-1 envelope glycoprotein (Env, thereby inhibiting viral infection. IFITM proteins interact with HIV-1 Env in viral producer cells, leading to impaired Env processing and virion incorporation. Notably, the level of IFITM incorporation into HIV-1 virions does not strictly correlate with the extent of inhibition. Prolonged passage of HIV-1 in IFITM-expressing T lymphocytes leads to emergence of Env mutants that overcome IFITM restriction. The ability of IFITMs to inhibit cell-to-cell infection can be extended to HIV-1 primary isolates, HIV-2 and SIVs; however, the extent of inhibition appears to be virus-strain dependent. Overall, our study uncovers a mechanism by which IFITM proteins specifically antagonize HIV-1 Env to restrict HIV-1 infection and provides insight into the specialized role of IFITMs in HIV infection.

  6. Non-redundant functional groups of chemokines operate in a coordinate manner during the inflammatory response in the lung.

    Science.gov (United States)

    Gutierrez-Ramos, J C; Lloyd, C; Kapsenberg, M L; Gonzalo, J A; Coyle, A J

    2000-10-01

    The understanding of the relative contribution of particular chemokines to the selective accumulation of leukocyte subsets to an organ site during an inflammatory response is made difficult by the simultaneous presence of multiple chemokines with partially overlapping functions at the inflammatory site. The study of several chemokine pathways (expression and function) during the development of a mouse model of allergic airway disease (AAD) has revealed differential expression regulation with distinct cellular sources for individual chemokines with functional bias for the recruitment/localization of regulatory and/or effector leukocyte subsets. In the present review, we propose that distinct functional groups of chemokines co-operate to generate the complete inflammatory response in the lung during AAD. We will also extend these concepts to the specific recruitment of a key cellular subset such as T helper type 2 (Th2) lymphocytes. We propose that the long term recruitment of antigen-specific Th2 cells to target organs, such as airways during chronic lung inflammation, is the result the sequential involvement of several chemotactic axes. Specifically, the CCR3/eotaxin and the CCR4/MDC pathway act in a coordinated co-operative manner, with the CCR3/eotaxin pathway being critical in the acute/early stages of a response, followed by the CCR4/MDC pathway, which ultimately dominates in the recruitment of antigen-specific Th2 cells. Other chemokines/receptors participate in this process possibly by amplifying/priming the Th2 recruitment response.

  7. Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment.

    Science.gov (United States)

    Günaltay, Sezin; Kumawat, Ashok Kumar; Nyhlin, Nils; Bohr, Johan; Tysk, Curt; Hultgren, Olof; Hultgren Hörnquist, Elisabeth

    2015-01-01

    Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhea. Various immune cell infiltrations in the epithelium and lamina propria are seen in MC immunopathology. We compared gene and protein expressions of different immune cell attracting chemokines and their receptors in colon biopsies from MC patients in active disease or histopathological remission (CC/LC-HR) with controls, using qRT-PCR and Luminex, respectively. CC and LC patients with active disease demonstrated a mixed chemokine profile with significantly enhanced gene and/or protein expressions of the chemokines CCL2, CCL3, CCL4, CCL5, CCL7, CCL22, CXCL8, CXCL9, CXCL10, CXCL11, and CX3CL1 and the receptors CCR2, CCR3, CCR4, CXCR1, CXCR2, and CX3CR1. Enhanced chemokine/chemokine receptor gene and protein levels in LC-HR patients were similar to LC patients, whereas CC-HR patients demonstrated almost normalized levels. These findings expand the current understanding of the involvement of various immune cells in MC immunopathology and endorse chemokines as potential diagnostic markers as well as therapeutic candidates. Moreover, this study further supports the hypothesis that CC and LC are two different entities due to differences in their immunoregulatory responses.

  8. Tacrolimus suppresses atopic dermatitis-associated cytokines and chemokines in monocytes.

    Science.gov (United States)

    Chang, Kai-Ting; Lin, Hugo You-Hsien; Kuo, Chang-Hung; Hung, Chih-Hsing

    2016-06-01

    Calcineurin inhibitors (CNIs) exhibit remarkable efficacy in atopic dermatitis (AD). Tacrolimus, one type of CNI, is prevalently used to treat AD. AD is a chronic inflammatory disease that exhibits predominant infiltration of T-helper type 2 (Th2) cell in the acute phase and a mixed Th1 and Th0 cell pattern in chronic lesions. Cytokines such as tumor necrosis factor-α (TNF-α), Th2-related chemokines [e.g., macrophage-derived chemokine (MDC)/CCL22 and I-309/CCL1], Th1-related chemokines [e.g., interferon γ-induced protein 10 (IP-10)/CXCL10], and neutrophil chemoattractant growth-related oncogene-α (GRO-α)/CXCL1 are involved in the pathogenesis of AD. However, whether tacrolimus modulates the expression of AD-associated cytokines and chemokines remains unknown. The intracellular mechanisms of tacrolimus are also unclear. Human monocytic cell line THP-1 cells were pretreated with tacrolimus and stimulated with lipopolysaccharide (LPS). The MDC, I-309, IP-10, GRO-α, and TNF-α concentrations of the cell supernatants were measured using enzyme-linked immunosorbent assay. Intracellular signaling was investigated using the Western blot analysis. Tacrolimus suppressed the expression of MDC, IP-10, I-309, GRO-α, and TNF-α in LPS-stimulated THP-1 cells in a dose- and time-dependent manner. All three mitogen-activated protein kinase (MAPK) inhibitors and the nuclear factor-κB inhibitor suppressed LPS-induced MDC, I-309, and TNF-α expressions in THP-1 cells. Only MAPK inhibitors suppressed LPS-induced expression of IP-10 and GRO-α. Tacrolimus suppressed the LPS-induced phosphorylation of MAPK-extracellular signal-related kinase (ERK). Tacrolimus suppressed LPS-induced MDC, I-309, IP-10, GRO-α, and TNF-α expressions in monocytes through the MAPK-ERK pathway; thus, tacrolimus may yield therapeutic efficacy by modulating AD-associated cytokines and chemokines. Copyright © 2014. Published by Elsevier B.V.

  9. Intra- and inter-day variation of cytokines and chemokines in tears of healthy subjects.

    Science.gov (United States)

    Benito, María Jesús; González-García, María J; Tesón, Marisa; García, Noelia; Fernández, Itziar; Calonge, Margarita; Enríquez-de-Salamanca, Amalia

    2014-03-01

    Tear levels of certain cytokines/chemokines can potentially serve as biomarkers for dry eye and other ocular surface diseases if they remain stable from day-to-day in healthy eyes. The aim of this study was to determine the normal intra- and inter-day variation of selected tear cytokines/chemokines. Tear samples from 24 young, healthy adults were collected 11:00 AM-1:00 PM (mid-day) and 5:00-7:00 PM (evening) on three non-consecutive days. Concentrations of 18 cytokines/chemokines (EGF, eotaxin, CX3CL1/fractalkine, GM-CSF, IFN-γ, IL-10, IL-1β, IL-13, IL-17A, IL-1RA, IL-5, IL-6, CXCL8/IL-8, IL-9, CXCL10/IP-10, CCL5/RANTES, TNF-α, and VEGF) were measured by multiplex bead analysis. Ocular surface disease was ruled out by clinical tests. A random-effects ANOVA model was used to evaluate intra- and inter-day effects on cytokine/chemokine levels. Repeatability of intra-subject inter-day measurements was assayed by coefficient of variation. Ten out of the 18 molecules had detectable tear levels in >50% of the subjects. Of those, only IL-10 and IL-1β levels had significant inter-day variations. EGF, CX3CL1/fractalkine, CXCL10/IP-10, and VEGF were consistently higher in the evening compared to the mid-day measurements. EGF, CXCL10/IP-10, VEGF and CXCL8/IL-8had good intra-subject reproducibility. In conclusion, tear cytokines/chemokines can be measured reproducibly over time, with most not having significant inter-day variability. Some varied significantly depending upon the time of tear collection, and these variations should be taken into account when comparisons are made. The good intra-subject reproducibility for EGF, CXCL10/IP-10, CXCL8/IL-8, and VEGF indicates that these molecules could potentially serve as biomarkers of ocular surface disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Selective loss of chemokine receptor expression on leukocytes after cell isolation.

    Directory of Open Access Journals (Sweden)

    Juan C Nieto

    Full Text Available Chemokine receptors are distinctively exposed on cells to characterize their migration pattern. However, little is known about factors that may regulate their expression. To determine the optimal conditions for an accurate analysis of chemokine receptors, we compared the expression of CCR2, CCR4, CCR5, CCR6, CXCR3 and CXCR4 on different leukocyte subsets using whole blood (WB plus erythrocyte lysis and density gradient isolation (Ficoll. Most WB monocytes were CCR2+ (93.5 ± 2.9% whereas 32.8 ± 6.0% of monocytes from Ficoll-PBMC expressed CCR2 (p<0.001. Significant reductions of CCR6 and CXCR3 on monocytes were also observed after Ficoll isolation (WB: 46.4 ± 7.5% and 57.1 ± 5.5%; Ficoll: 29.5 ± 2.2% and 5.4 ± 4.3% respectively (p<0.01. Although comparable percentages of WB and Ficoll-PBMC monocytes expressed CCR4, CCR5 and CXCR4, Ficoll isolation significantly reduced the levels of CXCR4 (WB: MFI 5 ± 0.4 and Ficoll: MFI 3.3 ± 0.1 (p<0.05. Similarly to monocytes, CCR2, CXCR3 and CXCR4 were also reduced on lymphocytes. In addition, Ficoll isolation significantly reduced the percentage of CCR4 positive lymphocytes (WB: 90.2 ± 4.5% and Ficoll: 55 ± 4.1% (p<0.01. The loss of expression of chemokine receptors after isolation of monocytes was not dependent on either the anticoagulant or the density gradient method. It was irreversible and could not be restored by LPS activation or in vitro macrophage differentiation. Experiments tagged with anti-CCR2 antibodies prior to density gradient isolation demonstrated that Ficoll internalized chemokine receptors. The method for cell isolation may alter not only the expression of certain chemokine receptors but also the respective functional migration assay. The final choice to analyze their expression should therefore depend on the receptor to be measured.

  11. Differential Antagonism of Human Innate Immune Responses by Tick-Borne Phlebovirus Nonstructural Proteins.

    Science.gov (United States)

    Rezelj, Veronica V; Li, Ping; Chaudhary, Vidyanath; Elliott, Richard M; Jin, Dong-Yan; Brennan, Benjamin

    2017-01-01

    In recent years, several newly discovered tick-borne viruses causing a wide spectrum of diseases in humans have been ascribed to the Phlebovirus genus of the Bunyaviridae family. The nonstructural protein (NSs) of bunyaviruses is the main virulence factor and interferon (IFN) antagonist. We studied the molecular mechanisms of IFN antagonism employed by the NSs proteins of human apathogenic Uukuniemi virus (UUKV) and those of Heartland virus (HRTV) and severe fever with thrombocytopenia syndrome virus (SFTSV), both of which cause severe disease. Using reporter assays, we found that UUKV NSs weakly inhibited the activation of the beta interferon (IFN-β) promoter and response elements. UUKV NSs weakly antagonized human IFN-β promoter activation through a novel interaction with mitochondrial antiviral-signaling protein (MAVS), confirmed by coimmunoprecipitation and confocal microscopy studies. HRTV NSs efficiently antagonized both IFN-β promoter activation and type I IFN signaling pathways through interactions with TBK1, preventing its phosphorylation. HRTV NSs exhibited diffused cytoplasmic localization. This is in comparison to the inclusion bodies formed by SFTSV NSs. HRTV NSs also efficiently interacted with STAT2 and impaired IFN-β-induced phosphorylation but did not affect STAT1 or its translocation to the nucleus. Our results suggest that a weak interaction between STAT1 and HRTV or SFTSV NSs may explain their inability to block type II IFN signaling efficiently, thus enabling the activation of proinflammatory responses that lead to severe disease. Our findings offer insights into how pathogenicity may be linked to the capacity of NSs proteins to block the innate immune system and illustrate the plethora of viral immune evasion strategies utilized by emerging phleboviruses. IMPORTANCE Since 2011, there has been a large expansion in the number of emerging tick-borne viruses that have been assigned to the Phlebovirus genus. Heartland virus (HRTV) and SFTS

  12. HIV-1 Group P is unable to antagonize human tetherin by Vpu, Env or Nef

    Directory of Open Access Journals (Sweden)

    Sauter Daniel

    2011-12-01

    Full Text Available Abstract Background A new subgroup of HIV-1, designated Group P, was recently detected in two unrelated patients of Cameroonian origin. HIV-1 Group P phylogenetically clusters with SIVgor suggesting that it is the result of a cross-species transmission from gorillas. Until today, HIV-1 Group P has only been detected in two patients, and its degree of adaptation to the human host is largely unknown. Previous data have shown that pandemic HIV-1 Group M, but not non-pandemic Group O or rare Group N viruses, efficiently antagonize the human orthologue of the restriction factor tetherin (BST-2, HM1.24, CD317 suggesting that primate lentiviruses may have to gain anti-tetherin activity for efficient spread in the human population. Thus far, three SIV/HIV gene products (vpu, nef and env are known to have the potential to counteract primate tetherin proteins, often in a species-specific manner. Here, we examined how long Group P may have been circulating in humans and determined its capability to antagonize human tetherin as an indicator of adaptation to humans. Results Our data suggest that HIV-1 Group P entered the human population between 1845 and 1989. Vpu, Env and Nef proteins from both Group P viruses failed to counteract human or gorilla tetherin to promote efficient release of HIV-1 virions, although both Group P Nef proteins moderately downmodulated gorilla tetherin from the cell surface. Notably, Vpu, Env and Nef alleles from the two HIV-1 P strains were all able to reduce CD4 cell surface expression. Conclusions Our analyses of the two reported HIV-1 Group P viruses suggest that zoonosis occurred in the last 170 years and further support that pandemic HIV-1 Group M strains are better adapted to humans than non-pandemic or rare Group O, N and P viruses. The inability to antagonize human tetherin may potentially explain the limited spread of HIV-1 Group P in the human population.

  13. Estradiol and striatal dopamine receptor antagonism influence memory system bias in the female rat.

    Science.gov (United States)

    Quinlan, Matthew G; Almey, Anne; Caissie, Meghen; LaChappelle, Ivonne; Radiotis, George; Brake, Wayne G

    2013-11-01

    Estradiol (E2) has been shown to influence learning and memory systems used by female rats to find a reward. Rats with high levels of E2 tend to use allocentric, or place, memory while rats with low levels of E2 use egocentric, or response, memory. It has been shown that systemic dopamine receptor antagonism interacts with E2 to affect which memory system is used. Here, dopamine antagonists were administered directly into either the dorsal striatum or nucleus accumbens to determine where in the brain this interaction takes place. Seventy-four young adult, female, Sprague-Dawley rats were trained and tested in a modified plus-maze. All rats were ovariectomized, received a subcutaneous low E2 implant, and were implanted with bilateral cannulae into either the dorsal striatum or the nucleus accumbens. Additionally, high E2 rats received daily injections of E2 in a sesame oil solution while low E2 rats received daily injections of vehicle. After reaching criterion levels of performance in a plus-maze task, rats were administered microinjections of either a dopamine D1 receptor (SCH 23390; 0.1 μg/ml and 0.01 μg/ml) or D2 receptor (raclopride; 2 μg/ml and 0.5 μg/ml) antagonist or a vehicle control (saline) in a counterbalanced manner. High E2 rats exhibited a trend towards a place memory bias while low E2 rats showed a response memory bias. Dorsal striatal administration of a D1, but not D2, dopamine receptor antagonist caused a switch in the memory system used by both high and low E rats. There was no significant effect of dopamine receptor antagonism in the nucleus accumbens group. Thus, E2 determined which memory system controlled behavior in a plus-maze task. Moreover, this effect was modulated by dopamine D1R antagonism in the dorsal but not ventral striatum suggesting that memory systems are, in part, mediated by E2 and dopamine in this region. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Efficient Vpu-Mediated Tetherin Antagonism by an HIV-1 Group O Strain.

    Science.gov (United States)

    Mack, Katharina; Starz, Kathrin; Sauter, Daniel; Langer, Simon; Bibollet-Ruche, Frederic; Learn, Gerald H; Stürzel, Christina M; Leoz, Marie; Plantier, Jean-Christophe; Geyer, Matthias; Hahn, Beatrice H; Kirchhoff, Frank

    2017-03-15

    Simian immunodeficiency viruses (SIVs) use their Nef proteins to counteract the restriction factor tetherin. However, a deletion in human tetherin prevents antagonism by the Nef proteins of SIVcpz and SIVgor, which represent the ape precursors of human immunodeficiency virus type 1 (HIV-1). To promote virus release from infected cells, pandemic HIV-1 group M strains evolved Vpu as a tetherin antagonist, while the Nef protein of less widespread HIV-1 group O strains acquired the ability to target a region adjacent to this deletion. In this study, we identified an unusual HIV-1 group O strain (RBF206) that evolved Vpu as an effective antagonist of human tetherin. While both RBF206 Vpu and Nef exert anti-tetherin activity in transient-transfection assays, mainly Vpu promotes RBF206 release in infected CD4(+) T cells. Although mutations distinct from the adaptive changes observed in group M Vpus (M-Vpus) were critical for the acquisition of its anti-tetherin activity, RBF206 O-Vpu potently suppresses NF-κB activation and reduces CD4 cell surface expression. Interestingly, RBF206 Vpu counteracts tetherin in a largely species-independent manner, degrading both the long and short isoforms of human tetherin. Downmodulation of CD4, but not counteraction of tetherin, by RBF206 Vpu was dependent on the cellular ubiquitin ligase machinery. Our data present the first example of an HIV-1 group O Vpu that efficiently antagonizes human tetherin and suggest that counteraction by O-Nefs may be suboptimal.IMPORTANCE Previous studies showed that HIV-1 groups M and O evolved two alternative strategies to counteract the human ortholog of the restriction factor tetherin. While HIV-1 group M switched from Nef to Vpu due to a deletion in the cytoplasmic domain of human tetherin, HIV-1 group O, which lacks Vpu-mediated anti-tetherin activity, acquired a Nef protein that is able to target a region adjacent to the deletion. Here we report an unusual exception, identifying a strain of HIV-1

  15. Doxycycline and Benznidazole Reduce the Profile of Th1, Th2, and Th17 Chemokines and Chemokine Receptors in Cardiac Tissue from Chronic Trypanosoma cruzi-Infected Dogs

    Directory of Open Access Journals (Sweden)

    Guilherme de Paula Costa

    2016-01-01

    Full Text Available Chemokines (CKs and chemokine receptors (CKR promote leukocyte recruitment into cardiac tissue infected by the Trypanosoma cruzi. This study investigated the long-term treatment with subantimicrobial doses of doxycycline (Dox in association, or not, with benznidazole (Bz on the expression of CK and CKR in cardiac tissue. Thirty mongrel dogs were infected, or not, with the Berenice-78 strain of T. cruzi and grouped according their treatments: (i two months after infection, Dox (50 mg/kg 2x/day for 12 months; (ii nine months after infection, Bz (3,5 mg/kg 2x/day for 60 days; (iii Dox + Bz; and (iv vehicle. After 14 months of infection, hearts were excised and processed for qPCR analysis of Th1 (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL11, Th2 (CCL1, CCL17, CCL24, and CCL26, Th17 (CCL20 CKs, Th1 (CCR5, CCR6, and CXCR3, and Th2/Th17 (CCR3, CCR4, and CCR8 CKR, as well as IL-17. T. cruzi infection increases CCL1, CCL2, CCL4, CCL5, CCL17, CXCL10, and CCR5 expression in the heart. Dox, Bz, or Dox + Bz treatments cause a reversal of CK and CKR and reduce the expression of CCL20, IL-17, CCR6, and CXCR3. Our data reveal an immune modulatory effect of Dox with Bz, during the chronic phase of infection suggesting a promising therapy for cardiac protection.

  16. Structural Basis for Agonism and Antagonism for a Set of Chemically Related Progesterone Receptor Modulators

    Science.gov (United States)

    Lusher, Scott J.; Raaijmakers, Hans C. A.; Vu-Pham, Diep; Dechering, Koen; Lam, Tsang Wai; Brown, Angus R.; Hamilton, Niall M.; Nimz, Olaf; Bosch, Rolien; McGuire, Ross; Oubrie, Arthur; de Vlieg, Jacob

    2011-01-01

    The progesterone receptor is able to bind to a large number and variety of ligands that elicit a broad range of transcriptional responses ranging from full agonism to full antagonism and numerous mixed profiles inbetween. We describe here two new progesterone receptor ligand binding domain x-ray structures bound to compounds from a structurally related but functionally divergent series, which show different binding modes corresponding to their agonistic or antagonistic nature. In addition, we present a third progesterone receptor ligand binding domain dimer bound to an agonist in monomer A and an antagonist in monomer B, which display binding modes in agreement with the earlier observation that agonists and antagonists from this series adopt different binding modes. PMID:21849509

  17. Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism.

    Science.gov (United States)

    Chen, H S; Lipton, S A

    1997-01-01

    1. N-methyl-D-aspartic acid (NMDA)-activated currents were recorded from dissociated rat retinal ganglion cells using whole-cell recording. The NMDA open-channel blocking drug memantine was evaluated for non-competitive and/or uncompetitive components of antagonism. A rapid superfusion system was used to apply various drugs for kinetic analysis. 2. Dose-response data revealed that memantine blocked 200 microM NMDA-evoked responses with a 50% inhibition constant (IC50) of approximately 1 microM at -60 mV and an empirical Hill coefficient of approximately 1. The antagonism followed a bimolecular reaction process. This 1:1 stoichiometry is supported by the fact that the macroscopic blocking rate of memantine (kon) increased linearly with memantine concentration and the macroscopic unblocking rate (koff) was independent of it. The estimated pseudo-first order rate constant for macroscopic blockade was 4 x 10(5) M-1 S-1 and the rate constant for unblocking was 0.44 s-1. Both the blocking and unblocking actions of memantine were well fitted by a single exponential process. 3. The kon for 2 microM memantine decreased with decreasing concentrations of NMDA. By analysing kon behaviour, we estimate that memantine has minimal interaction with the closed-unliganded state of the channel. As channel open probability (Po) approached zero, a small residual action of memantine may be explained by the presence of endogenous glutamate and glycine. 4. Memantine could be trapped within the NMDA-gated channel if it was suddenly closed by fast washout of agonist. The measured gating process of channel activation and deactivation appeared at least 10-20-fold faster than the kinetics of memantine action. By combining the agonist and voltage dependence of antagonism, a trapping scheme was established for further kinetic analysis. 5. With low agonist concentrations, NMDA-gated channels recovered slowly from memantine blockade. By analysing the probability of a channel remaining blocked, we

  18. Impairments of exploration and memory after systemic or prelimbic D1-receptor antagonism in rats

    DEFF Research Database (Denmark)

    Clausen, Bettina; Schachtman, Todd R.; Mark, Louise T.

    2011-01-01

    to examine the effects on memory: cross-maze and object recognition task. Systemic administration reduced spatial exploration in cross-maze as well as in an open field test, and also reduced object exploration. Spatial (hippocampus-dependent) short-term memory was inhibited in the cross-maze and non......-spatial short-term object retention was also impaired. In contrast to these systemic effects, bilateral injections of SCH23390 into the prelimbic cortices altered neither spatial nor object exploration, but did inhibit short-term memory in both cross-maze and object recognition task. Therefore, the inhibiting......D1-receptor antagonism is known to impair rodent memory but also inhibits spontaneous exploration of stimuli to be remembered. Hypo-exploration could contribute to impaired memory by influencing event processing. In order to explore this effect, the D1 receptor antagonist, SCH23390...

  19. Transcription Factor Antagonism Controls Enteroendocrine Cell Specification from Intestinal Stem Cells.

    Science.gov (United States)

    Li, Yumei; Pang, Zhimin; Huang, Huanwei; Wang, Chenhui; Cai, Tao; Xi, Rongwen

    2017-04-20

    The balanced maintenance and differentiation of local stem cells is required for Homeostatic renewal of tissues. In the Drosophila midgut, the transcription factor Escargot (Esg) maintains undifferentiated states in intestinal stem cells, whereas the transcription factors Scute (Sc) and Prospero (Pros) promote enteroendocrine cell specification. However, the mechanism through which Esg and Sc/Pros coordinately regulate stem cell differentiation is unknown. Here, by combining chromatin immunoprecipitation analysis with genetic studies, we show that both Esg and Sc bind to a common promoter region of pros. Moreover, antagonistic activity between Esg and Sc controls the expression status of Pros in stem cells, thereby, specifying whether stem cells remain undifferentiated or commit to enteroendocrine cell differentiation. Our study therefore reveals transcription factor antagonism between Esg and Sc as a novel mechanism that underlies fate specification from intestinal stem cells in Drosophila.

  20. Numb/Numbl-Opo antagonism controls retinal epithelium morphogenesis by regulating integrin endocytosis.

    Science.gov (United States)

    Bogdanović, Ozren; Delfino-Machín, Mariana; Nicolás-Pérez, María; Gavilán, María P; Gago-Rodrigues, Inês; Fernández-Miñán, Ana; Lillo, Concepción; Ríos, Rosa M; Wittbrodt, Joachim; Martínez-Morales, Juan R

    2012-10-16

    Polarized trafficking of adhesion receptors plays a pivotal role in controlling cellular behavior during morphogenesis. Particularly, clathrin-dependent endocytosis of integrins has long been acknowledged as essential for cell migration. However, little is known about the contribution of integrin trafficking to epithelial tissue morphogenesis. Here we show how the transmembrane protein Opo, previously described for its essential role during optic cup folding, plays a fundamental role in this process. Through interaction with the PTB domain of the clathrin adaptors Numb and Numbl via an integrin-like NPxF motif, Opo antagonizes Numb/Numbl function and acts as a negative regulator of integrin endocytosis in vivo. Accordingly, numb/numbl gain-of-function experiments in teleost embryos mimic the retinal malformations observed in opo mutants. We propose that developmental regulator Opo enables polarized integrin localization by modulating Numb/Numbl, thus directing the basal constriction that shapes the vertebrate retina epithelium. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. USP10 Antagonizes c-Myc Transcriptional Activation through SIRT6 Stabilization to Suppress Tumor Formation

    Directory of Open Access Journals (Sweden)

    Zhenghong Lin

    2013-12-01

    Full Text Available The reduced protein expression of SIRT6 tumor suppressor is involved in tumorigenesis. The molecular mechanisms underlying SIRT6 protein downregulation in human cancers remain unknown. Using a proteomic approach, we have identified the ubiquitin-specific peptidase USP10, another tumor suppressor, as one of the SIRT6-interacting proteins. USP10 suppresses SIRT6 ubiquitination to protect SIRT6 from proteasomal degradation. USP10 antagonizes the transcriptional activity of the c-Myc oncogene through SIRT6, as well as p53, to inhibit cell-cycle progression, cancer cell growth, and tumor formation. To support this conclusion, we detected significant reductions in both USP10 and SIRT6 protein expression in human colon cancers. Our study discovered crosstalk between two tumor-suppressive genes in regulating cell-cycle progression and proliferation and showed that dysregulated USP10 function promotes tumorigenesis through SIRT6 degradation.

  2. Antagonism of nerve growth factor-TrkA signaling and the relief of pain.

    Science.gov (United States)

    Mantyh, Patrick W; Koltzenburg, Martin; Mendell, Lorne M; Tive, Leslie; Shelton, David L

    2011-07-01

    Nerve growth factor (NGF) was originally discovered as a neurotrophic factor essential for the survival of sensory and sympathetic neurons during development. However, in the adult NGF has been found to play an important role in nociceptor sensitization after tissue injury. The authors outline mechanisms by which NGF activation of its cognate receptor, tropomyosin-related kinase A receptor, regulates a host of ion channels, receptors, and signaling molecules to enhance acute and chronic pain. The authors also document that peripherally restricted antagonism of NGF-tropomyosin-related kinase A receptor signaling is effective for controlling human pain while appearing to maintain normal nociceptor function. Understanding whether there are any unexpected adverse events and how humans may change their behavior and use of the injured/degenerating tissue after significant pain relief without sedation will be required to fully appreciate the patient populations that may benefit from these therapies targeting NGF.

  3. Antagonism between penicillin and erythromycin against Streptococcus pneumoniae in vitro and in vivo

    DEFF Research Database (Denmark)

    Johansen, H K; Jensen, T G; Dessau, Ram

    2000-01-01

    the effect of the bactericidal agent. In this study, the possible interaction between penicillin and erythromycin was investigated in vitro and in vivo against four clinical isolates of Streptococcus pneumoniae with MICs of penicillin ranging from 0.016 to 0.5 mg/L and of erythromycin from 0. 25 to >128 mg....../L. In vitro time-kill curves were generated with clinically relevant concentrations of penicillin (10 mg/L) and erythromycin (1 mg/L), either individually or in combination. Antagonism between penicillin and erythromycin was observed for the four isolates. In vivo interaction was investigated in the mouse...... peritonitis model. After intraperitoneal inoculation, penicillin and erythromycin were given either individually or in combination. For two of the four isolates, mortality was significantly higher in the groups treated with the combination of penicillin and erythromycin than in the groups treated...

  4. Convergent evolution of argonaute-2 slicer antagonism in two distinct insect RNA viruses.

    Directory of Open Access Journals (Sweden)

    Joël T van Mierlo

    Full Text Available RNA interference (RNAi is a major antiviral pathway that shapes evolution of RNA viruses. We show here that Nora virus, a natural Drosophila pathogen, is both a target and suppressor of RNAi. We detected viral small RNAs with a signature of Dicer-2 dependent small interfering RNAs in Nora virus infected Drosophila. Furthermore, we demonstrate that the Nora virus VP1 protein contains RNAi suppressive activity in vitro and in vivo that enhances pathogenicity of recombinant Sindbis virus in an RNAi dependent manner. Nora virus VP1 and the viral suppressor of RNAi of Cricket paralysis virus (1A antagonized Argonaute-2 (AGO2 Slicer activity of RNA induced silencing complexes pre-loaded with a methylated single-stranded guide strand. The convergent evolution of AGO2 suppression in two unrelated insect RNA viruses highlights the importance of AGO2 in antiviral defense.

  5. Neuropeptide Y Y5 receptor antagonism attenuates cocaine-induced effects in mice

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Jensen, Morten; Weikop, Pia

    2012-01-01

    Rationale Several studies suggest a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. However, the NPY receptors mediating addiction-related effects remain to be determined. Objectives To explore the potential role of Y5 NPY receptors in cocaine-induced behavioural...... effects. Methods The Y5 antagonist L-152,804 and Y5-knockout (Y5-KO) mice were tested in two models of cocaine addiction-related behaviour: acute self-administration and cocaine-induced hyperactivity. We also studied effects of Y5 receptor antagonism on cocaine-induced c-fos expression and extracellular...... effects, suggesting that Y5 receptors could be a potential therapeutic target in cocaine addiction....

  6. Tetrahydro-iso-alpha Acids Antagonize Estrogen Receptor Alpha Activity in MCF-7 Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Maëlle Lempereur

    2016-01-01

    Full Text Available Tetrahydro-iso-alpha acids commonly called THIAA or Tetra are modified hop acids extracted from hop (Humulus lupulus L. which are frequently used in brewing industry mainly in order to provide beer bitterness and foam stability. Interestingly, molecular structure of tetrahydro-iso-alpha acids is close to a new type of estrogen receptor alpha (ERα antagonists aimed at disrupting the binding of coactivators containing an LxxLL motif (NR-box. In this work we show that THIAA decreases estradiol-stimulated proliferation of MCF-7 (ERα-positive breast cancer cells. Besides, we show that it inhibits ERα transcriptional activity. Interestingly, this extract fails to compete with estradiol for ERα binding and does not significantly impact the receptor turnover rate in MCF-7 cells, suggesting that it does not act like classical antiestrogens. Hence, we demonstrate that THIAA is able to antagonize ERα estradiol-induced recruitment of the LxxLL binding motif.

  7. Small molecule antagonism of oxysterol-induced Epstein-Barr virus induced gene 2 (EBI2) activation

    DEFF Research Database (Denmark)

    Benned-Jensen, Tau; Madsen, Christian M; Arfelt, Kristine N

    2013-01-01

    The Epstein-Barr virus induced gene 2 (EBI2) was recently identified as the first oxysterol-activated 7TM receptor. EBI2 is essential for B cell trafficking within lymphoid tissues and thus the humoral immune response in general. Here we characterize the antagonism of the non-peptide molecule GSK...

  8. Comparison of vascular alpha(1)-adrenoceptor antagonism of tamsulosin in oral controlled absorption system (OCAS) and modified release (MR) formulations

    NARCIS (Netherlands)

    Michel, M. C.; Korstanje, C.; Krauwinkel, W.; Shear, M.; Davies, J.; Quartel, A.

    2005-01-01

    Objective: The cardiovascular a-l-adrenoceptor (AR) antagonism of the new oral controlled absorption system (OCAS) 0.4 mg tablet formulation of tamsulosin was compared with that of the modified release (MR) 0.4 mg capsule formulation in healthy male volunteers after a single dose in the fasted

  9. Social antagonism and socio-environmental struggles in Mexico: Body, emotions and subjectivity as a combat ground against affectation

    Directory of Open Access Journals (Sweden)

    Mina Lorena Navarro Trujillo

    2010-12-01

    Full Text Available Infront of the dispossession of common, tangible and intangible assets, is emerging a new social antagonism against extractive paradigm and the commodification of life. The relationship of body and emotions emerges as a field of fight against environmental impairment, at the same time that enables an autonomous time and space for the prefiguration of a future society.

  10. Self-Regulation in Early Adolescence: Relations with Mother-Son Relationship Quality and Maternal Regulatory Support and Antagonism

    Science.gov (United States)

    Moilanen, Kristin L.; Shaw, Daniel S.; Fitzpatrick, Amber

    2010-01-01

    The purpose of the current investigation was to examine relations among maternal regulatory support, maternal antagonism, and mother-son relationship quality in relation to boys' self-regulation during early adolescence. As part of a larger longitudinal study on 263 low-income, ethnically diverse boys, multiple informants and methods were used to…

  11. Competitive androgen receptor antagonism as a factor determining the predictability of cumulative antiandrogenic effects of widely used pesticides.

    Science.gov (United States)

    Orton, Frances; Rosivatz, Erika; Scholze, Martin; Kortenkamp, Andreas

    2012-11-01

    Many pesticides in current use have recently been revealed as in vitro androgen receptor (AR) antagonists, but information about their combined effects is lacking. We investigated the combined effects and the competitive AR antagonism of pesticide mixtures. We used the MDA-kb2 assay to test a combination of eight AR antagonists that did not also possess AR agonist properties ("pure" antagonists; 8 mix: fludioxonil, fenhexamid, ortho-phenylphenol, imazalil, tebuconazole, dimethomorph, methiocarb, pirimiphos-methyl), a combination of five AR antagonists that also showed agonist activity (5 mix: cyprodinil, pyrimethanil, vinclozolin, chlorpropham, linuron), and all pesticides combined (13 mix). We used concentration addition (CA) and independent action (IA) to formulate additivity expectations, and Schild plot analyses to investigate competitive AR antagonism. A good agreement between the effects of the mixture of eight "pure" AR antagonists and the responses predicted by CA was observed. Schild plot analysis revealed that the 8 mix acted by competitive AR antagonism. However, the observed responses of the 5 mix and the 13 mix fell within the "prediction window" boundaries defined by the predicted regression curves of CA and IA. Schild plot analysis with these mixtures yielded anomalous responses incompatible with competitive receptor antagonism. A mixture of widely used pesticides can, in a predictable manner, produce combined AR antagonist effects that exceed the responses elicited by the most potent component alone. Inasmuch as large populations are regularly exposed to mixtures of antiandrogenic pesticides, our results underline the need for considering combination effects for these substances in regulatory practice.

  12. SSX2 is a novel DNA-binding protein that antagonizes polycomb group body formation and gene repression

    DEFF Research Database (Denmark)

    Gjerstorff, Morten; Greve, Katrine Buch Vidén; Møller, Jesper Bonnet

    Polycomb group (PcG) complexes regulate cellular identity through epigenetic programming of chromatin. Here, we show that SSX2, a germline-specific protein ectopically expressed in melanoma, is a chromatin-associated protein that antagonizes BMI1 and EZH2 PcG body formation and derepresses PcG ta...

  13. SSX2 is a novel DNA-binding protein that antagonizes polycomb group body formation and gene repression

    DEFF Research Database (Denmark)

    Gjerstorff, Morten Frier; Relster, Mette Marie; Greve, Katrine Buch Viden

    2014-01-01

    Polycomb group (PcG) complexes regulate cellular identity through epigenetic programming of chromatin. Here, we show that SSX2, a germline-specific protein ectopically expressed in melanoma and other types of human cancers, is a chromatin-associated protein that antagonizes BMI1 and EZH2 PcG body...

  14. The effects of conformational constraints and steric bulk in the amino acid moiety of philanthotoxins on AMPAR antagonism

    DEFF Research Database (Denmark)

    Jørgensen, Malene; Olsen, Christian A; Mellor, Ian R

    2005-01-01

    , establishing general protocols for philanthotoxin solution- and solid-phase synthesis (39-90% and 42-54% overall yields, respectively). The analogues were tested for their ability to antagonize kainate-induced currents of 2-amino-3-(3-hydroxy-5-methyl-4-isoxazoyl)propanoic acid receptors (AMPAR) expressed...

  15. Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive.

    Directory of Open Access Journals (Sweden)

    Antoine eHuart

    2015-02-01

    Full Text Available Background: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease. Currently, inhibitors of the renin angiotensin system (RAS remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed. We have recently reported that the delayed blockade of the bradykinin B1 receptor (B1R reduced the development of fibrosis in two animal models of renal fibrosis. The usefulness of new drugs also resides in outperforming the gold standards and eventually being additive or complementary to existing therapies. Methods: In this study we compared the efficacy of a B1R antagonist (B1Ra with that of an angiotensin type 1 receptor antagonist (AT1a in the unilateral ureteral obstruction (UUO model of renal fibrosis and determined whether bi-therapy presented higher efficacy than any of the drugs alone. Results: B1R antagonism was as efficient as the gold-standard AT1a treatment. However bitherapy did not improve the antifibrotic effects at the protein level. We sought for the reason of the absence of this additive effect by studying the expression of a panel of genes involved in the fibrotic process. Interestingly, at the molecular level the different drugs targeted different players of fibrosis that, however, in this severe model did not result in improved reduction of fibrosis at the protein level. Conclusions: As the B1R is induced specifically in the diseased organ and thus potentially displays low side effects it might be an interesting alternative in cases of poor tolerability to RAS inhibitors.

  16. Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive

    Science.gov (United States)

    Huart, Antoine; Klein, Julie; Gonzalez, Julien; Buffin-Meyer, Bénédicte; Neau, Eric; Delage, Christine; Calise, Denis; Ribes, David; Schanstra, Joost P.; Bascands, Jean-Loup

    2015-01-01

    Background: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease (CKD). Currently, inhibitors of the renin–angiotensin system (RAS) remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed. We have recently reported that the delayed blockade of the bradykinin B1 receptor (B1R) reduced the development of fibrosis in two animal models of renal fibrosis. The usefulness of new drugs also resides in outperforming the gold standards and eventually being additive or complementary to existing therapies. Methods: In this study we compared the efficacy of a B1R antagonist (B1Ra) with that of an angiotensin type 1 receptor antagonist (AT1a) in the unilateral ureteral obstruction (UUO) model of renal fibrosis and determined whether bi-therapy presented higher efficacy than any of the drugs alone. Results: B1R antagonism was as efficient as the gold-standard AT1a treatment. However, bitherapy did not improve the antifibrotic effects at the protein level. We sought for the reason of the absence of this additive effect by studying the expression of a panel of genes involved in the fibrotic process. Interestingly, at the molecular level the different drugs targeted different players of fibrosis that, however, in this severe model did not result in improved reduction of fibrosis at the protein level. Conclusions: As the B1R is induced specifically in the diseased organ and thus potentially displays low side effects it might be an interesting alternative in cases of poor tolerability to RAS inhibitors. PMID:25698969

  17. Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer.

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E; Tarulli, Gerard; Zarnke, Allison L; Bourgo, Ryan J; Laine, Muriel; Chang, Ya-Fang; Ma, Shihong; Dembo, Anna G; Raj, Ganesh V; Hickey, Theresa E; Tilley, Wayne D; Greene, Geoffrey L

    2016-06-01

    The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER(+) (estrogen receptor-positive)/PR(+) human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER(+)/PR(+) breast cancers should be explored.

  18. Long-term NMDAR antagonism correlates reduced astrocytic glutamate uptake with anxiety-like phenotype

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    Eduardo R Zimmer

    2015-06-01

    Full Text Available The role of glutamate N-methyl-D-Aspartate receptor (NMDAR hypofunction has been extensively studied in schizophrenia; however, less is known about its role in anxiety disorders. Recently, it was demonstrated that astrocytic GLT-1 blockade leads to an anxiety-like phenotype. Although astrocytes are capable of modulating NMDAR activity through glutamate uptake transporters, the relationship between astrocytic glutamate uptake and the development of an anxiety phenotype remains poorly explored. Here, we aimed to investigative whether long-term antagonism of NMDAR impacts anxiety-related behaviors and astrocytic glutamate uptake. Memantine, an NMDAR antagonist, was administered daily for 24 days to healthy adult CF-1 mice by oral gavage at doses of 5, 10 or 20 mg/kg. The mice were submitted to a sequential battery of behavioral tests (open field, light-dark box and elevated plus-maze tests. We then evaluated glutamate uptake activity and the immunocontents of glutamate transporters in the frontoparietal cortex and hippocampus. Our results demonstrated that long-term administration of memantine induces anxiety-like behavior in mice in the light-dark box and elevated plus-maze paradigms. Additionally, the administration of memantine decreased glutamate uptake activity in both the frontoparietal cortex and hippocampus without altering the immunocontent of either GLT-1 or GLAST. Remarkably, the memantine-induced reduction in glutamate uptake was correlated with enhancement of an anxiety-like phenotype. In conclusion, long-term NMDAR antagonism with memantine induces anxiety-like behavior that is associated with reduced glutamate uptake activity but that is not dependent on GLT-1 or GLAST protein expression. Our study suggests that NMDAR and glutamate uptake hypofunction may contribute to the development of conditions that fall within the category of anxiety disorders.

  19. Dopamine Receptor D1 Agonism and Antagonism Using a Field-Effect Transistor Assay.

    Science.gov (United States)

    Park, Seon Joo; Yang, Heehong; Lee, Seung Hwan; Song, Hyun Seok; Park, Chul Soon; Bae, Joonwon; Kwon, Oh Seok; Park, Tai Hyun; Jang, Jyongsik

    2017-06-27

    The field-effect transistor (FET) has been used in the development of diagnostic tools for several decades, leading to high-performance biosensors. Therefore, the FET platform can provide the foundation for the next generation of analytical methods. A major role of G-protein-coupled receptors (GPCRs) is in the transfer of external signals into the cell and promoting human body functions; thus, their principle application is in the screening of new drugs. The research community uses efficient systems to screen potential GPCR drugs; nevertheless, the need to develop GPCR-conjugated analytical devices remains for next-generation new drug screening. In this study, we proposed an approach for studying receptor agonism and antagonism by combining the roles of FETs and GPCRs in a dopamine receptor D1 (DRD1)-conjugated FET system, which is a suitable substitute for conventional cell-based receptor assays. DRD1 was reconstituted and purified to mimic native binding pockets that have highly discriminative interactions with DRD1 agonists/antagonists. The real-time responses from the DRD1-nanohybrid FET were highly sensitive and selective for dopamine agonists/antagonists, and their maximal response levels were clearly different depending on their DRD1 affinities. Moreover, the equilibrium constants (K) were estimated by fitting the response levels. Each K value indicates the variation in the affinity between DRD1 and the agonists/antagonists; a greater K value corresponds to a stronger DRD1 affinity in agonism, whereas a lower K value in antagonism indicates a stronger dopamine-blocking effect.

  20. RAB-7 antagonizes LET-23 EGFR signaling during vulva development in Caenorhabditis elegans.

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    Olga Skorobogata

    Full Text Available The Rab7 GTPase regulates late endosome trafficking of the Epidermal Growth Factor Receptor (EGFR to the lysosome for degradation. However, less is known about how Rab7 activity, functioning late in the endocytic pathway, affects EGFR signaling. Here we used Caenorhabditis elegans vulva cell fate induction, a paradigm for genetic analysis of EGFR/Receptor Tyrosine Kinase (RTK signaling, to assess the genetic requirements for rab-7. Using a rab-7 deletion mutant, we demonstrate that rab-7 antagonizes LET-23 EGFR signaling to a similar extent, but in a distinct manner, as previously described negative regulators such as sli-1 c-Cbl. Epistasis analysis places rab-7 upstream of or in parallel to lin-3 EGF and let-23 EGFR. However, expression of gfp::rab-7 in the Vulva Presursor Cells (VPCs is sufficient to rescue the rab-7(- VPC induction phenotypes indicating that RAB-7 functions in the signal receiving cell. We show that components of the Endosomal Sorting Complex Required for Transport (ESCRT-0, and -I, complexes, hgrs-1 Hrs, and vps-28, also antagonize signaling, suggesting that LET-23 EGFR likely transits through Multivesicular Bodies (MVBs en route to the lysosome. Consistent with RAB-7 regulating LET-23 EGFR trafficking, rab-7 mutants have increased number of LET-23::GFP-positive endosomes. Our data imply that Rab7, by mediating EGFR trafficking and degradation, plays an important role in downregulation of EGFR signaling. Failure to downregulate EGFR signaling contributes to oncogenesis, and thus Rab7 could possess tumor suppressor activity in humans.

  1. Anthranilate deteriorates the structure of Pseudomonas aeruginosa biofilms and antagonizes the biofilm-enhancing indole effect.

    Science.gov (United States)

    Kim, Soo-Kyoung; Park, Ha-Young; Lee, Joon-Hee

    2015-04-01

    Anthranilate and indole are alternative degradation products of tryptophan, depending on the bacterial species. While indole enhances the biofilm formation of Pseudomonas aeruginosa, we found that anthranilate, the tryptophan degradation product of P. aeruginosa, had an opposite effect on P. aeruginosa biofilm formation, in which anthranilate deteriorated the mushroom structure of biofilm. The anthranilate effect on biofilm formation was differentially exerted depending on the developmental stage and the presence of shear force. Anthranilate slightly accelerated the initial attachment of P. aeruginosa at the early stage of biofilm development and appeared to build more biofilm without shear force. But anthranilate weakened the biofilm structure in the late stage, deteriorating the mushroom structure of biofilms with shear force to make a flat biofilm. To investigate the interplay of anthranilate with indole in biofilm formation, biofilms were cotreated with anthranilate and indole, and the results showed that anthranilate antagonized the biofilm-enhancing effect of indole. Anthranilate was able to deteriorate the preformed biofilm. The effect of anthranilate and indole on biofilm formation was quorum sensing independent. AntR, a regulator of anthranilate-degrading metabolism was synergistically activated by cotreatment with anthranilate and indole, suggesting that indole might enhance biofilm formation by facilitating the degradation of anthranilate. Anthranilate slightly but significantly affected the cyclic diguaniylate (c-di-GMP) level and transcription of major extracellular polysaccharide (Psl, Pel, and alginate) operons. These results suggest that anthranilate may be a promising antibiofilm agent and antagonize the effect of indole on P. aeruginosa biofilm formation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  2. Des-Gamma-Carboxy Prothrombin (DCP Antagonizes the Effects of Gefitinib on Human Hepatocellular Carcinoma Cells

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    Yu-Sheng Zhang

    2015-01-01

    Full Text Available Background/Aims: Des-gamma-carboxy prothrombin (DCP, an aberrant prothrombin produced by hepatocellular carcinoma (HCC cells, is known as a marker for HCC. Recent studies indicated that high levels of DCP are associated with the malignant potential of HCC. In this study, we aimed to investigate the association of DCP with gefitinib treatment failure in HCC and whether DCP counteracts gefitinib-induced growth inhibition and apoptosis of HCC. Methods: The experiments were performed in HCC cell lines HepG2 and PLC/PRF/5. The effects of gefitinib on HCC in the presence or absence of DCP were evaluated by the 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide (MTT assay. Apoptotic cells were identified by Annexin V-FITC/PI staining. Western blotting was performed to analyze the expressions of molecules related to the apoptotic caspase-dependent pathway and epidermal growth factor receptor (EGFR pathway. Results: Gefitinib inhibited HCC cell proliferation and induced apoptosis in HCC cells. The effects of gefitinib on HCC cells were antagonized by DCP. In the presence of DCP, HCC cells were resistant to the gefitinib-induced inhibition of proliferation and stimulation of apoptosis. DCP prevented the activation of the apoptotic caspase-dependent pathway induced by gefitinib. These antagonistic effects of DCP also arose from its ability to up-regulate EGFR, c-Met and hepatocyte growth factor (HGF in HCC cells. Conclusion: DCP antagonized gefitinib-induced HCC cell growth inhibition by counteracting apoptosis and up-regulating the EGFR pathway. High levels of DCP might thus lead to low response rates or possibly no response to gefitinib in patients with HCC.

  3. Targeting chromatin defects in selected solid tumors based on oncogene addiction, synthetic lethality and epigenetic antagonism.

    Science.gov (United States)

    Morel, D; Almouzni, G; Soria, J-C; Postel-Vinay, S

    2017-02-01

    Although the role of epigenetic abnormalities has been studied for several years in cancer genesis and development, epigenetic-targeting drugs have historically failed to demonstrate efficacy in solid malignancies. However, successful targeting of chromatin remodeling deficiencies, histone writers and histone reader alterations has been achieved very recently using biomarker-driven and mechanism-based approaches. Epigenetic targeting is now one of the most active areas in drug development and could represent novel therapeutic opportunity for up to 25% of all solid tumors. We reviewed preclinical and clinical studies that described epigenetic oncogenic addictions, synthetic lethal relationships or epigenetic antagonisms in chromatin regulators. Experimental approaches, their clinical relevance and applicability, as well as corresponding on-going studies are described. The most successful approaches that have been clinically validated so far include the targeting of the BRD4-NUT fusion transcript in NUT-midline carcinoma by BET (Bromodomain Extra-Terminal) inhibitors, and the use of EZH2 (Enhancer of Zest Homolog 2) inhibitors in SMARCB1-deficient malignant rhabdoid tumors and SMARCA4-deficient ovarian small cell carcinomas. Clinical validation is still required for other synthetic lethal relationships or epigenetic antagonisms, including those described between EZH2 inhibitors and deficiencies in components of the Polycomb or SWI/SNF chromatin-remodeling complexes (including BAP1, ARID1A and PBRM1 subunits), as well as between the CREBBP and EP300 histone acetylases. Further, interplays between epigenetic modifiers and non-epigenetic cellular processes might be therapeutically exploited, and combinatorial strategies could be envisioned to overcome resistance or to sensitize cells to already approved drugs. Epigenetic-targeting drugs have historically failed proving efficacy in solid malignancies when used broadly, but novel mechanism-based approaches in molecularly

  4. Antagonism pattern detection between microRNA and target expression in Ewing's sarcoma.

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    Loredana Martignetti

    Full Text Available MicroRNAs (miRNAs have emerged as fundamental regulators that silence gene expression at the post-transcriptional and translational levels. The identification of their targets is a major challenge to elucidate the regulated biological processes. The overall effect of miRNA is reflected on target mRNA expression, suggesting the design of new investigative methods based on high-throughput experimental data such as miRNA and transcriptome profiles. We propose a novel statistical measure of non-linear dependence between miRNA and mRNA expression, in order to infer miRNA-target interactions. This approach, which we name antagonism pattern detection, is based on the statistical recognition of a triangular-shaped pattern in miRNA-target expression profiles. This pattern is observed in miRNA-target expression measurements since their simultaneously elevated expression is statistically under-represented in the case of miRNA silencing effect. The proposed method enables miRNA target prediction to strongly rely on cellular context and physiological conditions reflected by expression data. The procedure has been assessed on synthetic datasets and tested on a set of real positive controls. Then it has been applied to analyze expression data from Ewing's sarcoma patients. The antagonism relationship is evaluated as a good indicator of real miRNA-target biological interaction. The predicted targets are consistently enriched for miRNA binding site motifs in their 3'UTR. Moreover, we reveal sets of predicted targets for each miRNA sharing important biological function. The procedure allows us to infer crucial miRNA regulators and their potential targets in Ewing's sarcoma disease. It can be considered as a valid statistical approach to discover new insights in the miRNA regulatory mechanisms.

  5. The Role of the Chemokine System in Tissue Response to Prosthetic By-products Leading to Periprosthetic Osteolysis and Aseptic Loosening

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    Tereza Dyskova

    2017-08-01

    Full Text Available Millions of total joint replacements are performed annually worldwide, and the number is increasing every year. The overall proportion of patients achieving a successful outcome is about 80–90% in a 10–20-years time horizon postoperatively, periprosthetic osteolysis (PPOL and aseptic loosening (AL being the most frequent reasons for knee and hip implant failure and reoperations. The chemokine system (chemokine receptors and chemokines is crucially involved in the inflammatory and osteolytic processes leading to PPOL/AL. Thus, the modulation of the interactions within the chemokine system may influence the extent of PPOL. Indeed, recent studies in murine models reported that (i blocking the CCR2–CCL2 or CXCR2–CXCL2 axis or (ii activation of the CXCR4–CXCL12 axis attenuate the osteolysis of artificial joints. Importantly, chemokines, inhibitory mutant chemokines, antagonists of chemokine receptors, or neutralizing antibodies to the chemokine system attached to or incorporated into the implant surface may influence the tissue responses and mitigate PPOL, thus increasing prosthesis longevity. This review summarizes the current state of the art of the knowledge of the chemokine system in human PPOL/AL. Furthermore, the potential for attenuating cell trafficking to the bone–implant interface and influencing tissue responses through modulation of the chemokine system is delineated. Additionally, the prospects of using immunoregenerative biomaterials (including chemokines for the prevention of failed implants are discussed. Finally, this review highlights the need for a more sophisticated understanding of implant debris-induced changes in the chemokine system to mitigate this response effectively.

  6. Increased plasma chemokine levels in children with Prader-Willi syndrome.

    Science.gov (United States)

    Butler, Merlin G; Hossain, Waheeda; Sulsona, Carlos; Driscoll, Daniel J; Manzardo, Ann M

    2015-03-01

    Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes from the 15q11-q13 region and reportedly rearranged as a cause of autism. Additionally, increased inflammatory markers and features of autism are reported in PWS. Cytokines encoded by genes involved with inflammation, cell proliferation, migration, and adhesion play a role in neurodevelopment and could be disturbed in PWS as abnormal plasma cytokine levels are reported in autism. We analyzed 41 plasma cytokines in a cohort of well-characterized children with PWS between 5 and 11 years of age and unaffected unrelated siblings using multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Data were analyzed using ANOVA testing for effects of diagnosis, gender, body mass index (BMI) and age on the 24 cytokines meeting laboratory criteria for inclusion. No significant effects were observed for age, gender or BMI. The log-transformed levels of the 24 analyzable cytokines were examined simultaneously using MANOVA adjusting for age and gender and a main effect of diagnosis was found (P-value <0.03). Four of 24 plasma cytokine levels (MCP1, MDC, Eotaxin, RANTES) were significantly higher in children with PWS compared with controls and classified as bioinflammatory chemokines supporting a disturbed immune response unrelated to obesity status. BMI was not statistically different in the two subject groups (PWS or unaffected unrelated siblings) and chemokine levels were not correlated with percentage of total body fat. Additional studies are required to identify whether possible early immunological disturbances and chemokine inflammatory processes found in PWS may contribute to neurodevelopment and behavioral features. © 2015 Wiley Periodicals, Inc.

  7. Chemokine-mediated distribution of dendritic cell subsets in renal cell carcinoma

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    Meyer Werner

    2010-10-01

    Full Text Available Abstract Background Renal cell carcinoma (RCC represents one of the most immunoresponsive cancers. Antigen-specific vaccination with dendritic cells (DCs in patients with metastatic RCC has been shown to induce cytotoxic T-cell responses associated with objective clinical responses. Thus, clinical trials utilizing DCs for immunotherapy of advanced RCCs appear to be promising; however, detailed analyses concerning the distribution and function of DC subsets in RCCs are lacking. Methods We characterized the distribution of the different immature and mature myeloid DC subsets in RCC tumour tissue and the corresponding normal kidney tissues. In further analyses, the expression of various chemokines and chemokine receptors controlling the migration of DC subsets was investigated. Results The highest numbers of immature CD1a+ DCs were found within RCC tumour tissue. In contrast, the accumulation of mature CD83+/DC-LAMP+ DCs were restricted to the invasive margin of the RCCs. The mature DCs formed clusters with proliferating T-cells. Furthermore, a close association was observed between MIP-3α-producing tumour cells and immature CCR6+ DC recruitment to the tumour bed. Conversely, MIP-3β and SLC expression was only detected at the tumour border, where CCR7-expressing T-cells and mature DCs formed clusters. Conclusion Increased numbers of immature DCs were observed within the tumour tissue of RCCs, whereas mature DCs were found in increased numbers at the tumour margin. Our results strongly implicate that the distribution of DC subsets is controlled by local lymphoid chemokine expression. Thus, increased expression of MIP-3α favours recruitment of immature DCs to the tumour bed, whereas de novo local expression of SLC and MIP-3β induces accumulation of mature DCs at the tumour margin forming clusters with proliferating T-cells reflecting a local anti-tumour immune response.

  8. Chemokines in the cerebrospinal fluid of patients with active and stable relapsing-remitting multiple sclerosis

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    M.A. Moreira

    2006-04-01

    Full Text Available Multiple sclerosis (MS is a chronic inflammatory demyelinating disease of the human central nervous system. Although its etiology is unknown, the accumulation and activation of mononuclear cells in the central nervous system are crucial to its pathogenesis. Chemokines have been proposed to play a major role in the recruitment and activation of leukocytes in inflammatory sites. They are divided into subfamilies on the basis of the location of conserved cysteine residues. We determined the levels of some CC and CXC chemokines in the cerebrospinal fluid (CSF of 23 relapsing-remitting MS patients under interferon-ß-1a therapy and 16 control subjects using ELISA. MS patients were categorized as having active or stable disease. CXCL10 was significantly increased in the CSF of active MS patients (mean ± SEM, 369.5 ± 69.3 pg/mL when compared with controls (178.5 ± 29.1 pg/mL, P < 0.05. CSF levels of CCL2 were significantly lower in active MS (144.7 ± 14.4 pg/mL than in controls (237.1 ± 16.4 pg/mL, P < 0.01. There was no difference in the concentration of CCL2 and CXCL10 between patients with stable MS and controls. CCL5 was not detectable in the CSF of most patients or controls. The qualitative and quantitative differences of chemokines in CSF during relapses of MS suggest that they may be useful as a marker of disease activity and of the mechanisms involved in the pathogenesis of the disease.

  9. Stat3 inhibition attenuates mechanical allodynia through transcriptional regulation of chemokine expression in spinal astrocytes.

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    Xiaodong Liu

    Full Text Available BACKGROUND: Signal transducer and activator of transcription 3 (Stat3 is known to induce cell proliferation and inflammation by regulating gene transcription. Recent studies showed that Stat3 modulates nociceptive transmission by reducing spinal astrocyte proliferation. However, it is unclear whether Stat3 also contributes to the modulation of nociceptive transmission by regulating inflammatory response in spinal astrocytes. This study aimed at investigating the role of Stat3 on neuroinflammation during development of pain in rats after intrathecal injection of lipopolysaccharide (LPS. METHODS: Stat3 specific siRNA oligo and synthetic selective inhibitor (Stattic were applied to block the activity of Stat3 in primary astrocytes or rat spinal cord, respectively. LPS was used to induce the expression of proinflammatory genes in all studies. Immunofluorescence staining of cells and slices of spinal cord was performed to monitor Stat3 activation. The impact of Stat3 inhibition on proinflammatory genes expression was determined by cytokine antibody array, enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Mechanical allodynia, as determined by the threshold pressure that could induce hind paw withdrawal after application of standardized von Frey filaments, was used to detect the effects of Stat3 inhibition after pain development with intrathecal LPS injection. RESULTS: Intrathecal injection of LPS activated Stat3 in reactive spinal astrocytes. Blockade of Stat3 activity attenuated mechanical allodynia significantly and was correlated with a lower number of reactive astrocytes in the spinal dorsal horn. In vitro study demonstrated that Stat3 modulated inflammatory response in primary astrocytes by transcriptional regulation of chemokine expression including Cx3cl1, Cxcl5, Cxcl10 and Ccl20. Similarly, inhibition of Stat3 reversed the expression of these chemokines in the spinal dorsal horn. CONCLUSIONS: Stat3 acted as a

  10. The chemokine receptor CXCR3 and its splice variant are expressed in human airway epithelial cells.

    Science.gov (United States)

    Kelsen, Steven G; Aksoy, Mark O; Yang, Yi; Shahabuddin, Syed; Litvin, Judith; Safadi, Fayez; Rogers, Thomas J

    2004-09-01

    Activation of the chemokine receptor CXCR3 by its cognate ligands induces several differentiated cellular responses important to the growth and migration of a variety of hematopoietic and structural cells. In the human respiratory tract, human airway epithelial cells (HAEC) release the CXCR3 ligands Mig/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11. Simultaneous expression of CXCR3 by HAEC would have important implications for the processes of airway inflammation and repair. Accordingly, in the present study we sought to determine whether HAEC also express the classic CXCR3 chemokine receptor CXCR3-A and its splice variant CXCR3-B and hence may respond in autocrine fashion to its ligands. We found that cultured HAEC (16-HBE and tracheocytes) constitutively expressed CXCR3 mRNA and protein. CXCR3 mRNA levels assessed by expression array were approximately 35% of beta-actin expression. In contrast, CCR3, CCR4, CCR5, CCR8, and CX3CR1 were <5% beta-actin. Both CXCR3-A and -B were expressed. Furthermore, tracheocytes freshly harvested by bronchoscopy stained positively for CXCR3 by immunofluorescence microscopy, and 68% of cytokeratin-positive tracheocytes (i.e., the epithelial cell population) were positive for CXCR3 by flow cytometry. In 16-HBE cells, CXCR3 receptor density was approximately 78,000 receptors/cell when assessed by competitive displacement of 125I-labeled IP-10/CXCL10. Finally, CXCR3 ligands induced chemotactic responses and actin reorganization in 16-HBE cells. These findings indicate constitutive expression by HAEC of a functional CXC chemokine receptor, CXCR3. Our data suggest the possibility that autocrine activation of CXCR3 expressed by HAEC may contribute to airway inflammation and remodeling in obstructive lung disease by regulating HAEC migration.

  11. Expression of mRNA of chemokine receptor CXCR4 in feline mammary adenocarcinoma.

    Science.gov (United States)

    Tanabe, S; Nakadai, T; Furuoka, H; Oomachi, T; Kobayashi, Y; Omata, Y; Koyama, T; Hondo, E; Uzuka, Y; Sarashina, T; Ducusin, R J T; Shida, T; Dorf, M E

    2002-12-14

    The expression of mRNA of the chemokine receptor CXCR4 in 65 surgically resected mammary adenocarcinomas from cats was investigated by in situ hybridisation. No expression of the receptor's mRNA was detectable in the mammary tissue of healthy cats, but it was expressed in areas adjacent to necrosis, surrounding blood vessels and cells infiltrating the lymphatics of 47 (72.3 per cent) of the 65 samples. There was a significant relationship between lymphatic infiltration by neoplastic cells and the expression of the receptor's mRNA (P < 0.005), but there was no significant relationship between its expression and the one-year survival of the cats.

  12. Diversity and inter-connections in the CXCR4 chemokine receptor/ligand family: molecular perspectives

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    Lukas ePawig

    2015-08-01

    Full Text Available CXCR4 and its ligand CXCL12 mediate the homing of progenitor cells in the bone marrow and their recruitment to sites of injury, as well as affect processes such as cell arrest, survival and angiogenesis. CXCL12 was long thought to be the sole CXCR4 ligand, but more recently the atypical chemokine macrophage migration inhibitory factor (MIF was identified as an alternative, non-cognate ligand for CXCR4 and shown to mediate chemotaxis and arrest of CXCR4-expressing T-cells. This has complicated the understanding of CXCR4-mediated signaling and associated biological processes. Compared to CXCL12/CXCR4-induced signaling, only few details are known on MIF/CXCR4-mediated signaling and it remains unclear to which extent MIF and CXCL12 reciprocally influence CXCR4 binding and signaling. Furthermore, the atypical chemokine receptor ACKR3 (previously CXCR7 has added to the complexity of CXCR4 signaling due to its ability to bind CXCL12 and MIF, and evoke CXCL12- and MIF-triggered signaling independently of CXCR4. Also, extracellular ubiquitin (eUb and the viral protein gp120 (HIV have been reported as CXCR4 ligands, whereas viral chemokine vMIP-II (Herpesvirus and human beta-defensin 3 (HBD-3 have been identified as CXCR4 antagonists. This review will provide insight into the diversity and inter-connections in the CXCR4 receptor/ligand family. We will discuss signaling pathways initiated by binding of CXCL12 vs MIF to CXCR4, elaborate on how ACKR3 affects CXCR4 signaling and summarize biological functions of CXCR4 signaling mediated by CXCL12 or MIF. Also, we will discuss eUb and gp120 as alternative ligands for CXCR4, and describe vMIP-II and HBD-3 as antagonists for CXCR4. Detailed insight into biological effects of CXCR4 signaling und underlying mechanisms, including diversity of CXCR4 ligands and inter-connections with other (chemokine receptors, is clinically important, as the CXCR4 antagonist AMD3100 has been approved as stem cell mobilizer in

  13. Differential modulation of retinal degeneration by Ccl2 and Cx3cr1 chemokine signalling.

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    Ulrich F O Luhmann

    Full Text Available Microglia and macrophages are recruited to sites of retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD. Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO mice show an early onset retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to retinal telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2(-/-/Crb1(Rd8/RD8, Cx3cr1(-/-/Crb1(Rd8/RD8 and CCl2(-/-/Cx3cr1(-/-/Crb1(Rd8/RD8 mice, we observed a differential modulation of the retinal phenotype by genetic background and both chemokine signalling pathways. These

  14. Robust Cytokine and Chemokine Response in Nasopharyngeal Secretions: Association With Decreased Severity in Children With Physician Diagnosed Bronchiolitis.

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    Nicholson, Erin G; Schlegel, Chelsea; Garofalo, Roberto P; Mehta, Reena; Scheffler, Margaret; Mei, Minghua; Piedra, Pedro A

    2016-08-15

    Bronchiolitis causes substantial disease in young children. Previous findings had indicated that a robust innate immune response was not associated with a poor clinical outcome in bronchiolitis. This study tested the hypothesis that increased concentrations of cytokines and chemokines in nasal wash specimens were associated with decreased severity in bronchiolitis. Children bronchiolitis were eligible for enrollment. Nasal wash specimens were analyzed for viral pathogens and cytokine/chemokine concentrations. These results were evaluated with regard to disposition. One hundred eleven children with bronchiolitis were enrolled. A viral pathogen was identified in 91.9% of patients (respiratory syncytial virus in 51.4%, human rhinovirus in 11.7%). Higher levels of cytokines and chemokines (interferon [IFN] γ; interleukin [IL] 4, 15, and 17; CXCL10; and eotaxin) were significantly associated with a decreased risk of hospitalization. IL-17, IL-4, IFN-γ, and IFN-γ-inducible protein 10 (CXCL10 or IP-10) remained statistically significant in the multivariate analyses. The cytokines and chemokines significantly associated with decreased bronchiolitis severity are classified in a wide range of functional groups (T-helper 1 and 2, regulatory, and chemoattractant). The involvement of these functional groups suggest that a broadly overlapping cytokine/chemokine response is required for control of virus-mediated respiratory disease in young children. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  15. Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases.

    Science.gov (United States)

    Schulte, A; Schulz, B; Andrzejewski, M G; Hundhausen, C; Mletzko, S; Achilles, J; Reiss, K; Paliga, K; Weber, C; John, S Rose; Ludwig, A

    2007-06-22

    The chemokines CX3CL1/Fractalkine and CXCL16 are expressed as transmembrane molecules and can mediate cell-cell-adhesion. By proteolytic processing, CX3CL1 and CXCL16 are released from the cell surface by proteolytic shedding resulting in the generation of soluble chemoattractants. This ectodomain release is mediated by the alpha-secretase-like activity of the two disintegrins and metalloproteinases ADAM10 and ADAM17. Using CX3CL1 and CXCL16 constructs C-terminally fused to two Z-domains of Protein A (2Z-tag) we detect C-terminal fragments (CTFs) of both chemokines resulting from ADAM10-mediated cleavages at multiple sites as examined by inhibitor studies. Furthermore, inhibitor studies as well as genetic studies using presenilin 1/2-deficient cell lines suggest the involvement of gamma-secretase-but not beta-secretase-like activity in the processing of transmembrane chemokines. The combination of alpha- and gamma-secretase and proteasomal inhibitors points towards a sequential processing of transmembrane chemokines by first ADAM10 and then gamma-secretases and possible further degradation. This proteolytic processing cascade of transmembrane chemokines is similar to that described for Notch and E-cadherin where CTFs generated by gamma-secretase serve as intracellular signal transmitters.

  16. Genetic characterization of the chemokine receptor CXCR4 gene in lagomorphs: comparison between the families Ochotonidae and Leporidae.

    Science.gov (United States)

    Abrantes, J; Esteves, P J; Carmo, C R; Müller, A; Thompson, G; van der Loo, W

    2008-04-01

    Chemokines receptors are transmembrane proteins that bind chemokines. Chemokines and their receptors are known to play a crucial role in the immune system and in pathogen entry. There is evidence that myxoma virus, the causative agent of myxomatosis, can use the chemokine receptor CXCR4 to infect cells. This virus causes a benign disease in its natural host, Sylvilagus, but in the European rabbit (Oryctolagus cuniculus) it causes a highly fatal and infectious disease known as myxomatosis. We have characterized the chemokine receptor CXCR4 gene in five genera of the order Lagomorpha, Ochotona (Ochotonidae), and Oryctolagus, Lepus, Bunolagus and Sylvilagus (Leporidae). In lagomorphs, the CXCR4 is highly conserved, with most of the protein diversity found at surface regions. Five amino acid replacements were observed, two in the intracellular loops, one in the transmembrane domain and two in the extracellular loops. Oryctolagus features unique amino acid changes at the intracellular domains, putting this genus apart of all other lagomorphs. Furthermore, in the 37 European rabbits analysed, which included healthy rabbits and rabbits with clinical symptoms of myxomatosis, 14 nucleotide substitutions were obtained but no amino acid differences were observed.

  17. Cytokine and Chemokine Expression in CSF May Differentiate Viral and Autoimmune NMDAR Encephalitis in Children.

    Science.gov (United States)

    Ygberg, Sofia; Fowler, Åsa; Wickström, Ronny

    2016-11-01

    Childhood encephalitis is a potentially devastating condition with significant morbidity and mortality. Researchers currently lack biomarkers for differentiating infectious encephalitis from those with autoimmune causes which may delay adequate treatment. The authors studied the possibility of using cerebrospinal fluid cytokine and chemokine levels for this purpose. Children admitted to hospital care fulfilling criteria for encephalitis were prospectively included. Children who underwent lumbar puncture but were not classified as central nervous system infections served as controls. Cytokine and chemokine levels in the cerebrospinal fluid obtained upon initial presentation were analyzed using Luminex technology. In children with infectious encephalitis (n = 13), the cerebrospinal fluid displayed markedly elevated mean levels of IL6, IL7, and IL13 as compared to N-methyl-D-aspartate receptor (NMDAR) encephalitis (n = 4) and controls (n = 13). The expression of IL6 appeared to precede that of IL13. Analysis of selected cerebrospinal fluid cytokines may thus allow differential diagnosis of infectious and NMDAR encephalitis already at the initial lumbar puncture and enable immediate therapy. © The Author(s) 2016.

  18. Disruption of Stromal-Derived Factor-1/Chemokine Receptor 4 by Simvastatin

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    A Jalili

    2010-03-01

    Full Text Available Background: The alpha chemokine, stromal-derived factor (SDF-1 is produced by bone marrow stromal cells and other cells, especially damaged tissues. SDF-1 receptor, a chemokine receptor 4 (CXCR4, is expressed on inflammatory cells and that SDF-1/CXCR4 axis plays a critical role in migration of inflammatory cells. In cardiovascular diseases, SDF-1 is produced by endothelial cells and plaques and that SDF-1 chemoattracts monocytes to the endothelial cells resulting in a local inflammation. Simvastatin, a cholesterol-lowering agent, is a general drug for treatment of cardiovascular diseases. However, its molecular mechanism has not yet been completely elucidated.Method: Herein, we investigated the role of simvastatin on the SDF- 1/CXCR4 axis by employing flow cytometry, RT-PCR, chemotaxis and adhesion assays. Results: Simvastatin (i downregulates CXCR4 expression on monocytic cell line (THP-1 and primary monocyte in a dose-dependent manner, (ii inhibits adhesion of monocytes to endothelial cells and (iii decreases SDF-1 production by endothelial cells. Moreover, preincubation with simvastatin significantly decreased the migration of THP-1 towards the SDF-1 gradient.Conclusion: All together our data indicate that simvastatin inhibits the binding of monocytes to endothelial cells through disrupting of the SDF-1/CXCR4 axis.

  19. Relationships Between Metformin, Paraoxonase-1 and the Chemokine (C-C Motif) Ligand 2.

    Science.gov (United States)

    Camps, Jordi; Hernandez-Aguilera, Anna; Garcia-Heredia, Anabel; Cabre, Noemi; Luciano-Mateo, Fedra; Arenas, Meritxell; Joven, Jorge

    2016-01-01

    Metformin is a biguanide used in the treatment of type 2 diabetes mellitus and obesity. The main mechanism of action is to decrease the intestinal glucose absorption and the hepatic glucose production, however, it does not influence insulin secretion. Metformin also increases the affinity of the insulin receptor, reduces high insulin levels and improves insulin resistance. Additionally, it promotes weight loss. Metformin is a pleiotropic compound but acts, largely, by activating 5 adenosine monophosphate (AMP)-activated protein kinase (AMPK). Data suggest that the therapeutic effects of this compound are mediated, at least in part, through an upregulation of paraoxonase-1 (PON1) synthesis. PON1 is a thiolactonase that degrades lipid peroxides, and downregulates the chemokine (C-C motif) ligand 2 (CCL2) which is a pro-inflammatory chemokine that stimulates the migration of monocytes to areas of inflammation where they differentiate into macrophages. However, the prescription of metformin in patients with liver disease is controversial since, in some cases, this drug causes worsening of liver function. Patients with chronic liver disease have decreased hepatic PON1 activity. A study in mice deficient in PON1 showed that in this experimental model, metformin administration increased the severity of steatosis, increased CCL2 expression, did not activate AMPK, and increased the expression of the apoptosis marker caspase-9. These results suggest that PON1 is essential for the successful activation of AMPK in the liver, and for metformin to demonstrate its therapeutic function.

  20. Sex Hormones Coordinate Neutrophil Immunity in the Vagina by Controlling Chemokine Gradients.

    Science.gov (United States)

    Lasarte, Sandra; Samaniego, Rafael; Salinas-Muñoz, Laura; Guia-Gonzalez, Mauriel A; Weiss, Linnea A; Mercader, Enrique; Ceballos-García, Elena; Navarro-González, Teresa; Moreno-Ochoa, Laura; Perez-Millan, Federico; Pion, Marjorie; Sanchez-Mateos, Paloma; Hidalgo, Andres; Muñoz-Fernandez, Maria A; Relloso, Miguel

    2016-02-01

    Estradiol-based contraceptives and hormonal replacement therapy predispose women to Candida albicans infections. Moreover, during the ovulatory phase (high estradiol), neutrophil numbers decrease in the vaginal lumen and increase during the luteal phase (high progesterone). Vaginal secretions contain chemokines that drive neutrophil migration into the lumen. However, their expression during the ovarian cycle or in response to hormonal treatments are controversial and their role in vaginal defense remains unknown.To investigate the transepithelial migration of neutrophils, we used adoptive transfer of Cxcr2(-/-) neutrophils and chemokine immunofluorescence quantitative analysis in response to C. albicans vaginal infection in the presence of hormones.Our data show that the Cxcl1/Cxcr2 axis drives neutrophil transepithelial migration into the vagina. Progesterone promotes the Cxcl1 gradient to favor neutrophil migration. Estradiol disrupts the Cxcl1 gradient and favors neutrophil arrest in the vaginal stroma; as a result, the vagina becomes more vulnerable to pathogens. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  1. The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density

    Science.gov (United States)

    Lee, Kit M; Danuser, Renzo; Stein, Jens V; Graham, Delyth; Nibbs, Robert JB; Graham, Gerard J

    2014-01-01

    Macrophages regulate lymphatic vasculature development; however, the molecular mechanisms regulating their recruitment to developing, and adult, lymphatic vascular sites are not known. Here, we report that resting mice deficient for the inflammatory chemokine-scavenging receptor, ACKR2, display increased lymphatic vessel density in a range of tissues under resting and regenerating conditions. This appears not to alter dendritic cell migration to draining lymph nodes but is associated with enhanced fluid drainage from peripheral tissues and thus with a hypotensive phenotype. Examination of embryonic skin revealed that this lymphatic vessel density phenotype is developmentally established. Further studies indicated that macrophages and the inflammatory CC-chemokine CCL2, which is scavenged by ACKR2, are associated with this phenotype. Accordingly, mice deficient for the CCL2 signalling receptor, CCR2, displayed a reciprocal phenotype of reduced lymphatic vessel density. Further examination revealed that proximity of pro-lymphangiogenic macrophages to developing lymphatic vessel surfaces is increased in ACKR2-deficient mice and reduced in CCR2-deficient mice. Therefore, these receptors regulate vessel density by reciprocally modulating pro-lymphangiogenic macrophage recruitment, and proximity, to developing, resting and regenerating lymphatic vessels. PMID:25271254

  2. Alpha-mangostin inhibits both dengue virus production and cytokine/chemokine expression.

    Science.gov (United States)

    Tarasuk, Mayuri; Songprakhon, Pucharee; Chimma, Pattamawan; Sratongno, Panudda; Na-Bangchang, Kesara; Yenchitsomanus, Pa-Thai

    2017-08-15

    Since severe dengue virus (DENV) infection in humans associates with both high viral load and massive cytokine production - referred to as "cytokine storm", an ideal drug for treatment of DENV infection should efficiently inhibit both virus production and cytokine expression. In searching for such an ideal drug, we discovered that α-mangostin (α-MG), a major bioactive compound purified from the pericarp of the mangosteen fruit (Garcinia mangostana Linn), which has been used in traditional medicine for several conditions including trauma, diarrhea, wound infection, pain, fever, and convulsion, inhibits both DENV production in cultured hepatocellular carcinoma HepG2 and Huh-7 cells, and cytokine/chemokine expression in HepG2 cells. α-MG could also efficiently inhibit all four serotypes of DENV. Treatment of DENV-infected cells with α-MG (20μM) significantly reduced the infection rates of four DENV serotypes by 47-55%. α-MG completely inhibited production of DENV-1 and DENV-3, and markedly reduced production of DENV-2 and DENV-4 by 100 folds. Furthermore, it could markedly reduce cytokine (IL-6 and TNF-α) and chemokine (RANTES, MIP-1β, and IP-10) transcription. These actions of α-MG are more potent than those of antiviral agent (ribavirin) and anti-inflammatory drug (dexamethasone). Thus, α-MG is potential to be further developed as therapeutic agent for DENV infection. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. CXCL12 chemokine and GABA neurotransmitter systems crosstalk and their putative roles

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    Guyon eAlice

    2014-04-01

    Full Text Available Since CXCL12 and its receptors, CXCR4 and CXCR7, have been found in the brain, the role of this chemokine has been expanded from chemoattractant in the immune system to neuromodulatory in the brain. Several pieces of evidence suggest that this chemokine system could crosstalk with the GABAergic system, known to be the main inhibitory neurotransmitter system in the brain. Indeed, GABA and CXCL12 as well as their receptors are colocalized in many cell types including neurons and there are several examples in which these two systems interact. Several mechanisms can be proposed to explain how these systems interact, including receptor-receptor interactions, crosstalk at the level of second messenger cascades, or direct pharmacological interactions, as GABA and GABAB receptor agonists/antagonists have been shown to be allosteric modulators of CXCR4.The interplay between CXCL12/CXCR4-CXCR7 and GABA/GABAA-GABAB receptors systems could have many physiological implications in neurotransmission, cancer and inflammation. In addition, the GABAB agonist baclofen is currently used in medicine to treat spasticity in patients with spinal cord injury, cerebral palsy, traumatic brain injury, multiple sclerosis and other disorders. More recently it has also been used in the treatment of alcohol dependence and withdrawal. The allosteric effects of this agent on CXCR4 could contribute to these beneficial effects or at the opposite, to its side effects.

  4. Statins affect the presentation of endothelial chemokines by targeting to multivesicular bodies.

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    Johanna Hol

    Full Text Available BACKGROUND: In addition to lowering cholesterol, statins are thought to beneficially modulate inflammation. Several chemokines including CXCL1/growth-related oncogene (GRO-α, CXCL8/interleukin (IL-8 and CCL2/monocyte chemoattractant protein (MCP-1 are important in the pathogenesis of atherosclerosis and can be influenced by statin-treatment. Recently, we observed that atorvastatin-treatment alters the intracellular content and subcellular distribution of GRO-α in cultured human umbilical vein endothelial cells (HUVECs. The objective of this study was to investigate the mechanisms involved in this phenomenon. METHODOLOGY/ PRINCIPAL FINDINGS: The effect of atorvastatin on secretion levels and subcellular distribution of GRO-α, IL-8 and MCP-1 in HUVECs activated by interleukin (IL-1β were evaluated by ELISA, confocal microscopy and immunoelectron microscopy. Atorvastatin increased the intracellular contents of GRO-α, IL-8, and MCP-1 and induced colocalization with E-selectin in multivesicular bodies. This effect was prevented by adding the isoprenylation substrate GGPP, but not the cholesterol precursor squalene, indicating that atorvastatin exerts these effects by inhibiting isoprenylation rather than depleting the cells of cholesterol. CONCLUSIONS/ SIGNIFICANCE: Atorvastatin targets inflammatory chemokines to the endocytic pathway and multivesicular bodies and may contribute to explain the anti-inflammatory effect of statins at the level of endothelial cell function.

  5. Humoral Immune Pressure Selects for HIV-1 CXC-chemokine Receptor 4-using Variants.

    Science.gov (United States)

    Lin, Nina; Gonzalez, Oscar A; Registre, Ludy; Becerril, Carlos; Etemad, Behzad; Lu, Hong; Wu, Xueling; Lockman, Shahin; Essex, Myron; Moyo, Sikhulile; Kuritzkes, Daniel R; Sagar, Manish

    2016-06-01

    Although both C-C chemokine receptor 5 (CCR5)- and CXC chemokine receptor 4 (CXCR4)-using HIV-1 strains cause AIDS, the emergence of CXCR4-utilizing variants is associated with an accelerated decline in CD4+ T cells. It remains uncertain if CXCR4-using viruses hasten disease or if these variants only emerge after profound immunological damage. We show that exclusively CXCR4- as compared to cocirculating CCR5-utilizing variants are less sensitive to neutralization by both contemporaneous autologous plasma and plasma pools from individuals that harbor only CCR5-using HIV-1. The CXCR4-utilizing variants, however, do not have a global antigenic change because they remain equivalently susceptible to antibodies that do not target coreceptor binding domains. Studies with envelope V3 loop directed antibodies and chimeric envelopes suggest that the neutralization susceptibility differences are potentially influenced by the V3 loop. In vitro passage of a neutralization sensitive CCR5-using virus in the presence of autologous plasma and activated CD4+ T cells led to the emergence of a CXCR4-utilizing virus in 1 of 3 cases. These results suggest that in some but not necessarily all HIV-1 infected individuals humoral immune pressure against the autologous virus selects for CXCR4-using variants, which potentially accelerates disease progression. Our observations have implications for using antibodies for HIV-1 immune therapy. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  6. UNBS5162, a Novel Naphthalimide That Decreases CXCL Chemokine Expression in Experimental Prostate Cancers

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    Tatjana Mijatovic

    2008-06-01

    Full Text Available Several naphthalimides have been evaluated clinically as potential anticancer agents. UNBS3157, a naphthalimide that belongs to the same class as amonafide, was designed to avoid the specific activating metabolism that induces amonafide’s hematotoxicity. The current study shows that UNBS3157 rapidly and irreversibly hydrolyzes to UNBS5162 without generating amonafide. In vivo UNBS5162 after repeat administration significantly increased survival in orthotopic human prostate cancer models. Results obtained by the National Cancer Institute (NCI using UNBS3157 and UNBS5162 against the NCI 60 cell line panel did not show a correlation with any other compound present in the NCI database, including amonafide, thereby suggesting a unique mechanism of action for these two novel naphthalimides. Affymetrix genome-wide microarray analysis and enzyme-linked immunosorbent assay revealed that in vitro exposure of PC-3 cells to UNBS5162 (1 μM for 5 successive days dramatically decreased the expression of the proangiogenic CXCL chemokines. Histopathology additionally revealed antiangiogenic properties in vivo for UNBS5162 in the orthotopic PC-3 model. In conclusion, the present study reveals UNBS5162 to be a pan-antagonist of CXCL chemokine expression, with the compound displaying antitumor effects in experimental models of human refractory prostate cancer when administered alone and found to enhance the activity of taxol when coadministered with the taxoid.

  7. Lipopolysaccharide Biosynthesis Genes of Yersinia pseudotuberculosis Promote Resistance to Antimicrobial Chemokines.

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    David L Erickson

    Full Text Available Antimicrobial chemokines (AMCs are a recently described family of host defense peptides that play an important role in protecting a wide variety of organisms from bacterial infection. Very little is known about the bacterial targets of AMCs or factors that influence bacterial susceptibility to AMCs. In an effort to understand how bacterial pathogens resist killing by AMCs, we screened Yersinia pseudotuberculosis transposon mutants for those with increased binding to the AMCs CCL28 and CCL25. Mutants exhibiting increased binding to AMCs were subjected to AMC killing assays, which revealed their increased sensitivity to chemokine-mediated cell death. The majority of the mutants exhibiting increased binding to AMCs contained transposon insertions in genes related to lipopolysaccharide biosynthesis. A particularly strong effect on susceptibility to AMC mediated killing was observed by disruption of the hldD/waaF/waaC operon, necessary for ADP-L-glycero-D-manno-heptose synthesis and a complete lipopolysaccharide core oligosaccharide. Periodate oxidation of surface carbohydrates also enhanced AMC binding, whereas enzymatic removal of surface proteins significantly reduced binding. These results suggest that the structure of Y. pseudotuberculosis LPS greatly affects the antimicrobial activity of AMCs by shielding a protein ligand on the bacterial cell surface.

  8. Involvement of β-chemokines in the development of inflammatory demyelination

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    Leist Thomas P

    2005-02-01

    Full Text Available Abstract The importance of β-chemokines (or CC chemokine ligands – CCL in the development of inflammatory lesions in the central nervous system of patients with multiple sclerosis and rodents with experimental allergic encephalomyelitis is strongly supported by descriptive studies and experimental models. Our recent genetic scans in families identified haplotypes in the genes of CCL2, CCL3 and CCL11-CCL8-CCL13 which showed association with multiple sclerosis. Complementing the genetic associations, we also detected a distinct regional expression regulation for CCL2, CCL7 and CCL8 in correlation with chronic inflammation in multiple sclerosis brains. These observations are in consensus with previous studies, and add new data to support the involvement of CCL2, CCL7, CCL8 and CCL3 in the development of inflammatory demyelination. Along with our own data, here we review the literature implicating CCLs and their receptors (CCRs in multiple sclerosis and experimental allergic encephalomyelitis. The survey reflects that the field is in a rapid expansion, and highlights some of the pathways which might be suitable to pharmaceutical interventions.

  9. The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density.

    Science.gov (United States)

    Lee, Kit M; Danuser, Renzo; Stein, Jens V; Graham, Delyth; Nibbs, Robert J B; Graham, Gerard J

    2014-11-03

    Macrophages regulate lymphatic vasculature development; however, the molecular mechanisms regulating their recruitment to developing, and adult, lymphatic vascular sites are not known. Here, we report that resting mice deficient for the inflammatory chemokine-scavenging receptor, ACKR2, display increased lymphatic vessel density in a range of tissues under resting and regenerating conditions. This appears not to alter dendritic cell migration to draining lymph nodes but is associated with enhanced fluid drainage from peripheral tissues and thus with a hypotensive phenotype. Examination of embryonic skin revealed that this lymphatic vessel density phenotype is developmentally established. Further studies indicated that macrophages and the inflammatory CC-chemokine CCL2, which is scavenged by ACKR2, are associated with this phenotype. Accordingly, mice deficient for the CCL2 signalling receptor, CCR2, displayed a reciprocal phenotype of reduced lymphatic vessel density. Further examination revealed that proximity of pro-lymphangiogenic macrophages to developing lymphatic vessel surfaces is increased in ACKR2-deficient mice and reduced in CCR2-deficient mice. Therefore, these receptors regulate vessel density by reciprocally modulating pro-lymphangiogenic macrophage recruitment, and proximity, to developing, resting and regenerating lymphatic vessels. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

  10. Extracellular Histones Induce Chemokine Production in Whole Blood Ex Vivo and Leukocyte Recruitment In Vivo.

    Science.gov (United States)

    Westman, Johannes; Papareddy, Praveen; Dahlgren, Madelene W; Chakrakodi, Bhavya; Norrby-Teglund, Anna; Smeds, Emanuel; Linder, Adam; Mörgelin, Matthias; Johansson-Lindbom, Bengt; Egesten, Arne; Herwald, Heiko

    2015-12-01

    The innate immune system relies to a great deal on the interaction of pattern recognition receptors with pathogen- or damage-associated molecular pattern molecules. Extracellular histones belong to the latter group and their release has been described to contribute to the induction of systemic inflammatory reactions. However, little is known about their functions in the early immune response to an invading pathogen. Here we show that extracellular histones specifically target monocytes in human blood and this evokes the mobilization of the chemotactic chemokines CXCL9 and CXCL10 from these cells. The chemokine induction involves the toll-like receptor 4/myeloid differentiation factor 2 complex on monocytes, and is under the control of interferon-γ. Consequently, subcutaneous challenge with extracellular histones results in elevated levels of CXCL10 in a murine air pouch model and an influx of leukocytes to the site of injection in a TLR4 dependent manner. When analyzing tissue biopsies from patients with necrotizing fasciitis caused by Streptococcus pyogenes, extracellular histone H4 and CXCL10 are immunostained in necrotic, but not healthy tissue. Collectively, these results show for the first time that extracellular histones have an important function as chemoattractants as their local release triggers the recruitment of immune cells to the site of infection.

  11. Endothelial Cells Enhance Tumor Cell Invasion through a Crosstalk Mediated by CXC Chemokine Signaling

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    Kristy A. Warner

    2008-02-01

    Full Text Available Field cancerization involves the lateral spread of premalignant or malignant disease and contributes to the recurrence of head and neck tumors. The overall hypothesis underlying this work is that endothelial cells actively participate in tumor cell invasion by secreting chemokines and creating a chemotactic gradient for tumor cells. Here we demonstrate that conditioned medium from head and neck tumor cells enhance Bcl-2 expression in neovascular endothelial cells. Oral squamous cell carcinoma-3 (OSCC3 and Kaposi's sarcoma (SLK show enhanced invasiveness when cocultured with pools of human dermal microvascular endothelial cells stably expressing Bcl-2 (HDMEC-Bcl-2, compared to cocultures with empty vector controls (HDMEC-LXSN. Xenografted OSCC3 tumors vascularized with HDMEC-Bcl-2 presented higher local invasion than OSCC3 tumors vascularized with control HDMEC-LXSN. CXCL1 and CXCL8 were upregulated in primary endothelial cells exposed to vascular endothelial growth factor (VEGF, as well as in HDMEC-Bcl-2. Notably, blockade of CXCR2 signaling, but not CXCR1, inhibited OSCC3 and SLK invasion toward endothelial cells. These data demonstrate that CXC chemokines secreted by endothelial cells induce tumor cell invasion and suggest that the process of lateral spread of tumor cells observed in field cancerization is guided by chemotactic signals that originated from endothelial cells.

  12. The chemokine fractalkine inhibits Fas-mediated cell death of brain microglia.

    Science.gov (United States)

    Boehme, S A; Lio, F M; Maciejewski-Lenoir, D; Bacon, K B; Conlon, P J

    2000-07-01

    Fractalkine is a CX3C-family chemokine, highly and constitutively expressed on the neuronal cell surface, for which a clear CNS physiological function has yet to be determined. Its cognate receptor, CX3CR-1, is constitutively expressed on microglia, the brain-resident macrophages; however, these cells do not express fractalkine. We now show that treatment of microglia with fractalkine maintains cell survival and inhibits Fas ligand-induced cell death in vitro. Biochemical characterization indicates that this occurs via mechanisms that may include 1) activation of the phosphatidylinositol-3 kinase/protein kinase B pathway, resulting in phosphorylation and blockade of the proapoptotic functions of BAD; 2) up-regulation of the antiapoptotic protein Bcl-xL; and 3) inhibition of the cleavage of BH3-interacting domain death agonist (BID). The observation that fractalkine serves as a survival factor for primary microglia in part by modulating the protein levels and the phosphorylation status of Bcl-2 family proteins reveals a novel physiological role for chemokines. These results, therefore, suggest that the interaction between fractalkine and CX3CR-1 may play an important role in promoting and preserving microglial cell survival in the CNS.

  13. The chemokines CCR1 and CCRL2 have a role in colorectal cancer liver metastasis.

    Science.gov (United States)

    Akram, Israa G; Georges, Rania; Hielscher, Thomas; Adwan, Hassan; Berger, Martin R

    2016-02-01

    C-C chemokine receptor type 1 (CCR1) and chemokine C-C motif receptor-like 2 (CCRL2) have not yet been sufficiently investigated for their role in colorectal cancer (CRC). Here, we investigated their expression in rat and human CRC samples, their modulation of expression in a rat liver metastasis model, as well as the effects on cellular properties resulting from their knockdown. One rat and five human colorectal cancer cell lines were used. CC531 rat colorectal cells were injected via the portal vein into rats and re-isolated from rat livers after defined periods. Following mRNA isolation, the gene expression was investigated by microarray. In addition, all cell lines were screened for mRNA expression of CCR1 and CCRL2 by reverse transcription polymerase chain reaction (RT-PCR). Cell lines with detectable expression were used for knockdown experiments; and the respective influence was determined on the cells' proliferation, scratch closure, and colony formation. Finally, specimens from the primaries of 50 patients with CRC were monitored by quantitative RT-PCR for CCR1 and CCRL2 expression levels. The microarray studies showed peak increases of CCR1 and CCRL2 in the early phase of liver colonization. Knockdown was sufficient at mRNA but only moderate at protein levels and resulted in modest but significant inhibition of proliferation (p cancer liver metastasis.

  14. DISTINCT CHEMOKINE RECEPTOR AXES REGULATE T HELPER 9 CELL TRAFFICKING TO ALLERGIC AND AUTOIMMUNE INFLAMMATORY SITES

    Science.gov (United States)

    Kara, Ervin E.; Comerford, Iain; Bastow, Cameron R.; Fenix, Kevin A.; Litchfield, Wendel; Handel, Tracy M.; McColl, Shaun R.

    2013-01-01

    Migration of TH cells to peripheral sites of inflammation is essential for execution of their effector function. The recently described TH9 subset characteristically produces IL-9 and has been implicated in both allergy and autoimmunity. Despite this, the migratory properties of TH9 cells remain enigmatic. In this study, we have examined chemokine receptor usage by TH9 cells and demonstrate, in models of allergy and autoimmunity, that these cells express functional CCR3, CCR6 and CXCR3, chemokine receptors commonly associated with other, functionally opposed, effector TH subsets. Most TH9 cells that express CCR3 also express CXCR3 and CCR6 and expression of these receptors appears to account for the recruitment of TH9 cells to disparate inflammatory sites. During allergic inflammation, TH9 cells utilize CCR3 and CCR6 but not CXCR3 to home to the peritoneal cavity, whereas TH9 homing to the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE) involves CXCR3 and CCR6 but not CCR3. These data provide the first insights into regulation of TH9 cell trafficking in allergy and autoimmunity. PMID:23797668

  15. Distinct chemokine receptor axes regulate Th9 cell trafficking to allergic and autoimmune inflammatory sites.

    Science.gov (United States)

    Kara, Ervin E; Comerford, Iain; Bastow, Cameron R; Fenix, Kevin A; Litchfield, Wendel; Handel, Tracy M; McColl, Shaun R

    2013-08-01

    Migration of Th cells to peripheral sites of inflammation is essential for execution of their effector function. The recently described Th9 subset characteristically produces IL-9 and has been implicated in both allergy and autoimmunity. Despite this, the migratory properties of Th9 cells remain enigmatic. In this study, we examined chemokine receptor usage by Th9 cells and demonstrate, in models of allergy and autoimmunity, that these cells express functional CCR3, CCR6, and CXCR3, chemokine receptors commonly associated with other, functionally opposed effector Th subsets. Most Th9 cells that express CCR3 also express CXCR3 and CCR6, and expression of these receptors appears to account for the recruitment of Th9 cells to disparate inflammatory sites. During allergic inflammation, Th9 cells use CCR3 and CCR6, but not CXCR3, to home to the peritoneal cavity, whereas Th9 homing to the CNS during experimental autoimmune encephalomyelitis involves CXCR3 and CCR6 but not CCR3. To our knowledge, these data provide the first insights into regulation of Th9 cell trafficking in allergy and autoimmunity.

  16. The CXCL12/CXCR4 chemokine ligand/receptor axis in cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Yvonne eDöring

    2014-06-01

    Full Text Available The chemokine receptor CXCR4 and its ligand CXCL12 play an important homeostatic function by mediating the homing of progenitor cells in the bone marrow and regulating their mobilization into peripheral tissues upon injury or stress. Although the CXCL12/CXCR4 interaction has long been regarded as a monogamous relation, the identification of the pro-inflammatory chemokine MIF as an important second ligand for CXCR4, and of CXCR7 as an alternative receptor for CXCL12, has undermined this interpretation and has considerably complicated the understanding of CXCL12/CXCR4 signaling and associated biological functions. This review aims to provide insight into the current concept of the CXCL12/CXCR4 axis in myocardial infarction and its underlying pathologies such as atherosclerosis and injury-induced vascular restenosis. It will discuss main findings from in vitro studies, animal experiments and large-scale genome-wide association studies. The importance of the CXCL12/CXCR4 axis in progenitor cell homing and mobilization will be addressed, as will be the function of CXCR4 in different cell types involved in atherosclerosis. Finally, a potential translation of current knowledge on CXCR4 into future therapeutical application will be discussed.

  17. Tissue-specific regulation of CXCL9/10/11 chemokines in keratinocytes: Implications for oral inflammatory disease.

    Directory of Open Access Journals (Sweden)

    Alison Marshall

    Full Text Available The IFN-γ-inducible chemokines CXCL9, CXCL10, and CXCL11 play a key role in many inflammatory conditions, particularly those mediated by T cells. Therefore, the production of these chemokines in peripheral tissues could be instrumental in the pathophysiology of tissue-specific immunological diseases such as oral lichen planus (OLP. In the present study, we assessed the production of keratinocyte-derived CXCL9/10/11 under basal and inflammatory conditions and investigated whether these chemokines were involved in the pathogenesis of OLP. We used semi-quantitative PCR, ELISA, chemotaxis assays, and fluorescence-activated cell sorting (FACS to assess the expression and functional role of CXCL9/10/11 in oral keratinocytes (three strains of normal human oral keratinocytes (NHOK, and the H357 oral cancer cell line in the presence or absence of IFN-γ. CXCL9/10/11 were also assessed in tissues from normal patients and those with oral lichen planus (OLP. The time course study in oral keratinocytes treated with IFN-γ showed that expression of CXCL9/10/11 chemokines was significantly enhanced by IFN-γ in a time-dependent manner. In particular, CXCL10, a prominent chemokine that was overexpressed by IFN-γ-stimulated NHOK, was able to effectively recruit CD4 lymphocytes, mainly CD4+CD45RA- cells. Significantly higher levels of CXCL9/10/11 were found in tissues from patients with OLP compared to normal oral mucosa. Taken together, the results demonstrate that normal oral keratinocytes produce chemotactic molecules that mediate T cell recruitment. This study furthers understanding of chemokine production in oral keratinocytes and their role in the pathophysiology of oral mucosa, with particular relevance to OLP.

  18. Effects of leukotriene B4 on interleukin-32, interferon-γ and chemokines in rats with rheumatoid arthritis.

    Science.gov (United States)

    Bi, Danyan; Bi, Danqing; Zhong, Ming; Zhang, Hong; Jin, Song; Ma, Sha; Luo, Huayou

    2017-10-01

    The objective of this study was to investigate the effects of leukotriene B4 (LTB4) on the expression of interleukin-32 (IL-32) interferon-γ (IFN-γ) and chemokine monocyte chemoattractant protein (MCP-1) and macrophage inhibitory protein (MIP-1α) in rheumatoid arthritis (RA). The rat model of RA collagen induced-arthritis (CIA) was established. The levels of LTB4, interleukin-32, IFN-γ and chemokines MCP-1 and MIP-1α in CIA rats were detected by ELISA. After the rat synovial cells were isolated and treated with different concentrations of LTB4, the effect of LTB4 the expression of IL-32, IFN-γ and chemokines MCP-1 and MIP-1α mRNA in synovial cells was detected by real-time quantitative PCR, the effect of LTB4 on protein expression was detected by immunoblotting. The effects of different concentrations of LTB4 on the viability and apoptosis of synovial cells were detected by LDH and cell proliferation reagent WST-1. Compared with the control group, the levels of LTB4, IL-32, IFN-γ and chemokines MCP-1 and MIP-1α were significantly increased in the serum of the CIA group. After treatment of CIA rat synovial cells with different concentrations of LTB4, the expression of IL-32, IFN-γ and chemokines MCP-1 and MIP-1α mRNA and protein were increased with significant differences among groups. WST-1 and flow cytometry showed that LTB4 had significant toxic effects on synovial cells and promoted apoptosis. In conclusion, LTB4 promotes the expression of interleukin-32, IFN-γ and chemokines MCP-1 and MIP-1α in synovial cells and facilitates apoptosis of synovial cells.

  19. Human Macrophage–derived Chemokine (MDC), a Novel Chemoattractant for Monocytes, Monocyte-derived Dendritic Cells, and Natural Killer Cells

    Science.gov (United States)

    Godiska, Ronald; Chantry, David; Raport, Carol J.; Sozzani, Silvano; Allavena, Paola; Leviten, Dina; Mantovani, Alberto; Gray, Patrick W.

    1997-01-01

    A cDNA encoding a novel human chemokine was isolated by random sequencing of cDNA clones from human monocyte-derived macrophages. This protein has been termed macrophagederived chemokine (MDC) because it appears to be synthesized specifically by cells of the macrophage lineage. MDC has the four-cysteine motif and other highly conserved residues characteristic of CC chemokines, but it shares <35% identity with any of the known chemokines. Recombinant MDC was expressed in Chinese hamster ovary cells and purified by heparin– Sepharose chromatography. NH2-terminal sequencing and mass spectrophotometry were used to verify the NH2 terminus and molecular mass of recombinant MDC (8,081 dalton). In microchamber migration assays, monocyte-derived dendritic cells and IL-2–activated natural killer cells migrated to MDC in a dose-dependent manner, with a maximal chemotactic response at 1 ng/ml. Freshly isolated monocytes also migrated toward MDC, but with a peak response at 100 ng/ml MDC. Northern analyses indicated MDC is highly expressed in macrophages and in monocyte-derived dendritic cells, but not in monocytes, natural killer cells, or several cell lines of epithelial, endothelial, or fibroblast origin. High expression was also detected in normal thymus and less expression in lung and spleen. Unlike most other CC chemokines, MDC is encoded on human chromosome 16. MDC is thus a unique member of the CC chemokine family that may play a fundamental role in the function of dendritic cells, natural killer cells, and monocytes. PMID:9151897

  20. Human macrophage-derived chemokine (MDC), a novel chemoattractant for monocytes, monocyte-derived dendritic cells, and natural killer cells.

    Science.gov (United States)

    Godiska, R; Chantry, D; Raport, C J; Sozzani, S; Allavena, P; Leviten, D; Mantovani, A; Gray, P W

    1997-05-05

    A cDNA encoding a novel human chemokine was isolated by random sequencing of cDNA clones from human monocyte-derived macrophages. This protein has been termed macrophage-derived chemokine (MDC) because it appears to be synthesized specifically by cells of the macrophage lineage. MDC has the four-cysteine motif and other highly conserved residues characteristic of CC chemokines, but it shares <35% identity with any of the known chemokines. Recombinant MDC was expressed in Chinese hamster ovary cells and purified by heparin-Sepharose chromatography. NH2-terminal sequencing and mass spectrophotometry were used to verify the NH2 terminus and molecular mass of recombinant MDC (8,081 dalton). In microchamber migration assays, monocyte-derived dendritic cells and IL-2-activated natural killer cells migrated to MDC in a dose-dependent manner, with a maximal chemotactic response at 1 ng/ml. Freshly isolated monocytes also migrated toward MDC, but with a peak response at 100 ng/ml MDC. Northern analyses indicated MDC is highly expressed in macrophages and in monocyte-derived dendritic cells, but not in monocytes, natural killer cells, or several cell lines of epithelial, endothelial, or fibroblast origin. High expression was also detected in normal thymus and less expression in lung and spleen. Unlike most other CC chemokines, MDC is encoded on human chromosome 16. MDC is thus a unique member of the CC chemokine family that may play a fundamental role in the function of dendritic cells, natural killer cells, and monocytes.

  1. DNA vaccination against a fish rhabdovirus promotes an early chemokine-related recruitment of B cells to the muscle.

    Science.gov (United States)

    Castro, Rosario; Martínez-Alonso, Susana; Fischer, Uwe; Haro, Neila Álvarez de; Soto-Lampe, Verónica; Wang, Tiehui; Secombes, Christopher J; Lorenzen, Niels; Lorenzen, Ellen; Tafalla, Carolina

    2014-02-26

    In fish, intramuscular (i.m) injection of plasmid DNA encoding viral proteins has proved a highly effective vaccination strategy against some viral pathogens. The efficacy of DNA vaccination in teleost fish is based on the high level of viral antigen expression in muscle cells inducing a strong and long-lasting protection. However, the mechanisms through which this protection is established and effectuated in fish are still not fully understood. Moreover, similarities to mammalian models cannot be established since DNA vaccination in mammals usually induces much weaker responses. In this work, we have focused on the characterization of the immune cells that infiltrate the muscle at the site of DNA injection in vaccinated fish and the chemokines and chemokine receptors that may be involved in their infiltration. We have demonstrated through diverse techniques that B lymphocytes, both IgM⁺ and IgT⁺ cells, represented a major infiltrating cell type in fish vaccinated with a viral haemorrhagic septicaemia virus (VHSV) glycoprotein-encoding DNA vaccine, whereas in control fish injected with an oil adjuvant mainly granulocyte/monocyte-type cells were attracted. Among twelve chemokine genes studied, only CXCL11_L1, CK5B and CK6 mRNA levels were up-regulated in DNA vaccinated fish compared to fish injected with the corresponding vector backbone. Furthermore, the transcription of CXCR3B, a possible receptor for CXCL11_L1 was also significantly up-regulated in vaccinated fish. Finally, experiments performed with recombinant trout CK5B and CK6 and chemokine expression plasmids revealed that these chemokines have chemotactic capacities which might explain the recruitment of B cells to the site of DNA injection. Altogether, our results reveal that there is an early chemokine-related B cell recruitment triggered by i.m. DNA vaccination against VHSV which might play an important role in the initial phase of the immune response. Copyright © 2013 Elsevier Ltd. All rights

  2. Pathway-selective suppression of chemokine receptor signaling in B cells by LPS through downregulation of PLC-β2

    Science.gov (United States)

    Shirakawa, Aiko-Konno; Liao, Fang; Zhang, Hongwei H; Hedrick, Michael N; Singh, Satya P; Wu, Dianqing; Farber, Joshua M

    2010-01-01

    Lymphocyte activation leads to changes in chemokine receptor expression. There are limited data, however, on how lymphocyte activators can alter chemokine signaling by affecting downstream pathways. We hypothesized that B cell-activating agents might alter chemokine responses by affecting downstream signal transducers, and that such effects might differ depending on the activator. We found that activating mouse B cells using either anti-IgM or lipopolysaccharide (LPS) increased the surface expression of CCR6 and CCR7 with large increases in chemotaxis to their cognate ligands. By contrast, while anti-IgM also led to enhanced calcium responses, LPS-treated cells showed only small changes in calcium signaling as compared with cells that were freshly isolated. Of particular interest, we found that LPS caused a reduction in the level of B-cell phospholipase C (PLC)-β2 mRNA and protein. Data obtained using PLC-β2−/− mice showed that the β2 isoform mediates close to one-half the chemokine-induced calcium signal in resting and anti-IgM-activated B cells, and we found that calcium signals in the LPS-treated cells were boosted by increasing the level of PLC-β2 using transfection, consistent with a functional effect of downregulating PLC-β2. Together, our results show activator-specific effects on responses through B-cell chemokine receptors that are mediated by quantitative changes in a downstream signal-transducing protein, revealing an activity for LPS as a downregulator of PLC-β2, and a novel mechanism for controlling chemokine-induced signals in lymphocytes. PMID:20871625

  3. The role of the CXCL12 – CXCR4 chemokine ligand – receptor interaction in the metastasis of prostate cancer

    OpenAIRE

    Arya, M

    2011-01-01

    The aim was to investigate whether chemokine ligand – receptor interactions are involved in the chemotaxis of prostate cancer to favoured metastatic sites. Initially, chemokine receptor mRNA expression, CXCR and CCR groups, was determined using conventional RT-PCR in cell lines derived from prostate cancer metastases, DU145, LNCaP and PC3, the primary prostate cancer cell line 1542 CPT3X and the normal prostate epithelial/ stromal cell lines 1542 NPTX, Pre 2.8 and S2.13. It ...

  4. Modulation of Chemokine Gene Expression in CD133 Cord Blood-Derived Human Mast Cells by Cyclosporin A and Dexamethasone

    DEFF Research Database (Denmark)

    Holm, Mette; Kvistgaard, Helene; Dahl, Christine

    2006-01-01

    following receptor mediated mast cell activation or following pharmacological activation of specific signal transduction cascades that become activated upon classical FcepsilonRI receptor crosslinking. We demonstrate that chemokine genes encoding IL-8, MCP-1, MIP-1alpha, and MIP-1beta are induced...... 150-fold, which vastly exceeds the yields of conventional protocols using CD34(+) cells as a source of progenitors. Taking advantage of the large quantities of in vitro differentiated mast cells, here we assess at the levels of transcription and translation the kinetics of chemokine gene induction...

  5. Selective elimination of high constitutive activity or chemokine binding in the human herpesvirus 8 encoded seven transmembrane oncogene ORF74

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Kledal, T N; Holst, Peter Johannes

    2000-01-01

    Open reading frame 74 (ORF74) encoded by human herpesvirus 8 is a highly constitutively active seven transmembrane (7TM) receptor stimulated by angiogenic chemokines, e.g. growth-related oncogene-alpha, and inhibited by angiostatic chemokines e.g. interferon-gamma-inducible protein. Transgenic mice...... either agonist or inverse agonist modulation as well as high constitutive activity of the virally encoded oncogene ORF74 and that these mutant forms presumably can be used in transgenic animals to identify the molecular mechanism of its transforming activity....

  6. Randomly Amplified Polymorphic DNA of Trichoderma isolates and antagonism against Rhizoctonia solani

    Directory of Open Access Journals (Sweden)

    Larissa Brandão Góes

    2002-06-01

    Full Text Available Random Amplified Polymorphic DNA (RAPD procedure was used to examine the genetic variability among fourteen isolates of Trichoderma and their ability to antagonize Rhizoctonia solani using a dual-culture assay for correlation among RAPD products and their hardness to R. solani. Seven oligodeoxynucleotide primers were selected for the RAPD assays which resulted in 197 bands for 14 isolates of Trichoderma. The data were entered into a binary matrix and a similarity matrix was constructed using DICE similarity (SD index. A UPGMA cluster based on SD values was generated using NTSYS (Numerical Taxonomy System, Applied Biostatistics computer program. A mean coefficient of similarity obtained for pairwise comparisons among the most antagonics isolates was around 40%. The results presented here showed that the variability among the isolates of Trichoderma was very high. No relationship was found between the polymorphism showed by the isolates and their hardness, origin and substrata.A técnica de RAPD (Random Amplified Polymorphic DNA foi utilizada para examinar a variabilidade genética em quatorze isolados de Trichoderma além de sua capacidade de antagonizar o fungo fitopatogênico Rhizoctonia solani usando pareamento in vitro, e a possível relação entre perfís de RAPD e agressividade dos isolados de Trichoderma a R. solani. Foram selecionados sete primers para os ensaios de RAPD, os quais produziram 197 bandas. Os dados foram introduzidos no programa de computador NTSYS (Numerical Taxonomy System, Applied Biostatisticsna forma de uma matrix binária, sendo construída uma matriz de similaridade utilizando-se o coeficiente de similaridade de DICE (SD e baseado nos valores SD, pelo método de agrupamento UPGMA um dendrograma. Observou-se que o grau de similaridade das amostras que apresentaram melhor desempenho antagônico foi bastante baixo, em torno de 40%. Os resultados demonstraram que a variabilidade entre os isolados de Trichoderma é muito

  7. The parental antagonism theory of language evolution: preliminary evidence for the proposal.

    Science.gov (United States)

    Brown, William M

    2011-04-01

    not maternally silenced Alu elements are positively correlated with language diversity. Furthermore, there is a much higher than expected frequency of Alu elements inserted into the protein-coding machinery of imprinted and X-chromosomal language loci compared with nonimprinted language loci. Taken together these findings provide some support for parental antagonism theory. Unlike previous theories for language evolution, parental antagonism theory generates testable predictions at the proximate (e.g., neurocognitive areas important for social transmission and language capacities), ontogenetic (e.g., the function of language at different points of development), ultimate (e.g., inclusive fitness), and phylogenetic levels (e.g., the spread of maternally derived brain components in mammals, particularly in the hominin lineage), thus making human capacities for culture more tractable than previously thought.

  8. Interleukin-17 (IL-17) expression is reduced during acute myocardial infarction: role on chemokine receptor expression in monocytes and their in vitro chemotaxis towards chemokines.

    Science.gov (United States)

    Troitskaya, Maria; Baysa, Anton; Vaage, Jarle; Sand, Kristin L; Maghazachi, Azzam A; Valen, Guro

    2012-11-30

    The roles of immune cells and their soluble products during myocardial infarction (MI) are not completely understood. Here, we observed that the percentages of IL-17, but not IL-22, producing cells are reduced in mice splenocytes after developing MI. To correlate this finding with the functional activity of IL-17, we sought to determine its effect on monocytes. In particular, we presumed that this cytokine might affect the chemotaxis of monocytes important for cardiac inflammation and remodeling. We observed that IL-17 tends to reduce the expression of two major chemokine receptors involved in monocyte chemotaxis, namely CCR2 and CXCR4. Further analysis showed that monocytes pretreated with IL-17 have reduced in vitro chemotaxis towards the ligand for CCR2, i.e., MCP-1/CCL2, and the ligand for CXCR4, i.e., SDF-1α/CXCL12. Our results support the possibility that IL-17 may be beneficial in MI, and this could be due to its ability to inhibit the migration of monocytes.

  9. CXC-chemokines KC and macrophage inflammatory protein-2 (MIP-2) synergistically induce leukocyte recruitment to the central nervous system in rats

    NARCIS (Netherlands)

    Zwijnenburg, Petra J. G.; Polfliet, Machteld M. J.; Florquin, Sandrine; van den Berg, Timo K.; Dijkstra, Christine D.; van Deventer, Sander J. H.; Roord, John J.; van der Poll, Tom; van Furth, A. Marceline

    2003-01-01

    Intracisternal injection of the CXC-chemokines KC or macrophage inflammatory protein (MIP)-2 induced a pleocytosis in the cerebrospinal fluid (CSF) of rats in a dose dependent way. MIP-2 was much more potent than KC. The concurrent injection of both chemokines revealed a profound synergistic effect

  10. CXC-chemokines KC and macrophage inflammatory protein-2 (MIP-2) synergistically induce leukocyte recruitment to the central nervous system in rats.

    NARCIS (Netherlands)

    Zwijnenburg, P.J.G.; Polfliet, MM; Florquin, S; Berg, van den T.K.; Dijkstra, C.D.; Deventer, van S.J.; Roord, J.J.; Poll, van der T.; Furth, van A.M.

    2003-01-01

    Intracisternal injection of the CXC-chemokines KC or macrophage inflammatory protein (MIP)-2 induced a pleocytosis in the cerebrospinal fluid (CSF) of rats in a dose dependent way. MIP-2 was much more potent than KC. The concurrent injection of both chemokines revealed a profound synergistic effect

  11. Neuropeptide Y Y5 receptor antagonism causes faster extinction and attenuates reinstatement in cocaine-induced place preference

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Wörtwein, Gitta; Fink-Jensen, Anders

    2013-01-01

    , and reinstatement of cocaine-induced CPP was absent. The development of CPP for cocaine was similar between Y5-KO and WT mice. Taken together, the present data show that Y5 antagonism attenuates relapse to cocaine addiction-related behavior. Prevention of relapse is considered to be of pivotal importance......Several studies have suggested a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. Recently, our group showed a role for the NPY Y5 receptor in the modulation of acute reinforcing effects of cocaine using self-administration and hyperlocomotion paradigms....... In the present study, we further explored potential anti-addiction-related effects of Y5 antagonism in another murine model of cocaine addiction-related behavior: conditioned place-preference (CPP). Using this model, it was tested whether blockade or deficiency of the NPY Y5 receptor could influence...

  12. An immune paradox: how can the same chemokine axis regulate both immune tolerance and activation?: CCR6/CCL20: a chemokine axis balancing immunological tolerance and inflammation in autoimmune disease.

    Science.gov (United States)

    Comerford, Iain; Bunting, Mark; Fenix, Kevin; Haylock-Jacobs, Sarah; Litchfield, Wendel; Harata-Lee, Yuka; Turvey, Michelle; Brazzatti, Julie; Gregor, Carly; Nguyen, Phillip; Kara, Ervin; McColl, Shaun R

    2010-12-01

    Chemokines (chemotactic cytokines) drive and direct leukocyte traffic. New evidence suggests that the unusual CCR6/CCL20 chemokine receptor/ligand axis provides key homing signals for recently identified cells of the adaptive immune system, recruiting both pro-inflammatory and suppressive T cell subsets. Thus CCR6 and CCL20 have been recently implicated in various human pathologies, particularly in autoimmune disease. These studies have revealed that targeting CCR6/CCL20 can enhance or inhibit autoimmune disease depending on the cellular basis of pathogenesis and the cell subtype most affected through different CCR6/CCL20 manipulations. Here, we discuss the significance of this chemokine receptor/ligand axis in immune and inflammatory functions, consider the potential for targeting CCR6/CCL20 in human autoimmunity and propose that the shared evolutionary origins of pro-inflammatory and regulatory T cells may contribute to the reason why both immune activation and regulation might be controlled through the same chemokine pathway. Copyright © 2010 WILEY Periodicals, Inc.

  13. Innate immune activation of NFκB and its antagonism by poxviruses.

    Science.gov (United States)

    Brady, Gareth; Bowie, Andrew G

    2014-10-01

    In recent years there has been an acceleration of discovery in the field of innate anti-viral immunity to the point that many of the key events in early virus sensing and the discrete anti-viral responses they trigger have been elucidated in detail. In particular, pattern recognition receptors (PRRs) that detect viruses at the plasma membrane, in endosomes, and within the cytosol have been characterized. Upon stimulation by viruses, most of these PRRs trigger signal transduction pathways culminating in NFκB activation. NFκB contributes both to type I interferon induction, and to production of pro-inflammatory cytokines from infected cells. Our understanding of host anti-viral innate immunity has been greatly aided by an appreciation of the ways in which poxviruses have evolved strategies to inhibit both innate sensing and effector responses. A recurring feature of poxviral immunomodulation is the apparent necessity for poxviruses to evolve multiple, non-redundant inhibitors of NFκB activation which often appear to act on the same innate signalling pathway. The reason for such apparent over-targeting of one transcription factor is not clear. Here we describe the current understanding of how host cells sense poxvirus infection to trigger signalling pathways leading to NFκB activation and pro-inflammatory cytokine induction, and the ways in which poxviruses have evolved to concisely antagonize these systems. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. TRPV1 Antagonism by Capsazepine Modulates Innate Immune Response in Mice Infected with Plasmodium berghei ANKA

    Directory of Open Access Journals (Sweden)

    Elizabeth S. Fernandes

    2014-01-01

    Full Text Available Thousands of people suffer from severe malaria every year. The innate immune response plays a determinant role in host’s defence to malaria. Transient receptor potential vanilloid 1 (TRPV1 modulates macrophage-mediated responses in sepsis, but its role in other pathogenic diseases has never been addressed. We investigated the effects of capsazepine, a TRPV1 antagonist, in malaria. C57BL/6 mice received 105 red blood cells infected with Plasmodium berghei ANKA intraperitoneally. Noninfected mice were used as controls. Capsazepine or vehicle was given intraperitoneally for 6 days. Mice were culled on day 7 after infection and blood and spleen cell phenotype and activation were evaluated. Capsazepine decreased circulating but not spleen F4/80+Ly6G+ cell numbers as well as activation of both F4/80+and F4/80+Ly6G+ cells in infected animals. In addition, capsazepine increased circulating but not spleen GR1+ and natural killer (NK population, without interfering with natural killer T (NKT cell numbers and blood NK and NKT activation. However, capsazepine diminished CD69 expression in spleen NKT but not NK cells. Infection increased lipid peroxidation and the release of TNFα and IFNγ, although capsazepine-treated group exhibited lower levels of lipid peroxidation and TNFα. Capsazepine treatment did not affect parasitaemia. Overall, TRPV1 antagonism modulates the innate immune response to malaria.

  15. Evidence of pomegranate methanolic extract in antagonizing the endogenous SERM, 27-hydroxycholesterol.

    Science.gov (United States)

    Vini, Ravindran; Juberiya, Azeez M; Sreeja, Sreeharshan

    2016-02-01

    The direct relationship between obesity and breast cancer has been elucidated recently with the identification of a cholesterol derivative 27-hydroxycholesterol (27HC), an endogenous SERM that can act through estrogen receptor (ER)-mediated mechanisms. Our recent research shed light on the possible SERM-like property of methanol extract of pericarp of pomegranate (PME) by using human breast (MCF-7, MDA-MB-231), endometrial (HEC-1A), cervical (SiHa, HeLa), ovarian (SKOV3) cancer cell lines, normal breast fibroblasts (MCF-10A) and also by in vivo models (ovariectomized Swiss albino mice). Our findings demonstrated that PME binds to ER and downregulates the Estrogen response elements (ERE)-mediated transcription in breast cancer cells without being agonistic in the uterine endometrium and has cardioprotective effects comparable to that of 17-β-estradiol. This preliminary work indicates the ability of PME to antagonize the activity of 27HC. We hypothesize that PME can compete with 27HC for ERα and reduce 27HC-induced proliferation of MCF-7 cells. Relevant estrogen-regulated genes such as pS2, PR and ERα were checked to evaluate the ability of PME to abrogate 27HC-induced genes. This study is significant, being the first report describing that bioactive components of the methanolic extract of pericarp of PME, a proven SERM could plausibly compete for 27HC. © 2016 International Union of Biochemistry and Molecular Biology.

  16. Biological activity of the non-microbial fraction of kefir: antagonism against intestinal pathogens.

    Science.gov (United States)

    Iraporda, Carolina; Abatemarco Júnior, Mário; Neumann, Elisabeth; Nunes, Álvaro Cantini; Nicoli, Jacques R; Abraham, Analía G; Garrote, Graciela L

    2017-08-01

    Kefir is a fermented milk obtained by the activity of kefir grains which are composed of lactic and acetic acid bacteria, and yeasts. Many beneficial health effects have been associated with kefir consumption such as stimulation of the immune system and inhibition of pathogenic microorganisms. The biological activity of kefir may be attributed to the presence of a complex microbiota as well as the microbial metabolites that are released during fermentation. The aim of this work was to characterise the non-microbial fraction of kefir and to study its antagonism against Escherichia coli, Salmonella spp. and Bacillus cereus. During milk fermentation there was a production of organic acids, mainly lactic and acetic acid, with a consequent decrease in pH and lactose content. The non-microbial fraction of kefir added to nutrient broth at concentrations above 75% v/v induced a complete inhibition of pathogenic growth that could be ascribed to the presence of un-dissociated lactic acid. In vitro assays using an intestinal epithelial cell model indicated that pre-incubation of cells with the non-microbial fraction of kefir did not modify the association/invasion of Salmonella whereas pre-incubation of Salmonella with this fraction under conditions that did not affect their viability significantly decreased the pathogen's ability to invade epithelial cells. Lactate exerted a protective effect against Salmonella in a mouse model, demonstrating the relevance of metabolites present in the non-microbial fraction of kefir produced during milk fermentation.

  17. Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis

    Science.gov (United States)

    Griss, Takla; Vincent, Emma E.; Egnatchik, Robert; Chen, Jocelyn; Ma, Eric H.; Faubert, Brandon; Viollet, Benoit; DeBerardinis, Ralph J.; Jones, Russell G.

    2015-01-01

    Metformin is a biguanide widely prescribed to treat Type II diabetes that has gained interest as an antineoplastic agent. Recent work suggests that metformin directly antagonizes cancer cell growth through its actions on complex I of the mitochondrial electron transport chain (ETC). However, the mechanisms by which metformin arrests cancer cell proliferation remain poorly defined. Here we demonstrate that the metabolic checkpoint kinases AMP-activated protein kinase (AMPK) and LKB1 are not required for the antiproliferative effects of metformin. Rather, metformin inhibits cancer cell proliferation by suppressing mitochondrial-dependent biosynthetic activity. We show that in vitro metformin decreases the flow of glucose- and glutamine-derived metabolic intermediates into the Tricarboxylic Acid (TCA) cycle, leading to reduced citrate production and de novo lipid biosynthesis. Tumor cells lacking functional mitochondria maintain lipid biosynthesis in the presence of metformin via glutamine-dependent reductive carboxylation, and display reduced sensitivity to metformin-induced proliferative arrest. Our data indicate that metformin inhibits cancer cell proliferation by suppressing the production of mitochondrial-dependent metabolic intermediates required for cell growth, and that metabolic adaptations that bypass mitochondrial-dependent biosynthesis may provide a mechanism of tumor cell resistance to biguanide activity. PMID:26625127

  18. Streptococcus oralis maintains homeostasis in supragingival biofilms by antagonizing cariogenic pathogen Streptococcus mutans.

    Science.gov (United States)

    Thurnheer, Thomas; Belibasakis, Georgios N

    2018-01-11

    Bacteria residing in oral biofilms live in a state of dynamic equilibrium with one another. The intricate synergistic or antagonistic interactions between them are crucial for determining this balance. Using the 6-species Zürich "supragingival" biofilm model, this study aimed to investigate interactions regarding growth and localization of the constituent species. As control, an inoculum containing all six strains was used, whereas in each of the further five inocula one of the bacterial species was absent, and in the last both streptococci were absent. Biofilms were grown anaerobically on hydroxyapatite discs, and after 64 h they were harvested and quantified by culture analyses. For visualization, fluorescence in situ hybridization and confocal laser scanning microscopy was used. Compared to the control, no statistically significant difference of total CFU was observed in the absence of any of the biofilm species, except for F. nucleatum whose absence caused a significant decrease in total bacterial numbers. Absence of S. oralis resulted in a significant decrease in A. oris, and increase in S. mutans (pbiofilm with regards to the localization of the species did not result in observable changes. In summary, the most striking observation was that absence of S. oralis resulted in limited growth of commensal A. oris and overgrowth of S. mutans. This data establishes S. oralis as commensal keeper of homeostasis in the biofilm by antagonizing S. mutans, thus preventing a caries-favoring dysbiotic state. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  19. Tamoxifen Attenuates Lipopolysaccharide/Galactosamine-induced Acute Liver Failure by Antagonizing Hepatic Inflammation and Apoptosis.

    Science.gov (United States)

    Zhang, Peng; Zhang, Meisheng; Wan, Mengqi; Huang, Xiaoliu; Jiang, Yan; Xu, Siying; Luo, Mansheng

    2017-04-01

    Bacterial lipopolysaccharide (LPS)-induced acute liver failure (ALF) is a common severe clinical syndrome in intensive care unit. No other methods are available for its prevention apart from supportive treatment and liver transplantation. Tamoxifen (TAM) was reported to attenuate ALF induced by excessive acetaminophen, while its effect on LPS-induced ALF remained unknown. For this, in the present study, we comprehensively assessed whether TAM can attenuate ALF induced by LPS/galactosamine (GaIN). Mice were given TAM once a day for three times. Twelve hours after the last treatment, mice were given LPS/GaIN (intraperitoneally [i.p.]). Survival, plasma transaminases, and histopathology were examined. Serum TNF-α and IL-1β were analyzed by ELISA. Hepatic apoptosis was analyzed by TUNEL and caspase-3 Western blotting, respectively. Compared to the model group, ALF induced by LPS/GaIN was alleviated remarkably following TAM administration, as evidenced by the improvement of survival (87.5% vs. 37.5%), hepatic swell, moderate transaminases, slightly increased serum TNF-α, IL-1β (P < 0.05), and moderate histopathology. In respect of apoptosis, severe hepatocellular apoptosis was reduced notably by TAM treatment confirmed by less TUNEL-positive hepatocytes and decreased caspase-3 cleavage. The results demonstrated that TAM could attenuate LPS/GaIN-induced ALF effectively, probably due to hepatic inflammation and apoptosis antagonism. Furthermore, it was the first report about the effect of TAM on LPS/GaIN-induced ALF.

  20. Bazooka inhibits aPKC to limit antagonism of actomyosin networks during amnioserosa apical constriction.

    Science.gov (United States)

    David, Daryl J V; Wang, Qiming; Feng, James J; Harris, Tony J C

    2013-12-01

    Cell shape changes drive tissue morphogenesis during animal development. An important example is the apical cell constriction that initiates tissue internalisation. Apical constriction can occur through a phase of cyclic assembly and disassembly of apicomedial actomyosin networks, followed by stabilisation of these networks. Delayed negative-feedback mechanisms typically underlie cyclic behaviour, but the mechanisms regulating cyclic actomyosin networks remain obscure, as do mechanisms that transform overall network behaviour. Here, we show that a known inhibitor of apicomedial actomyosin networks in Drosophila amnioserosa cells, the Par-6-aPKC complex, is recruited to the apicomedial domain by actomyosin networks during dorsal closure of the embryo. This finding establishes an actomyosin-aPKC negative-feedback loop in the system. Additionally, we find that aPKC recruits Bazooka to the apicomedial domain, and phosphorylates Bazooka for a dynamic interaction. Remarkably, stabilising aPKC-Bazooka interactions can inhibit the antagonism of actomyosin by aPKC, suggesting that Bazooka acts as an aPKC inhibitor, and providing a possible mechanism for delaying the actomyosin-aPKC negative-feedback loop. Our data also implicate an increasing degree of Par-6-aPKC-Bazooka interactions as dorsal closure progresses, potentially explaining a developmental transition in actomyosin behaviour from cyclic to persistent networks. This later impact of aPKC inhibition is supported by mathematical modelling of the system. Overall, this work illustrates how shifting chemical signals can tune actomyosin network behaviour during development.

  1. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis.

    Science.gov (United States)

    Rayner, Katey J; Sheedy, Frederick J; Esau, Christine C; Hussain, Farah N; Temel, Ryan E; Parathath, Saj; van Gils, Janine M; Rayner, Alistair J; Chang, Aaron N; Suarez, Yajaira; Fernandez-Hernando, Carlos; Fisher, Edward A; Moore, Kathryn J

    2011-07-01

    Plasma HDL levels have a protective role in atherosclerosis, yet clinical therapies to raise HDL levels have remained elusive. Recent advances in the understanding of lipid metabolism have revealed that miR-33, an intronic microRNA located within the SREBF2 gene, suppresses expression of the cholesterol transporter ABC transporter A1 (ABCA1) and lowers HDL levels. Conversely, mechanisms that inhibit miR-33 increase ABCA1 and circulating HDL levels, suggesting that antagonism of miR-33 may be atheroprotective. As the regression of atherosclerosis is clinically desirable, we assessed the impact of miR-33 inhibition in mice deficient for the LDL receptor (Ldlr-/- mice), with established atherosclerotic plaques. Mice treated with anti-miR33 for 4 weeks showed an increase in circulating HDL levels and enhanced reverse cholesterol transport to the plasma, liver, and feces. Consistent with this, anti-miR33-treated mice showed reductions in plaque size and lipid content, increased markers of plaque stability, and decreased inflammatory gene expression. Notably, in addition to raising ABCA1 levels in the liver, anti-miR33 oligonucleotides directly targeted the plaque macrophages, in which they enhanced ABCA1 expression and cholesterol removal. These studies establish that raising HDL levels by anti-miR33 oligonucleotide treatment promotes reverse cholesterol transport and atherosclerosis regression and suggest that it may be a promising strategy to treat atherosclerotic vascular disease.

  2. Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Zhen [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China)

    2015-05-01

    Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocation and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.

  3. Antagonic-stress. A new treatment in gerontopsychiatry and for a healthy productive life.

    Science.gov (United States)

    Predescu, V; Riga, D; Riga, S; Turlea, J; Bărbat, I M; Botezat-Antonescu, L

    1994-06-30

    A complex antiaging formula--Antagonic-Stress--was investigated vs. placebo (PL), meclofenoxate (MF)--neurometabolic nootropic and vs. nicergoline (NE)--cerebral vasodilator by comparative multiple trials (double-blind, randomized, and parallel) in gerontopsychiatry (DSM-III-R, 1987 and ICD-10, 1992 criteria). AS vs. PL studies in organic mental disorders--amnestic, depressive, anxiety, associated with axis III physical disorders or conditions, and in multiinfarct dementia were followed by AS vs. MF or NE investigations in senile dementia of Alzheimer's type. A total of 343 old people, distributed in 4 PL groups, 1 MF group, 1 NE group, and 5 AS groups were studied. Multiple investigations, before and after three-month treatments were made: psychometric evaluation by Sandoz Clinical Assessment-Geriatric, Self-Assessment Scale-Geriatric and their 5 subscales; psychopathological rating by Hamilton Depression and Anxiety Scales; as well as psychometric testing by digit symbol of WAIS, Wechsler Memory Scale and Wechsler Adult Intelligence Scale (WAIS). Except PL, prolonged and large dose treatments with these cerebral activators (MF, NE and especially AS) reduced the psychogeriatric-psychopathological scores and the deterioration index, and improved cognitive performance. The therapeutical effectiveness of AS multiple formula in gerontopsychiatry and its superiority vs. monotherapy (MF or NE) are discussed in connection with its complex neurometabolic and synergetic composition, multiple antioxidative combinations, free radical scavengers, lipofuscinolytic agents, the antiischemic action of antioxidants, multivitamin and multimineral supplementation, and with the better efficacy of multitherapy vs. monotherapy in geriatrics.

  4. Antagonic-stress superiority versus meclofenoxate in gerontopsychiatry (alzheimer type dementia).

    Science.gov (United States)

    Popa, R; Schneider, F; Mihalas, G; Stefaniga, P; Mihalas, I G; Maties, R; Mateescu, R

    1994-01-01

    A double blind, comparative, parallel and randomized clinical trial was used for evaluation of two nootropics with anti-aging actions: Meclofenoxate (MF) and Antagonic-Stress (AS). Sixty-three old persons divided into 2 groups (average age: 68.6 and 70.8 years, respectively) with senile dementia of Alzheimer type (SDAT), of mild to moderate intensity (criteria of DSM-III-R, APA, 1987; and ICD-10, WHO, 1990) were treated with one of these nootropica. Baseline and final psychogeriatric symptomatology after three months of treatments were multiply assessed: psychogeriatric by Sandoz Clinical Assessment-Geriatric scale, Self-Assessment Scale-Geriatric and their subscales; psychometric by Wechsler Memory Scale and Wechsler Adult Intelligence Scale. Prolonged treatments with MF and AS significantly decreased the psychogeriatric scores in scales and subscales, improved the cognitive performance (attention, concentration, memory, performance IQ, full IQ) and diminshed the deterioration index (ANOVA). Therapeutical effects of AS (a neurometabolic complex containing MF) were significantly superior against MF alone (ANCOVA). MF and AS actions are discussed in connection with the brain cholinergic system, lipid peroxidation and free radical scavengers, deceleration of the aging rate, brain and erythrocyte lipofuscinolysis, multiple anti-oxidant formula, multivitamin and multimineral supplementation and with the superiority of multitherapy versus monotherapy in senile dementia and for improving the IQ and the maladaptative behavior.

  5. A Soluble Fluorescent Binding Assay Reveals PIP2 Antagonism of TREK-1 Channels.

    Science.gov (United States)

    Cabanos, Cerrone; Wang, Miao; Han, Xianlin; Hansen, Scott B

    2017-08-08

    Lipid regulation of ion channels by low-abundance signaling lipids phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid (PA) has emerged as a central cellular mechanism for controlling ion channels and the excitability of nerves. A lack of robust assays suitable for facile detection of a lipid bound to a channel has hampered the probing of the lipid binding sites and measuring the pharmacology of putative lipid agonists for ion channels. Here, we show a fluorescent PIP2 competition assay for detergent-purified potassium channels, including TWIK-1-related K+-channel (TREK-1). Anionic lipids PA and phosphatidylglycerol (PG) bind dose dependently (9.1 and 96 μM, respectively) and agonize the channel. Our assay shows PIP2 binds with high affinity (0.87 μM) but surprisingly can directly antagonize TREK-1 in liposomes. We propose a model for TREK-1 lipid regulation where PIP2 can compete with PA and PG agonism based on the affinity of the lipid for a site within the channel. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Conditions that Stabilize Membrane Domains Also Antagonize n-Alcohol Anesthesia

    Science.gov (United States)

    Machta, Benjamin B.; Gray, Ellyn; Nouri, Mariam; McCarthy, Nicola L. C.; Gray, Erin M.; Miller, Ann L.; Brooks, Nicholas J.; Veatch, Sarah L.

    2016-08-01

    Diverse molecules induce general anesthesia with potency strongly correlated both with their hydrophobicity and their effects on certain ion channels. We recently observed that several n-alcohol anesthetics inhibit heterogeneity in plasma membrane derived vesicles by lowering the critical temperature ($T_c$) for phase separation. Here we exploit conditions that stabilize membrane heterogeneity to further test the correlation between the anesthetic potency of n-alcohols and effects on $T_c$. First we show that hexadecanol acts oppositely to n-alcohol anesthetics on membrane mixing and antagonizes ethanol induced anesthesia in a tadpole behavioral assay. Second, we show that two previously described `intoxication reversers' raise $T_c$ and counter ethanol's effects in vesicles, mimicking the findings of previous electrophysiological and behavioral measurements. Third, we find that hydrostatic pressure, long known to reverse anesthesia, also raises $T_c$ in vesicles with a magnitude that counters the effect of butanol at relevant concentrations and pressures. Taken together, these results demonstrate that $\\Delta T_c$ predicts anesthetic potency for n-alcohols better than hydrophobicity in a range of contexts, supporting a mechanistic role for membrane heterogeneity in general anesthesia.

  7. Prolongevity medicine: Antagonic-Stress drug in distress, geriatrics, and related diseases. II. Clinical review--2003.

    Science.gov (United States)

    Riga, S; Riga, D; Schneider, F

    2004-06-01

    Distress and senescence, their reciprocal aggravating-quickening connections, and their related pathologies have a large worldwide impact on healthcare systems in this new millennium. For this reason, Antagonic-Stress (AS)--an advanced integrative therapy, with specific synergistic composition, and patented internationally--represents a significant strategy in health, aging, and longevity. Clinical research with AS proves the drug's efficacy in the management of distress (neurotic, stress-related, and affective disorders; behavioral syndromes associated with physiological disturbances and physical factors; mental and behavioral disorders due to psychoactive substance uses) and psychogeriatrics [organic, including symptomatic, mental disorders (OMD)]. Specific multiaxial psychopathological instruments and psychometric tests in multiple assessments used for gerontopsychiatry demonstrated strong improvements after AS administration in early-moderate stages of Alzheimer or vascular dementia, as well as in other OMD. In addition, comparative clinical studies evinced the superiority of AS (synergistic multitherapy) versus monotherapy [meclofenoxate (MF), piracetam (PA), pyritinol (PT), and nicergoline (NE), respectively]. These comparative clinical trials agreed closely with comparative preclinical research and confirmed AS synergistic homeostatic, adaptogenic, antioxidative, cerebrovascular, neurometabolic, and nootropic actions. Also, the AS protective actions against oxidative stress recommend this orthomolecular therapy in stress, aging, and free radical pathology.

  8. E1B and E4 oncoproteins of adenovirus antagonize the effect of apoptosis inducing factor

    Energy Technology Data Exchange (ETDEWEB)

    Turner, Roberta L. [Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States); Wilkinson, John C., E-mail: john.wilkinson@ndsu.edu [Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States); Ornelles, David A., E-mail: ornelles@wakehealth.edu [Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States)

    2014-05-15

    Adenovirus inundates the productively infected cell with linear, double-stranded DNA and an abundance of single-stranded DNA. The cellular response to this stimulus is antagonized by the adenoviral E1B and E4 early genes. A mutant group C adenovirus that fails to express the E1B-55K and E4ORF3 genes is unable to suppress the DNA-damage response. Cells infected with this double-mutant virus display significant morphological heterogeneity at late times of infection and frequently contain fragmented nuclei. Nuclear fragmentation was due to the translocation of apoptosis inducing factor (AIF) from the mitochondria into the nucleus. The release of AIF was dependent on active poly(ADP-ribose) polymerase-1 (PARP-1), which appeared to be activated by viral DNA replication. Nuclear fragmentation did not occur in AIF-deficient cells or in cells treated with a PARP-1 inhibitor. The E1B-55K or E4ORF3 proteins independently prevented nuclear fragmentation subsequent to PARP-1 activation, possibly by altering the intracellular distribution of PAR-modified proteins. - Highlights: • E1B-55K or E4orf3 prevents nuclear fragmentation. • Nuclear fragmentation requires AIF and PARP-1 activity. • Adenovirus DNA replication activates PARP-1. • E1B-55K or E4orf3 proteins alter the distribution of PAR.

  9. Plant Essential Oils Synergize and Antagonize Toxicity of Different Conventional Insecticides against Myzus persicae (Hemiptera: Aphididae).

    Science.gov (United States)

    Faraone, Nicoletta; Hillier, N Kirk; Cutler, G Christopher

    2015-01-01

    Plant-derived products can play an important role in pest management programs. Essential oils from Lavandula angustifolia (lavender) and Thymus vulgaris (thyme) and their main constituents, linalool and thymol, respectively, were evaluated for insecticidal activity and synergistic action in combination with insecticides against green peach aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae). The essential oils and their main constituents exerted similar insecticidal activity when aphids were exposed by direct sprays, but were non-toxic by exposure to treated leaf discs. In synergism experiments, the toxicity of imidacloprid was synergized 16- to 20-fold by L. angustifolia and T. vulgaris essential oils, but far less synergism occurred with linalool and thymol, indicating that secondary constituents of the oils were probably responsible for the observed synergism. In contrast to results with imidacloprid, the insecticidal activity of spirotetramat was antagonized by L. angustifolia and T. vulgaris essential oils, and linalool and thymol. Our results demonstrate the potential of plant essential oils as synergists of insecticides, but show that antagonistic action against certain insecticides may occur.

  10. Innate immune restriction and antagonism of viral RNA lacking 2'-O methylation

    Energy Technology Data Exchange (ETDEWEB)

    Hyde, Jennifer L. [Departments of Medicine, Washington University School of Medicine, St Louis., MO 63110 (United States); Diamond, Michael S., E-mail: diamond@borcim.wustl.edu [Departments of Medicine, Washington University School of Medicine, St Louis., MO 63110 (United States); Molecular Microbiology, Washington University School of Medicine, St Louis., MO 63110 (United States); Pathology & Immunology, Washington University School of Medicine, St Louis., MO 63110 (United States); The Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis., MO 63110 (United States)

    2015-05-15

    N-7 and 2′-O methylation of host cell mRNA occurs in the nucleus and results in the generation of cap structures (cap 0, m{sup 7}GpppN; cap 1, m{sup 7}GpppNm) that control gene expression by modulating nuclear export, splicing, turnover, and protein synthesis. Remarkably, RNA cap modification also contributes to mammalian cell host defense as viral RNA lacking 2′-O methylation is sensed and inhibited by IFIT1, an interferon (IFN) stimulated gene (ISG). Accordingly, pathogenic viruses that replicate in the cytoplasm have evolved mechanisms to circumvent IFIT1 restriction and facilitate infection of mammalian cells. These include: (a) generating cap 1 structures on their RNA through cap-snatching or virally-encoded 2′-O methyltransferases, (b) using cap-independent means of translation, or (c) using RNA secondary structural motifs to antagonize IFIT1 binding. This review will discuss new insights as to how specific modifications at the 5′-end of viral RNA modulate host pathogen recognition responses to promote infection and disease.

  11. Antagonism and synergism in Gardnerella vaginalis strains isolated from women with bacterial vaginosis.

    Science.gov (United States)

    Teixeira, G S; Soares-Brandão, K L K; Branco, K M G R; Sampaio, J L M; Nardi, R M D; Mendonça, M; Almeida, R B; Farias, L M; Carvalho, M A R; Nicoli, J R

    2010-08-01

    Antagonistic and synergistic substances are important for interactions between micro-organisms associated with human body surfaces, either in healthy or in diseased conditions. In the present study, such compounds produced by Gardnerella vaginalis strains isolated from women with bacterial vaginosis (BV) were detected in vitro and the antagonistic ones were partially characterized. Among 11 G. vaginalis strains tested, all showed antagonistic activity against at least one of the 22 indicator bacteria assayed. Interestingly, for some of these strains, antagonism reverted to synergism, favouring one of the indicator strains (Peptostreptococcus anaerobius) when the growth medium was changed. Partial characterization of antagonistic substances suggested a bacteriocin-like chemical nature. Depending on growth conditions, G. vaginalis isolated from women with BV produced antagonistic or synergistic compounds for other bacterial components of the vaginal ecosystem. This is the first report to our knowledge of the production of antagonistic and/or synergistic substances by G. vaginalis. This ability may be a pivotal factor in understanding BV and the ecological role of this bacterium in the vaginal environment.

  12. Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis.

    Directory of Open Access Journals (Sweden)

    Takla Griss

    2015-12-01

    Full Text Available Metformin is a biguanide widely prescribed to treat Type II diabetes that has gained interest as an antineoplastic agent. Recent work suggests that metformin directly antagonizes cancer cell growth through its actions on complex I of the mitochondrial electron transport chain (ETC. However, the mechanisms by which metformin arrests cancer cell proliferation remain poorly defined. Here we demonstrate that the metabolic checkpoint kinases AMP-activated protein kinase (AMPK and LKB1 are not required for the antiproliferative effects of metformin. Rather, metformin inhibits cancer cell proliferation by suppressing mitochondrial-dependent biosynthetic activity. We show that in vitro metformin decreases the flow of glucose- and glutamine-derived metabolic intermediates into the Tricarboxylic Acid (TCA cycle, leading to reduced citrate production and de novo lipid biosynthesis. Tumor cells lacking functional mitochondria maintain lipid biosynthesis in the presence of metformin via glutamine-dependent reductive carboxylation, and display reduced sensitivity to metformin-induced proliferative arrest. Our data indicate that metformin inhibits cancer cell proliferation by suppressing the production of mitochondrial-dependent metabolic intermediates required for cell growth, and that metabolic adaptations that bypass mitochondrial-dependent biosynthesis may provide a mechanism of tumor cell resistance to biguanide activity.

  13. A Soluble Fluorescent Binding Assay Reveals PIP2 Antagonism of TREK-1 Channels

    Directory of Open Access Journals (Sweden)

    Cerrone Cabanos

    2017-08-01

    Full Text Available Lipid regulation of ion channels by low-abundance signaling lipids phosphatidylinositol 4,5-bisphosphate (PIP2 and phosphatidic acid (PA has emerged as a central cellular mechanism for controlling ion channels and the excitability of nerves. A lack of robust assays suitable for facile detection of a lipid bound to a channel has hampered the probing of the lipid binding sites and measuring the pharmacology of putative lipid agonists for ion channels. Here, we show a fluorescent PIP2 competition assay for detergent-purified potassium channels, including TWIK-1-related K+-channel (TREK-1. Anionic lipids PA and phosphatidylglycerol (PG bind dose dependently (9.1 and 96 μM, respectively and agonize the channel. Our assay shows PIP2 binds with high affinity (0.87 μM but surprisingly can directly antagonize TREK-1 in liposomes. We propose a model for TREK-1 lipid regulation where PIP2 can compete with PA and PG agonism based on the affinity of the lipid for a site within the channel.

  14. Ketamine-xylazine anesthesia in red-tailed hawks with antagonism by yohimbine.

    Science.gov (United States)

    Degernes, L A; Kreeger, T J; Mandsager, R; Redig, P T

    1988-04-01

    Five red-tailed hawks (Buteo jamaicensis) were anesthetized at weekly intervals with intravenous ketamine hydrochloride (KET, 4.4 mg/kg) and xylazine hydrochloride (XYL, 2.2 mg/kg). Twenty min after anesthesia, yohimbine hydrochloride (YOH, 0.05, 0.10, 0.20 and 0.40 mg/kg) or a control was administered. All doses of YOH significantly reduced the head-up times (F = 20.84, df = 1,24, P less than 0.0001) and the standing times (F = 12.30, df = 1,24, P less than 0.0001), compared to the control group. The heart and respiratory rates following YOH (all doses) were significantly greater (P less than 0.01) than the anesthetized rates, but were comparable to the rates observed in restrained, unanesthetized hawks. Yohimbine did not appear to have any significant effect on body temperature. Based upon administration of 4.4 mg/kg KET and 2.2 mg/kg XYL, a dose of 0.10 mg/kg YOH was recommended to achieve antagonism without causing profound cardiovascular or respiratory changes.

  15. Omega-3 polyunsaturated fatty acids antagonize macrophage inflammation via activation of AMPK/SIRT1 pathway.

    Directory of Open Access Journals (Sweden)

    Bingzhong Xue

    Full Text Available Macrophages play a key role in obesity-induced inflammation. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA exert anti-inflammatory functions in both humans and animal models, but the exact cellular signals mediating the beneficial effects are not completely understood. We previously found that two nutrient sensors AMP-activated protein kinase (AMPK and SIRT1 interact to regulate macrophage inflammation. Here we aim to determine whether ω-3 PUFAs antagonize macrophage inflammation via activation of AMPK/SIRT1 pathway. Treatment of ω-3 PUFAs suppresses lipopolysaccharide (LPS-induced cytokine expression in macrophages. Luciferase reporter assays, electrophoretic mobility shift assays (EMSA and Chromatin immunoprecipitation (ChIP assays show that treatment of macrophages with ω-3 PUFAs significantly inhibits LPS-induced NF-κB signaling. Interestingly, DHA also increases expression, phosphorylation and activity of the major isoform α1AMPK, which further leads to SIRT1 over-expression. More importantly, DHA mimics the effect of SIRT1 on deacetylation of the NF-κB subunit p65, and the ability of DHA to deacetylate p65 and inhibit its signaling and downstream cytokine expression require SIRT1. In conclusion, ω-3 PUFAs negatively regulate macrophage inflammation by deacetylating NF-κB, which acts through activation of AMPK/SIRT1 pathway. Our study defines AMPK/SIRT1 as a novel cellular mediator for the anti-inflammatory effects of ω-3 PUFAs.

  16. NRPS-Derived Isoquinolines and Lipopetides Mediate Antagonism between Plant Pathogenic Fungi and Bacteria.

    Science.gov (United States)

    Khalid, Saima; Baccile, Joshua A; Spraker, Joseph E; Tannous, Joanna; Imran, Muhammad; Schroeder, Frank C; Keller, Nancy P

    2018-01-19

    Bacterial-fungal interactions are presumed to be mediated chiefly by small-molecule signals; however, little is known about the signaling networks that regulate antagonistic relationships between pathogens. Here, we show that the ralstonins, lipopeptides produced by the plant pathogenic bacteria Ralstonia solanacearum, interfere with germination of the plant-pathogenic fungus Aspergillus flavus by down-regulating expression of a cryptic biosynthetic gene cluster (BGC), named imq. Comparative metabolomic analysis of overexpression strains of the transcription factor ImqK revealed imq-dependent production of a family of tripeptide-derived alkaloids, the imizoquins. These alkaloids are produced via a nonribosomal peptide synthetase- (NRPS-)derived tripeptide and contain an unprecedented tricyclic imidazo[2,1-a]isoquinoline ring system. We show that the imizoquins serve a protective role against oxidative stress that is essential for normal A. flavus germination. Supplementation of purified imizoquins restored wildtype germination to a ΔimqK A. flavus strain and protected the fungus from ROS damage. Whereas the bacterial ralstonins retarded A. flavus germination and suppressed expression of the imq cluster, the fungal imizoquins in turn suppressed growth of R. solanacearum. We suggest such reciprocal small-molecule-mediated antagonism is a common feature in microbial encounters affecting pathogenicity and survival of the involved species.

  17. ToxR Antagonizes H-NS Regulation of Horizontally Acquired Genes to Drive Host Colonization.

    Directory of Open Access Journals (Sweden)

    Misha I Kazi

    2016-04-01

    Full Text Available The virulence regulator ToxR initiates and coordinates gene expression needed by Vibrio cholerae to colonize the small intestine and cause disease. Despite its prominence in V. cholerae virulence, our understanding of the direct ToxR regulon is limited to four genes: toxT, ompT, ompU and ctxA. Here, we determine ToxR's genome-wide DNA-binding profile and demonstrate that ToxR is a global regulator of both progenitor genome-encoded genes and horizontally acquired islands that encode V. cholerae's major virulence factors and define pandemic lineages. We show that ToxR shares more than a third of its regulon with the histone-like nucleoid structuring protein H-NS, and antagonizes H-NS binding at shared binding locations. Importantly, we demonstrate that this regulatory interaction is the critical function of ToxR in V. cholerae colonization and biofilm formation. In the absence of H-NS, ToxR is no longer required for V. cholerae to colonize the infant mouse intestine or for robust biofilm formation. We further illustrate a dramatic difference in regulatory scope between ToxR and other prominent virulence regulators, despite similar predicted requirements for DNA binding. Our results suggest that factors in addition to primary DNA structure influence the ability of ToxR to recognize its target promoters.

  18. Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines.

    Science.gov (United States)

    Stahl, Stephen M

    2008-12-01

    Numerous "antihistamines" as well as various psychotropic medications with antihistamine properties are widely utilized to treat insomnia. Over-the-counter sleep aids usually contain an antihistamine and various antidepressants and antipsychotics with antihistamine properties have sedative-hypnotic actions. Although widely used for the treatment of insomnia, many agents that block the histamine H1 receptor are also widely considered to have therapeutic limitations, including the development of next-day carryover sedation, as well as problems with chronic use, such as the development of tolerance to sedative-hypnotic actions and weight gain. Although these clinical actions are classically attributed to blockade of the H1 receptor, recent findings with H1 selective agents and H1 selective dosing of older agents are challenging these notions and suggest that some of the clinical limitations of current H1-blocking agents at their currently utilized doses could be attributable to other properties of these drugs, especially to their simultaneous actions on muscarinic, cholinergic, and adrenergic receptors. Selective H1 antagonism is emerging as a novel approach to the treatment of insomnia, without tolerance, weight gain, or the need for the restrictive prescription scheduling required of other hypnotics.

  19. Salicylic acid antagonizes abscisic acid inhibition of shoot growth and cell cycle progression in rice

    Science.gov (United States)

    Meguro, Ayano; Sato, Yutaka

    2014-04-01

    We analysed effects of abscisic acid (ABA, a negative regulatory hormone), alone and in combination with positive or neutral hormones, including salicylic acid (SA), on rice growth and expression of cell cycle-related genes. ABA significantly inhibited shoot growth and induced expression of OsKRP4, OsKRP5, and OsKRP6. A yeast two-hybrid assay showed that OsKRP4, OsKRP5, and OsKRP6 interacted with OsCDKA;1 and/or OsCDKA;2. When SA was simultaneously supplied with ABA, the antagonistic effect of SA completely blocked ABA inhibition. SA also blocked ABA inhibition of DNA replication and thymidine incorporation in the shoot apical meristem. These results suggest that ABA arrests cell cycle progression by inducing expression of OsKRP4, OsKRP5, and OsKRP6, which inhibit the G1/S transition, and that SA antagonizes ABA by blocking expression of OsKRP genes.

  20. A kinase-dependent role for Haspin in antagonizing Wapl and protecting mitotic centromere cohesion.

    Science.gov (United States)

    Liang, Cai; Chen, Qinfu; Yi, Qi; Zhang, Miao; Yan, Haiyan; Zhang, Bo; Zhou, Linli; Zhang, Zhenlei; Qi, Feifei; Ye, Sheng; Wang, Fangwei

    2017-11-14

    Sister-chromatid cohesion mediated by the cohesin complex is fundamental for precise chromosome segregation in mitosis. Through binding the cohesin subunit Pds5, Wapl releases the bulk of cohesin from chromosome arms in prophase, whereas centromeric cohesin is protected from Wapl until anaphase onset. Strong centromere cohesion requires centromeric localization of the mitotic histone kinase Haspin, which is dependent on the interaction of its non-catalytic N-terminus with Pds5B. It remains unclear how Haspin fully blocks the Wapl-Pds5B interaction at centromeres. Here, we show that the C-terminal kinase domain of Haspin (Haspin-KD) binds and phosphorylates the YSR motif of Wapl (Wapl-YSR), thereby directly inhibiting the YSR motif-dependent interaction of Wapl with Pds5B. Cells expressing a Wapl-binding-deficient mutant of Haspin or treated with Haspin inhibitors show centromeric cohesion defects. Phospho-mimetic mutation in Wapl-YSR prevents Wapl from binding Pds5B and releasing cohesin. Forced targeting Haspin-KD to centromeres partly bypasses the need for Haspin-Pds5B interaction in cohesion protection. Taken together, these results indicate a kinase-dependent role for Haspin in antagonizing Wapl and protecting centromeric cohesion in mitosis. © 2017 The Authors.

  1. Glucocorticoid Antagonism Reduces Insulin Resistance and Associated Lipid Abnormalities in High-Fructose-Fed Mice.

    Science.gov (United States)

    Priyadarshini, Emayavaramban; Anuradha, Carani Venkatraman

    2017-02-01

    High intake of dietary fructose causes perturbation in lipid metabolism and provokes lipid-induced insulin resistance. A rise in glucocorticoids (GCs) has recently been suggested to be involved in fructose-induced insulin resistance. The objective of the study was to investigate the effect of GC blockade on lipid abnormalities in insulin-resistant mice. Insulin resistance was induced in mice by administering a high-fructose diet (HFrD) for 60 days. Mifepristone (RU486), a GC antagonist, was administered to HFrD-fed mice for the last 18 days, and the intracellular and extracellular GC levels, the glucocorticoid receptor (GR) activation and the expression of GC-regulated genes involved in lipid metabolism were examined. HFrD elevated the intracellular GC content in both liver and adipose tissue and enhanced the GR nuclear translocation. The plasma GC level remained unchanged. The levels of free fatty acids and triglycerides in plasma were elevated, accompanied by increased plasma insulin and glucose levels and decreased hepatic glycogen content. Treatment with RU486 reduced plasma lipid levels, tissue GC levels and the expression of GC-targeted genes involved in lipid accumulation, and it improved insulin sensitivity. This study demonstrated that HFrD-induced lipid accumulation and insulin resistance are mediated by enhanced GC in liver and adipose tissue and that GC antagonism might reduce fructose-induced lipid abnormalities and insulin resistance. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  2. Functionalized Multiwalled Carbon Nanotubes as Carriers of Ruthenium Complexes to Antagonize Cancer Multidrug Resistance and Radioresistance.

    Science.gov (United States)

    Wang, Ni; Feng, Yanxian; Zeng, Lilan; Zhao, Zhennan; Chen, Tianfeng

    2015-07-15

    Multidrug resistance and radioresistance are major obstacles for successful cancer therapy. Due to the unique characteristics of high surface area, improved cellular uptake, and the possibility to be easily bound with therapeutics, carbon nanotubes (CNTs) have attracted increasing attention as potential nanodrug delivery systems. In this study, a CNT-based radiosensitive nanodrug delivery system was rationally designed to antagonize the multidrug resistance in hepatocellular carcinoma. The nanosystem was loaded with a potent anticancer ruthenium polypyridyl complex (RuPOP) via π-π interaction and formation of a hydrogen bond. The functionalized nanosystem (RuPOP@MWCNTs) enhanced the cellular uptake of RuPOP in liver cancer cells, especially drug-resistant R-HepG2 cells, through endocytosis. Consistently, the selective cellular uptake endowed the nanosystem amplified anticancer efficacy against R-HepG2 cells but not in normal cells. Interestingly, RuPOP@MWCNTs significantly enhanced the anticancer efficacy of clinically used X-ray against R-HepG2 cells through induction of apoptosis and G0/G1 cell cycle arrest, with the involvement of ROS overproduction, which activated several downstream signaling pathways, including DNA damage-mediated p53 phosphorylation, activation of p38, and inactivation of AKT and ERK. Moreover, the nanosystem also effectively reduces the toxic side effects of loaded drugs and prolongs the blood circulation in vivo. Taken together, the results demonstrate the rational design of functionalized carbon nanotubes and their application as effective nanomedicine to overcome cancer multidrug resistance.

  3. Structural insight into antibody-mediated antagonism of the Glucagon-like peptide-1 Receptor

    Science.gov (United States)

    Hennen, Stephanie; Kodra, János T.; Soroka, Vladyslav; Krogh, Berit O.; Wu, Xiaoai; Kaastrup, Peter; Ørskov, Cathrine; Rønn, Sif G.; Schluckebier, Gerd; Barbateskovic, Silvia; Gandhi, Prafull S.; Reedtz-Runge, Steffen

    2016-01-01

    The Glucagon-like peptide-1 receptor (GLP-1R) is a member of the class B G protein-coupled receptor (GPCR) family and a well-established target for the treatment of type 2 diabetes. The N-terminal extracellular domain (ECD) of GLP-1R is important for GLP-1 binding and the crystal structure of the GLP-1/ECD complex was reported previously. The first structure of a class B GPCR transmembrane (TM) domain was solved recently, but the full length receptor structure is still not well understood. Here we describe the molecular details of antibody-mediated antagonism of the GLP-1R using both in vitro pharmacology and x-ray crystallography. We showed that the antibody Fab fragment (Fab 3F52) blocked the GLP-1 binding site of the ECD directly and thereby acts as a competitive antagonist of native GLP-1. Interestingly, Fab 3F52 also blocked a short peptide agonist believed to engage primarily the transmembrane and extracellular loop region of GLP-1R, whereas functionality of an allosteric small-molecule agonist was not inhibited. This study has implications for the structural understanding of the GLP-1R and related class B GPCRs, which is important for the development of new and improved therapeutics targeting these receptors. PMID:27196125

  4. Bam and Bgcn antagonize Nanos-dependent germ-line stem cell maintenance.

    Science.gov (United States)

    Li, Yun; Minor, Nicole T; Park, Joseph K; McKearin, Dennis M; Maines, Jean Z

    2009-06-09

    The balance between germ-line stem cell (GSC) self-renewal and differentiation in Drosophila ovaries is mediated by the antagonistic relationship between the Nanos (Nos)-Pumilio translational repressor complex, which promotes GSC self-renewal, and expression of Bam, a key differentiation factor. Here, we find that Bam and Nos proteins are expressed in reciprocal patterns in young germ cells. Repression of Nos in Bam-expressing cells depends on sequences in the nos 3'-UTR, suggesting that Nos is regulated by translational repression. Ectopic Bam causes differentiation of GSCs, and this activity depends on the endogenous nos 3'-UTR sequence. Previous evidence showed that Bgcn is an obligate factor for the ability of Bam to drive differentiation, and we now report that Bam forms a complex with Bgcn, a protein related to the RNA-interacting DExH-box polypeptides. Together, these observations suggest that Bam-Bgcn act together to antagonize Nos expression; thus, derepressing cystoblast-promoting factors. These findings emphasize the importance of translational repression in balancing stem cell self-renewal and differentiation.

  5. Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity

    Science.gov (United States)

    Cheng, Pin-Nan; Liu, Cong; Zhao, Minglei; Eisenberg, David; Nowick, James S.

    2012-11-01

    The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β2-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.

  6. (-)-Delta9-tetrahydrocannabinol antagonizes the peripheral cannabinoid receptor-mediated inhibition of adenylyl cyclase.

    Science.gov (United States)

    Bayewitch, M; Rhee, M H; Avidor-Reiss, T; Breuer, A; Mechoulam, R; Vogel, Z

    1996-04-26

    (-)-Delta9-Tetrahydrocannabinol ((-)-Delta9-THC) is the major active psychotropic component of the marijuana plant, Cannabis sativa. The membrane proteins that have been found to bind this material or its derivatives have been called the cannabinoid receptors. Two GTP-binding protein-coupled cannabinoid receptors have been cloned. CB1 or the neuronal cannabinoid receptor is found mostly in neuronal cells and tissues while CB2 or the peripheral cannabinoid receptor has been detected in spleen and in several cells of the immune system. It has previously been shown that activation of CB1 or CB2 receptors by cannabinoid agonists inhibits adenylyl cyclase activity. Utilizing Chinese hamster ovary cells and COS cells transfected with the cannabinoid receptors we report that (-)-Delta9-THC binds to both receptors with similar affinity. However, in contrast to its capacity to serve as an agonist for the CB1 receptor, (-)-Delta9-THC was only able to induce a very slight inhibition of adenylyl cyclase at the CB2 receptor. Morever, (-)-Delta9-THC antagonizes the agonist-induced inhibition of adenylyl cyclase mediated by CB2. Therefore, we conclude that (-)-Delta9-THC constitutes a weak antagonist for the CB2 receptor.

  7. Calcitonin gene-related peptide antagonism and cluster headache: an emerging new treatment.

    Science.gov (United States)

    Ashina, Håkan; Newman, Lawrence; Ashina, Sait

    2017-08-30

    Calcitonin gene-related peptide (CGRP) is a key signaling molecule involved in migraine pathophysiology. Efficacy of CGRP monoclonal antibodies and antagonists in migraine treatment has fueled an increasing interest in the prospect of treating cluster headache (CH) with CGRP antagonism. The exact role of CGRP and its mechanism of action in CH have not been fully clarified. A search for original studies and randomized controlled trials (RCTs) published in English was performed in PubMed and in ClinicalTrials.gov . The search term used was "cluster headache and calcitonin gene related peptide" and "primary headaches and calcitonin gene related peptide." Reference lists of identified articles were also searched for additional relevant papers. Human experimental studies have reported elevated plasma CGRP levels during both spontaneous and glyceryl trinitrate-induced cluster attacks. CGRP may play an important role in cluster headache pathophysiology. More refined human studies are warranted with regard to assay validation and using larger sample sizes. The results from RCTs may reveal the therapeutic potential of CGRP monoclonal antibodies and antagonists for cluster headache treatment.

  8. Competitive Androgen Receptor Antagonism as a Factor Determining the Predictability of Cumulative Antiandrogenic Effects of Widely Used Pesticides

    Science.gov (United States)

    Rosivatz, Erika; Scholze, Martin; Kortenkamp, Andreas

    2012-01-01

    Background: Many pesticides in current use have recently been revealed as in vitro androgen receptor (AR) antagonists, but information about their combined effects is lacking. Objective: We investigated the combined effects and the competitive AR antagonism of pesticide mixtures. Methods: We used the MDA-kb2 assay to test a combination of eight AR antagonists that did not also possess AR agonist properties (“pure” antagonists; 8 mix: fludioxonil, fenhexamid, ortho-phenylphenol, imazalil, tebuconazole, dimethomorph, methiocarb, pirimiphos-methyl), a combination of five AR antagonists that also showed agonist activity (5 mix: cyprodinil, pyrimethanil, vinclozolin, chlorpropham, linuron), and all pesticides combined (13 mix). We used concentration addition (CA) and independent action (IA) to formulate additivity expectations, and Schild plot analyses to investigate competitive AR antagonism. Results: A good agreement between the effects of the mixture of eight “pure” AR antagonists and the responses predicted by CA was observed. Schild plot analysis revealed that the 8 mix acted by competitive AR antagonism. However, the observed responses of the 5 mix and the 13 mix fell within the “prediction window” boundaries defined by the predicted regression curves of CA and IA. Schild plot analysis with these mixtures yielded anomalous responses incompatible with competitive receptor antagonism. Conclusions: A mixture of widely used pesticides can, in a predictable manner, produce combined AR antagonist effects that exceed the responses elicited by the most potent component alone. Inasmuch as large populations are regularly exposed to mixtures of antiandrogenic pesticides, our results underline the need for considering combination effects for these substances in regulatory practice. PMID:23008280

  9. Mxi1 and Mxi1-0 Antagonize N-Myc Function and Independently Mediate Apoptosis in Neuroblastoma

    Science.gov (United States)

    Erichsen, David A.; Armstrong, Michael B.; Wechsler, Daniel S.

    2015-01-01

    Neuroblastoma (NB) is the third most common malignancy of childhood, and outcomes for children with advanced disease remain poor; amplification of the MYCN gene portends a particularly poor prognosis. Mxi1 antagonizes N-Myc by competing for binding to Max and E-boxes. Unlike N-Myc, Mxi1 mediates transcriptional repression and suppresses cell proliferation. Mxi1 and Mxi1-0 (an alternatively transcribed Mxi1 isoform) share identical Max and DNA binding domains but differ in amino-terminal sequences. Because of the conservation of these critical binding domains, we hypothesized that Mxi1-0 antagonizes N-Myc activity similar to Mxi1. SHEP NB cells and SHEP cells stably transfected with MYCN (SHEP/MYCN) were transiently transfected with vectors containing full-length Mxi1, full-length Mxi1-0, or the common Mxi domain encoded by exons 2 to 6 (ex2-6). After incubation in low serum, parental SHEP/MYCN cell numbers were reduced compared with SHEP cells. Activated caspase-3 staining and DNA fragmentation ELISA confirmed that SHEP/MYCN cells undergo apoptosis in low serum, while SHEP/MYCN cells transfected with Mxi1 or Mxi1-0 do not. However, SHEP/MYCN cells transfected with Mxi1 or Mxi1-0 and grown in normal serum showed proliferation rates similar to SHEP cells. Mxi ex2-6 did not affect cell number in low or normal serum, suggesting that amino terminal domains of Mxi1 and Mxi1-0 are critical for antagonism. In the absence of N-Myc, Mxi1 and Mxi1-0 induce apoptosis independently through the caspase-8–dependent extrinsic pathway, while N-Myc activates the caspase-9–dependent intrinsic pathway. Together, these data indicate that Mxi1 and Mxi1-0 antagonize N-Myc but also independently impact NB cell survival. PMID:25749179

  10. Mxi1 and Mxi1-0 Antagonize N-Myc Function and Independently Mediate Apoptosis in Neuroblastoma

    Directory of Open Access Journals (Sweden)

    David A. Erichsen

    2015-02-01

    Full Text Available Neuroblastoma (NB is the third most common malignancy of childhood, and outcomes for children with advanced disease remain poor; amplification of the MYCN gene portends a particularly poor prognosis. Mxi1 antagonizes N-Myc by competing for binding to Max and E-boxes. Unlike N-Myc, Mxi1 mediates transcriptional repression and suppresses cell proliferation. Mxi1 and Mxi1-0 (an alternatively transcribed Mxi1 isoform share identical Max and DNA binding domains but differ in amino-terminal sequences. Because of the conservation of these critical binding domains, we hypothesized that Mxi1-0 antagonizes N-Myc activity similar to Mxi1. SHEP NB cells and SHEP cells stably transfected with MYCN (SHEP/MYCN were transiently transfected with vectors containing full-length Mxi1, full-length Mxi1-0, or the common Mxi domain encoded by exons 2 to 6 (ex2-6. After incubation in low serum, parental SHEP/MYCN cell numbers were reduced compared with SHEP cells. Activated caspase-3 staining and DNA fragmentation ELISA confirmed that SHEP/MYCN cells undergo apoptosis in low serum, while SHEP/MYCN cells transfected with Mxi1 or Mxi1-0 do not. However, SHEP/MYCN cells transfected with Mxi1 or Mxi1-0 and grown in normal serum showed proliferation rates similar to SHEP cells. Mxi ex2-6 did not affect cell number in low or normal serum, suggesting that amino terminal domains of Mxi1 and Mxi1-0 are critical for antagonism. In the absence of N-Myc, Mxi1 and Mxi1-0 induce apoptosis independently through the caspase-8–dependent extrinsic pathway, while N-Myc activates the caspase-9–dependent intrinsic pathway. Together, these data indicate that Mxi1 and Mxi1-0 antagonize N-Myc but also independently impact NB cell survival.

  11. Rescue from acute neuroinflammation by pharmacological chemokine-mediated deviation of leukocytes

    Directory of Open Access Journals (Sweden)

    Berghmans Nele

    2012-10-01

    Full Text Available Abstract Background Neutrophil influx is an important sign of hyperacute neuroinflammation, whereas the entry of activated lymphocytes into the brain parenchyma is a hallmark of chronic inflammatory processes, as observed in multiple sclerosis (MS and its animal models of experimental autoimmune encephalomyelitis (EAE. Clinically approved or experimental therapies for neuroinflammation act by blocking leukocyte penetration of the blood brain barrier. However, in view of unsatisfactory results and severe side effects, complementary therapies are needed. We have examined the effect of chlorite-oxidized oxyamylose (COAM, a potent antiviral polycarboxylic acid on EAE. Methods EAE was induced in SJL/J mice by immunization with spinal cord homogenate (SCH or in IFN-γ-deficient BALB/c (KO mice with myelin oligodendrocyte glycoprotein peptide (MOG35-55. Mice were treated intraperitoneally (i.p. with COAM or saline at different time points after immunization. Clinical disease and histopathology were compared between both groups. IFN expression was analyzed in COAM-treated MEF cell cultures and in sera and peritoneal fluids of COAM-treated animals by quantitative PCR, ELISA and a bioassay on L929 cells. Populations of immune cell subsets in the periphery and the central nervous system (CNS were quantified at different stages of disease development by flow cytometry and differential cell count analysis. Expression levels of selected chemokine genes in the CNS were determined by quantitative PCR. Results We discovered that COAM (2 mg i.p. per mouse on days 0 and 7 protects significantly against hyperacute SCH-induced EAE in SJL/J mice and MOG35-55-induced EAE in IFN-γ KO mice. COAM deviated leukocyte trafficking from the CNS into the periphery. In the CNS, COAM reduced four-fold the expression levels of the neutrophil CXC chemokines KC/CXCL1 and MIP-2/CXCL2. Whereas the effects of COAM on circulating blood and splenic leukocytes were limited, significant

  12. Role of secreted conjunctival mucosal cytokine and chemokine proteins in different stages of trachomatous disease.

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    Troy A Skwor

    2008-07-01

    Full Text Available Chlamydia trachomatis is responsible for trachoma, the primary cause of preventable blindness worldwide. Plans to eradicate trachoma using the World Health Organization's SAFE program (Surgery, Antibiotics, Facial Cleanliness and Environment Improvement have resulted in recurrence of infection and disease following cessation of treatment in many endemic countries, suggesting the need for a vaccine to control infection and trachomatous disease. Vaccine development requires, in part, knowledge of the mucosal host immune responses in both healthy and trachomatous conjuctivae-an area of research that remains insufficiently studied.We characterized 25 secreted cytokines and chemokines from the conjunctival mucosa of individuals residing in a trachoma endemic region of Nepal using Luminex X100 multiplexing technology. Immunomodulating effects of concurrent C. trachomatis infection were also examined. We found that proinflammatory cytokines IL-1beta (r = 0.259, P = 0.001 and TNFalpha (r = 0.168, P<0.05 were significantly associated with trachomatous disease and concurrent C. trachomatis infection compared with age and sex matched controls from the same region who did not have trachoma. In support of these findings, anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra was negatively associated with chronic scarring trachoma (r = -0.249, P = 0.001. Additional cytokines (Th1, IL-12p40 [r = -0.212, P<0.01], and Th2, IL-4 and IL-13 [r = -0.165 and -0.189, respectively, P<0.05 for both] were negatively associated with chronic scarring trachoma, suggesting a protective role. Conversely, a pathogenic role for the Th3/Tr1 cytokine IL-10 (r = 0.180, P<0.05 was evident with increased levels for all trachoma grades. New risk factors for chronic scarring trachoma included IL-6 and IL-15 (r = 0.259 and 0.292, respectively, P<0.005 for both with increased levels for concurrent C. trachomatis infections (r = 0.206, P<0.05, and r = 0.304, P<0.005, respectively

  13. Cytokine and chemokine profile changes in patients with lower segment lumbar degenerative spondylolisthesis.

    Science.gov (United States)

    Sutovsky, Juraj; Benco, Martin; Sutovska, Martina; Kocmalova, Michaela; Pappova, Lenka; Miklusica, Juraj; Frano, Andrej; Kurca, Egon

    2017-07-01

    Lumbar degenerative spondylolisthesis (DS) develops as a result of inflammatory and remodeling processes in facet joints (FJs). Several inflammatory cytokines are involved in the osteoarthritic and remodeling changes that occur and in low-back and/or radicular pain, the most prevalent clinical symptom of disease. This study improves knowledge related to the roles that 27 cytokines, chemokines and growth factors play in the pathophysiology of lumbar DS. Cytokine levels were examined using capture sandwich immunoassay using the Bio-Plex(®) 200 System and the Bio-PlexTM Human Cytokine Standard 27-Plex, Group I (Bio-Rad, Hercules, California, USA) separately in intervertebral discs (IVDs) and FJ bone tissue. The samples were obtained during primary spinal surgery from 9 patients suffering from lower segment lumbar DS. The pain intensity was assessed using a visual analog scale. The controls were tissue samples collected from both lower lumbar segment levels of 6 male subjects during a multiorgan procurement procedure. The Bio-Plex(®) assay revealed significant differences between the patients and controls in cytokines, chemokines and growth factor profiles: i, The elevated interleukin-6 (IL-6), IL-7, IL-13, tumor necrosis factor α (TNF-α), interferon γ and platelet-derived growth factor levels in lumbar DS samples of subchondral FJ bone. These indicated ongoing inflammation, bone formation and increased fibroblasts activity in the FJ bone. ii, The elevated levels of IL-6, IL-8, TNF-α, granulocyte-macrophage colony-stimulating factor and monocyte chemoattractant protein-1 in anulus fibrosus together with increased IL-6, IL-8, TNF-α and eotaxin and decreased IL-1-receptor antagonist in nucleus pulposus confirmed advanced IVD degeneration in the patient samples. This study identified, for the first time, protective levels of cytokines, chemokines and growth factors in healthy subjects and supported their significant involvement in the pathogenesis of lumbar DS. The

  14. Neuroprotective peptides influence cytokine and chemokine alterations in a model of fetal alcohol syndrome.

    Science.gov (United States)

    Roberson, Robin; Kuddo, Thea; Benassou, Ines; Abebe, Daniel; Spong, Catherine Y

    2012-12-01

    Fetal alcohol syndrome (FAS) is associated with intellectual disability and neurodevelopmental abnormalities. Neuroprotective peptides NAPVSIPQ (NAP) and SALLRSIPA (SAL) can prevent some of the alcohol-induced teratogenesis including fetal death, growth abnormalities, and learning impairment in part by preventing alcohol-induced alterations in N-methyl-D-aspartate receptor gene expression in a mouse model for FAS. We evaluated a panel of cytokines and chemokines to determine whether NAP plus SAL work through a cytokine/chemokine-mediated pathway in preventing these alterations. Using a well-characterized FAS model, timed, pregnant C57BL6/J mice were treated on gestational day (E) 8 with alcohol (0.03 mL/g), placebo, or alcohol plus peptides. Embryos were evaluated at 2 time points: after 6 hours and 10 days later at E18. A panel of cytokines/chemokines was measured using a microsphere-based multiplex immunoassay (Luminex xMAP; Millipore, Billerica, MA). Statistical analysis included Kruskal-Wallis, with P Alcohol treatment resulted in detectable levels and significant increases in IL-6 (median, 15.7; range, 10.1-45.9 pg/mL) and KC (median, 45.9; range, 32.5-99.1 pg/mL). Embryos exposed to alcohol plus NAP plus SAL had undetectable IL-6 and KC (both P Alcohol exposure resulted in a significant increase of granulocyte colony-stimulating factor (G-CSF) (P alcohol-induced increase. IL-13 and IL-1β were decreased 6 hours after alcohol exposure, and exposure to alcohol plus NAP plus SAL did not completely ameliorate the decrease. At E18, 10 days after exposure, these alterations were no longer present. Several analytes (regulated upon activation, normal T cell expressed, and secreted, tumor necrosis factor-α, interferon-γ, and IL-4) were not detectable at either time point in any of the groups. Prenatal alcohol exposure acutely results in a significant elevation of IL-6, G-CSF and the KC, which are known to affect N-methyl-D-aspartate receptors. NAP plus SAL treatment

  15. Rose hip and its constituent galactolipids confer cartilage protection by modulating cytokine, and chemokine expression

    Directory of Open Access Journals (Sweden)

    Schwager Joseph

    2011-11-01

    Full Text Available Abstract Background Clinical studies have shown that rose hip powder (RHP alleviates osteoarthritis (OA. This might be due to anti-inflammatory and cartilage-protective properties of the complete RHP or specific constituents of RHP. Cellular systems (macrophages, peripheral blood leukocytes and chondrocytes, which respond to inflammatory and OA-inducing stimuli, are used as in vitro surrogates to evaluate the possible pain-relief and disease-modifying effects of RHP. Methods (1 Inflammatory processes were induced in RAW264.7 cells or human peripheral blood leukocytes (PBL with LPS. Inflammatory mediators (nitric oxide (NO, prostaglandin E2 (PGE2 and cytokines/chemokines were determined by the Griess reaction, EIA and multiplex ELISA, respectively. Gene expression was quantified by RT-PCR. RHP or its constituent galactolipid, GLGPG (galactolipid (2S-1, 2-di-O-[(9Z, 12Z, 15Z-octadeca-9, 12, 15-trienoyl]-3-O-β-D-galactopyranosyl glycerol, were added at various concentrations and the effects on biochemical and molecular parameters were evaluated. (2 SW1353 chondrosarcoma cells and primary human knee articular chondrocytes (NHAC-kn were treated with interleukin (IL-1β to induce in vitro processes similar to those occurring during in vivo degradation of cartilage. Biomarkers related to OA (NO, PGE2, cytokines, chemokines, metalloproteinases were measured by multiplex ELISA and gene expression analysis in chondrocytes. We investigated the modulation of these events by RHP and GLGPG. Results In macrophages and PBL, RHP and GLGPG inhibited NO and PGE2 production and reduced the secretion of cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-12 and chemokines (CCL5/RANTES, CXCL10/IP-10. In SW1353 cells and primary chondrocytes, RHP and GLGPG diminished catabolic gene expression and inflammatory protein secretion as shown by lower mRNA levels of matrix metalloproteinases (MMP-1, MMP-3, MMP-13, aggrecanase (ADAMTS-4, macrophage inflammatory protein (MIP-2, MIP-3

  16. Rac1/RhoA antagonism defines cell-to-cell heterogeneity during epidermal morphogenesis in nematodes.

    Science.gov (United States)

    Martin, Emmanuel; Ouellette, Marie-Hélène; Jenna, Sarah

    2016-11-21

    The antagonism between the GTPases Rac1 and RhoA controls cell-to-cell heterogeneity in isogenic populations of cells in vitro and epithelial morphogenesis in vivo. Its involvement in the regulation of cell-to-cell heterogeneity during epidermal morphogenesis has, however, never been addressed. We used a quantitative cell imaging approach to characterize epidermal morphogenesis at a single-cell level during early elongation of Caenorhabditis elegans embryos. This study reveals that a Rac1-like pathway, involving the Rac/Cdc42 guanine-exchange factor β-PIX/PIX-1 and effector PAK1/PAK-1, and a RhoA-like pathway, involving ROCK/LET-502, control the remodeling of apical junctions and the formation of basolateral protrusions in distinct subsets of hypodermal cells. In these contexts, protrusions adopt lamellipodia or an amoeboid morphology. We propose that lamella formation may reduce tension building at cell-cell junctions during morphogenesis. Cell-autonomous antagonism between these pathways enables cells to switch between Rac1- and RhoA-like morphogenetic programs. This study identifies the first case of cell-to-cell heterogeneity controlled by Rac1/RhoA antagonism during epidermal morphogenesis. © 2016 Martin et al.

  17. Insulin-like growth factor-I provokes functional antagonism and internalization of beta1-adrenergic receptors.

    Science.gov (United States)

    Gavi, Shai; Yin, Dezhong; Shumay, Elena; Wang, Hsien-yu; Malbon, Craig C

    2007-06-01

    Hormones that activate receptor tyrosine kinases have been shown to regulate G protein-coupled receptors, and herein we investigate the ability of IGF-I to regulate the beta(1)-adrenergic receptor. Treating Chinese hamster ovary cells in culture with IGF-I is shown to functionally antagonize the ability of expressed beta(1)-adrenergic receptors to accumulate intracellular cAMP in response to stimulation by the beta-adrenergic agonist Iso. The attenuation of beta(1)-adrenergic action was accompanied by internalization of beta(1)-adrenergic receptors in response to IGF-I. Inhibiting either phosphatidylinositol 3-kinase or the serine/threonine protein kinase Akt blocks the ability of IGF-I to antagonize and to internalize beta(1)-adrenergic receptors. Mutation of one potential Akt substrate site Ser412Ala, but not another Ser312Ala, of the beta(1)-adrenergic receptor abolishes the ability of IGF-I to functionally antagonize and to sequester the beta(1)-adrenergic receptor. We also tested the ability of IGF-I to regulate beta(1)-adrenergic receptors and their signaling in adult canine cardiac myocytes. IGF-I attenuates the ability of beta(1)-adrenergic receptors to accumulate intracellular cAMP in response to Iso and promotes internalization of beta(1)-adrenergic receptors in these cardiac myocytes.

  18. Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4.

    Science.gov (United States)

    Ward, Stacey A; Warrington, Nicole M; Taylor, Sara; Kfoury, Najla; Luo, Jingqin; Rubin, Joshua B

    2017-03-15

    The CXCR4 chemokine and Sonic Hedgehog (SHH) morphogen pathways are well-validated therapeutic targets in cancer, including medulloblastoma. However, single-agent treatments with SHH or CXCR4 antagonists have not proven efficacious in clinical trials to date. Here, we discovered that dual inhibition of the SHH and CXCR4 pathways in a murine model of SHH-subtype medulloblastoma exerts potent antitumor effects. This therapeutic synergy resulted in the suppression of tumor-propagating cell function and correlated with increased histone H3 lysine 27 trimethylation within the promoters of stem cell genes, resulting in their decreased expression. These results demonstrate that CXCR4 contributes to the epigenetic regulation of a tumor-propagating cell phenotype. Moreover, they provide a mechanistic rationale to evaluate the combination of SHH and CXCR4 inhibitors in clinical trials for the treatment of medulloblastoma, as well as other cancers driven by SHH that coexpress high levels of CXCR4. Cancer Res; 77(6); 1416-26. ©2016 AACR. ©2016 American Association for Cancer Research.

  19. Platelet-derived chemokines CXC chemokine ligand (CXCL)7, connective tissue-activating peptide III, and CXCL4 differentially affect and cross-regulate neutrophil adhesion and transendothelial migration.

    Science.gov (United States)

    Schenk, Birgit I; Petersen, Frank; Flad, Hans-Dieter; Brandt, Ernst

    2002-09-01

    In this study, we have examined the major platelet-derived CXC chemokines connective tissue-activating peptide III (CTAP-III), its truncation product neutrophil-activating peptide 2 (CXC chemokine ligand 7 (CXCL7)), as well as the structurally related platelet factor 4 (CXCL4) for their impact on neutrophil adhesion to and transmigration through unstimulated vascular endothelium. Using monolayers of cultured HUVEC, we found all three chemokines to promote neutrophil adhesion, while only CXCL7 induced transmigration. Induction of cell adhesion following exposure to CTAP-III, a molecule to date described to lack neutrophil-stimulating capacity, depended on proteolytical conversion of the inactive chemokine into CXCL7 by neutrophils. This was evident from experiments in which inhibition of the CTAP-III-processing protease and simultaneous blockade of the CXCL7 high affinity receptor CXCR-2 led to complete abrogation of CTAP-III-mediated neutrophil adhesion. CXCL4 at substimulatory dosages modulated CTAP-III- as well as CXCL7-induced adhesion. Although cell adhesion following exposure to CTAP-III was drastically reduced, CXCL7-mediated adhesion underwent significant enhancement. Transendothelial migration of neutrophils in response to CXCL7 or IL-8 (CXCL8) was subject to modulation by CTAP-III, but not CXCL4, as seen by drastic desensitization of the migratory response of neutrophils pre-exposed to CTAP-III, which was paralleled by selective down-modulation of CXCR-2. Altogether our results demonstrate that there exist multiple interactions between platelet-derived chemokines in the regulation of neutrophil adhesion and transendothelial migration.

  20. Novel Human Cytomegalovirus Viral Chemokines, vCXCL-1s, Display Functional Selectivity for Neutrophil Signaling and Function

    NARCIS (Netherlands)

    Heo, Jinho; Dogra, Pranay; Masi, Tom J; Pitt, Elisabeth A; de Kruijf, Petra; Smit, Martine J; Sparer, Tim E

    2015-01-01

    Human CMV (HCMV) uses members of the hematopoietic system including neutrophils for dissemination throughout the body. HCMV encodes a viral chemokine, vCXCL-1, that is postulated to attract neutrophils for dissemination within the host. The gene encoding vCXCL-1, UL146, is one of the most variable

  1. Dose Ramadan Fasting Affects Inflammatory Responses: Evidences for Modulatory Roles of This Unique Nutritional Status via Chemokine Network

    Directory of Open Access Journals (Sweden)

    Fateme Akrami Mohajeri

    2013-12-01

    The results of this study may reveal that Ramadan fasting is quite safe for normal healthy adults and so very useful in reduction of cholesterol and triglycerides in relation with dyslipidemia. It is also possible to conclude that fasting is important in controlling of inflammation via chemokines.

  2. Gene expression profile of cytokines and chemokines in skin lesions from Brazilian Indians with localized cutaneous leishmaniasis.

    Science.gov (United States)

    Costa-Silva, Matheus Fernandes; Gomes, Luciana Inácia; Martins-Filho, Olindo Assis; Rodrigues-Silva, Renata; Freire, Janaína de Moura; Quaresma, Patrícia Flávia; Pascoal-Xavier, Marcelo Antônio; Mendes, Tiago Antônio de Oliveira; Serakides, Rogéria; Zauli, Danielle Alves Gomes; Campi-Azevedo, Ana Carolina; Melo, Maria Norma; Gontijo, Célia Maria Ferreira; Peruhype-Magalhães, Vanessa; Teixeira-Carvalho, Andréa

    2014-02-01

    Cutaneous leishmaniasis (CL) is a chronic inflammatory disease caused by dermotropic Leishmania species belonging to the Viannia subgenera, with Leishmania (V.) braziliensis considered the main agent in Brazil. After infection, a local inflammatory process is initiated, inducing the expression of several cytokine/chemokine genes. We evaluated the immunity to CL of patients living in the indigenous community Xakriabá, Minas Gerais state, Brazil, by performing detailed analyses of the mRNA expression of different cytokines and chemokines in CL lesions, considering the time evolution (recent or late). We also studied the profile of the inflammatory infiltrate by histopathological analysis. The histopathological features of recent CL lesions showed an intense inflammatory reaction, characterized by the presence of both mononuclear and polymorphonuclear cells, whereas late CL lesions exhibited a predominance of mononuclear leukocytes. The gene expression of cytokines/chemokines in skin biopsies from the CL group showed higher transcript levels of modulatory (IL10 and TGFB1), anti-inflammatory (IL4), and pro-inflammatory (TNF, IFNG, IL12B, CCL2, CCL3, CCL5, CXCL10) biomarkers in recent lesions than in late lesions. Our findings suggest that differential gene expression of cytokines and chemokines found in skin lesions from CL patients is associated with time evolution of lesions. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Reversed binding of a small molecule ligand in homologous chemokine receptors - differential role of extracellular loop 2

    DEFF Research Database (Denmark)

    Jensen, P C; Thiele, S; Steen, A

    2012-01-01

    The majority of small molecule compounds targeting chemokine receptors share a similar pharmacophore with a centrally located aliphatic positive charge and flanking aromatic moieties. Here we describe a novel piperidine-based compound with structural similarity to previously described CCR8-specif...

  4. The C-C Chemokines CCL17 and CCL22 and Their Receptor CCR4 in CNS Autoimmunity

    Directory of Open Access Journals (Sweden)

    Stefanie Scheu

    2017-11-01

    Full Text Available Multiple sclerosis (MS is a chronic inflammatory demyelinating disease of the central nervous system (CNS. It affects more than two million people worldwide, mainly young adults, and may lead to progressive neurological disability. Chemokines and their receptors have been shown to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE, a murine disease model induced by active immunization with myelin proteins or transfer of encephalitogenic CD4+ T cells that recapitulates clinical and neuropathological features of MS. Chemokine ligand-receptor interactions orchestrate leukocyte trafficking and influence multiple pathophysiological cellular processes, including antigen presentation and cytokine production by dendritic cells (DCs. The C-C class chemokines 17 (CCL17 and 22 (CCL22 and their C-C chemokine receptor 4 (CCR4 have been shown to play an important role in homeostasis and inflammatory responses. Here, we provide an overview of the involvement of CCR4 and its ligands in CNS autoimmunity. We review key clinical studies of MS together with experimental studies in animals that have demonstrated functional roles of CCR4, CCL17, and CCL22 in EAE pathogenesis. Finally, we discuss the therapeutic potential of newly developed CCR4 antagonists and a humanized anti-CCR4 antibody for treatment of MS.

  5. GluVII:06--a highly conserved and selective anchor point for non-peptide ligands in chemokine receptors

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Schwartz, Thue W

    2006-01-01

    to be crucially important for the binding and action of a number of non-peptide ligands in for example the CCR1, CCR2 and CCR5 receptors. It is proposed that in chemokine receptors in general GluVII:06 serves as a selective anchor point for the centrally located, positively charged nitrogen of the small molecule...

  6. In vitro and in vivo dependency of chemokine generation on C5a and TNF-alpha

    DEFF Research Database (Denmark)

    Czermak, B J; Sarma, V; Bless, N M

    1999-01-01

    Under a variety of conditions, alveolar macrophages can generate early response cytokines (TNF-alpha, IL-1), complement components, and chemotactic cytokines (chemokines). In the current studies, we determined the requirements for TNF-alpha and the complement activation product C5a in chemokine...... was studied in rat alveolar macrophages stimulated with IgG immune complexes in the absence or presence of Abs to TNF-alpha or C5a. The rat lung injury model induced by IgG immune complex deposition was employed for in vivo studies. Abs to TNF-alpha or C5a were administered intratracheally or i.......v., and effects on chemokine levels in bronchoalveolar lavage fluids were quantitated by ELISA. Both in vitro and in vivo studies demonstrated the requirements for TNF-alpha and C5a for full generation of CXC and CC chemokines. In vitro and in vivo blockade of TNF-alpha or C5a resulted in significantly reduced...

  7. Selective suppression of chemokine receptor CXCR3 expression by interferon-beta1a in multiple sclerosis

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Sellebjerg, F

    2002-01-01

    We studied the expression of chemokine receptors CCR1, CCR2, CCR3, CCR5, and CXCR3 on CD4 and CD8 positive T cells, and on CD14 positive monocytes in blood from 10 patients with relapsing-remitting multiple sclerosis (MS) at initiation of interferon (IFN)-beta treatment, after 1 month and after 3...

  8. Multiplex array analysis of circulating cytokines and chemokines in natalizumab-treated patients with multiple sclerosis.

    Science.gov (United States)

    Villani, Sonia; Zanotta, Nunzia; Ambrogi, Federico; Comar, Manola; Franciotta, Diego; Dolci, Maria; Cason, Carolina; Ticozzi, Rosalia; Ferrante, Pasquale; Delbue, Serena

    2017-09-15

    Natalizumab greatly reduces inflammatory relapses in multiple sclerosis (MS) by blocking the integrin-mediated leukocyte traffic to the brain, but less is known about its effects on the systemic immunity. We measured 48 cytokines/chemokines in sera from 19 natalizumab-treated MS patients. Serum concentrations of both anti-(IL-10, IL1ra) and pro-inflammatory (IL7, IL16) molecules decreased after 21-month treatment, without associations to unbalanced Th2/Th1cytokine ratios, clinical responses, and blood/urine replication of polyomavirus JC (JCPyV). No patient developed the JCPyV-related progressive multifocal leukoencephalopathy (PML), the major risk factor of natalizumab therapy. Our data suggest that natalizumab has marginal impact on the systemic immunity. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

    DEFF Research Database (Denmark)

    Ockinger, J; Stridh, P; Beyeen, A D

    2010-01-01

    Multiple sclerosis (MS) is a complex disorder of the central nervous system, causing inflammation, demyelination and axonal damage. A limited number of genetic risk factors for MS have been identified, but the etiology of the disease remains largely unknown. For the identification of genes...... regulating neuroinflammation we used a rat model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), and carried out a linkage analysis in an advanced intercross line (AIL). We thereby redefine the Eae18b locus to a 0.88 Mb region, including a cluster...... of chemokine genes. Further, we show differential expression of Ccl2, Ccl11 and Ccl11 during EAE in rat strains with opposite susceptibility to EAE, regulated by genotype in Eae18b. The human homologous genes were tested for association to MS in 3841 cases and 4046 controls from four Nordic countries...

  10. Efficient T-cell surveillance of the CNS requires expression of the CXC chemokine receptor 3

    DEFF Research Database (Denmark)

    Christensen, Jeanette Erbo; Nansen, Anneline; Moos, Torben

    2004-01-01

    T-cells play an important role in controlling viral infections inside the CNS. To study the role of the chemokine receptor CXCR3 in the migration and positioning of virus-specific effector T-cells within the brain, CXCR3-deficient mice were infected intracerebrally with lymphocytic choriomeningitis......-cell-mediated immunopathology. Quantitative analysis of the cellular infiltrate in CSF of infected mice revealed modest, if any, decrease in the number of mononuclear cells recruited to the meninges in the absence of CXCR3. However, immunohistological analysis disclosed a striking impairment of CD8+ T-cells from CXCR3......-deficient mice to migrate from the meninges into the outer layers of the brain parenchyma despite similar localization of virus-infected target cells. Reconstitution of CXCR3-deficient mice with wild-type CD8+ T-cells completely restored susceptibility to LCMV-induced meningitis. Thus, taken together, our...

  11. The chemokine receptor CXCR2 and coronavirus-induced neurologic disease.

    Science.gov (United States)

    Weinger, Jason G; Marro, Brett S; Hosking, Martin P; Lane, Thomas E

    2013-01-05

    Inoculation with the neurotropic JHM strain of mouse hepatitis virus (MHV) into the central nervous system (CNS) of susceptible strains of mice results in an acute encephalomyelitis in which virus preferentially replicates within glial cells while excluding neurons. Control of viral replication during acute disease is mediated by infiltrating virus-specific T cells via cytokine secretion and cytolytic activity, however sterile immunity is not achieved and virus persists resulting in chronic neuroinflammation associated with demyelination. CXCR2 is a chemokine receptor that upon binding to specific ligands promotes host defense through recruitment of myeloid cells to the CNS as well as protecting oligodendroglia from cytokine-mediated death in response to MHV infection. These findings highlight growing evidence of the diverse and important role of CXCR2 in regulating neuroinflammatory diseases. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Induction of Chemokine Secretion and Monocyte Migration by Human Choroidal Melanocytes in Response to Proinflammatory Cytokines

    DEFF Research Database (Denmark)

    Jehs, Tina; Faber, Carsten; Udsen, Maja S.

    2016-01-01

    Purpose: To determine to which extent inflammatory cytokines affect chemokine secretion by primary human choroidal melanocytes (HCMs), their capacity to attract monocytes, and whether HCMs are able to influence the proliferation of activated T cells. Methods: Primary cultures of HCMs were...... and secretion of CXCL8, CXCL9, CXCL10, CXCL11, CCL2, CCL5 and intercellular adhesion molecule 1. Vascular endothelial growth factor and monocyte migration inhibitory factor were constitutively expressed without changes in response to proinflammatory cytokines. Supernatants derived from unstimulated cultures...... of 10 HCM donors induced a high initial level of monocyte migration, which decreased upon stimulation with either TCM or IFN-γ and TNF-α. The supernatants from three HCM donors initially showed a low level of monocyte attraction, which increased after exposure to proinflammatory cytokines. Direct...

  13. Human B cells produce chemokine CXCL10 in the presence of Mycobacterium tuberculosis specific T cells

    DEFF Research Database (Denmark)

    Hoff, Soren T; Salman, Ahmed M; Ruhwald, Morten

    2015-01-01

    BACKGROUND: The role of B cells in human host response to Mycobacterium tuberculosis (Mtb) infection is still controversial, but recent evidence suggest that B cell follicle like structures within the lung may influence host responses through regulation of the local cytokine environment. A candid......BACKGROUND: The role of B cells in human host response to Mycobacterium tuberculosis (Mtb) infection is still controversial, but recent evidence suggest that B cell follicle like structures within the lung may influence host responses through regulation of the local cytokine environment....... A candidate for such regulation could be the chemokine CXCL10. CXCL10 is mainly produced by human monocytes, but a few reports have also found CXCL10 production by human B cells. The objective of this study was to investigate CXCL10 production by human B cells in response to in vitro stimulation with Mtb...

  14. Cloning and functional characterization of the rabbit C-C chemokine receptor 2

    Directory of Open Access Journals (Sweden)

    Hamdouchi Chafiq

    2005-07-01

    Full Text Available Abstract Background CC-family chemokine receptor 2 (CCR2 is implicated in the trafficking of blood-borne monocytes to sites of inflammation and is implicated in the pathogenesis of several inflammatory diseases such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. The major challenge in the development of small molecule chemokine receptor antagonists is the lack of cross-species activity to the receptor in the preclinical species. Rabbit models have been widely used to study the role of various inflammatory molecules in the development of inflammatory processes. Therefore, in this study, we report the cloning and characterization of rabbit CCR2. Data regarding the activity of the CCR2 antagonist will provide valuable tools to perform toxicology and efficacy studies in the rabbit model. Results Sequence alignment indicated that rabbit CCR2 shares 80 % identity to human CCR2b. Tissue distribution indicated that rabbit CCR2 is abundantly expressed in spleen and lung. Recombinant rabbit CCR2 expressed as stable transfectants in U-937 cells binds radiolabeled 125I-mouse JE (murine MCP-1 with a calculated Kd of 0.1 nM. In competition binding assays, binding of radiolabeled mouse JE to rabbit CCR2 is differentially competed by human MCP-1, -2, -3 and -4, but not by RANTES, MIP-1α or MIP-1β. U-937/rabbit CCR2 stable transfectants undergo chemotaxis in response to both human MCP-1 and mouse JE with potencies comparable to those reported for human CCR2b. Finally, TAK-779, a dual CCR2/CCR5 antagonist effectively inhibits the binding of 125I-mouse JE (IC50 = 2.3 nM to rabbit CCR2 and effectively blocks CCR2-mediated chemotaxis. Conclusion In this study, we report the cloning of rabbit CCR2 and demonstrate that this receptor is a functional chemotactic receptor for MCP-1.

  15. Association between subchronic and chronic lead exposure and levels of antioxidants and chemokines.

    Science.gov (United States)

    Dobrakowski, Michał; Kasperczyk, Aleksandra; Pawlas, Natalia; Birkner, Ewa; Hudziec, Edyta; Chwalińska, Ewa; Kasperczyk, Sławomir

    2016-10-01

    This study aimed to compare the influence of lead on the non-enzymatic antioxidant defenses and the levels of chemokines in workers subchronically and chronically exposed to lead. The study population was divided into three groups. The first group consisted of male workers subchronically exposed to lead for 40 ± 3.2 days, while the second group included male workers chronically exposed to lead. The third group was a control group. The levels of uric acid and bilirubin were significantly higher after a subchronic exposure to lead compared to the baseline by 22 and 35 %, respectively. Similarly, the values of total antioxidant capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI) increased by 15, 50, and 33 %, respectively. At the same time, the levels of thiol groups and albumin decreased by 5 and 8 %, respectively. Additionally, the levels of interleukin-8 (IL-8) and macrophage inflammatory protein-1β (MIP-1β) were significantly higher after a subchronic exposure to lead compared to the baseline by 34 and 20 %, respectively. Moreover, IL-8 level was significantly higher by 40 % in the group of workers chronically exposed to lead than in the control group, while the level of interferon gamma-induced protein-10 (IP-10) was significantly lower by 28 %. Similar to chronic lead exposure, subchronic exposure to lead is associated with elevated blood levels of uric acid and bilirubin in humans. This probably results in increased TAC value despite thiol depletion. However, the compensatory activation of non-enzymatic antioxidant defenses seems to be insufficient to protect against lead-induced oxidative stress, which may be additively enhanced by the pro-inflammatory action of chemokines, especially IL-8.

  16. Effects of chemokine (C-C motif) ligand 1 on microglial function.

    Science.gov (United States)

    Akimoto, Nozomi; Ifuku, Masataka; Mori, Yuki; Noda, Mami

    2013-07-05

    Microglia, which constitute the resident macrophages of the central nervous system (CNS), are generally considered as the primary immune cells in the brain and spinal cord. Microglial cells respond to various factors which are produced following nerve injury of multiple aetiologies and contribute to the development of neuronal disease. Chemokine (C-C motif) ligand 1 (CCL-1), a well-characterized chemokine secreted by activated T cells, has been shown to play an important role in neuropathic pain induced by nerve injury and is also produced in various cell types in the CNS, especially in dorsal root ganglia (DRG). However, the role of CCL-1 in the CNS and the effects on microglia remains unclear. Here we showed the multiple effects of CCL-1 on microglia. We first showed that CCR-8, a specific receptor for CCL-1, was expressed on primary cultured microglia, as well as on astrocytes and neurons, and was upregulated in the presence of CCL-1. CCL-1 at concentration of 1 ng/ml induced chemotaxis, increased motility at a higher concentration (100 ng/ml), and increased proliferation and phagocytosis of cultured microglia. CCL-1 also activated microglia morphologically, promoted mRNA levels for brain-derived neurotrophic factor (BDNF) and IL-6, and increased the release of nitrite from microglia. These indicate that CCL-1 has a role as a mediator in neuron-glia interaction, which may contribute to the development of neurological diseases, especially in neuropathic pain. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Fractalkine receptor chemokine (CX3CR1 influences on cervical and lumbar disc herniation

    Directory of Open Access Journals (Sweden)

    In-Soo Oh

    2015-01-01

    of CX3CL1 and CX3CR1 in the disc degeneration and to compare between cervical and lumbar HNP. Materials and Methods: The mRNA concentrations of CX3CL1/CX3CR1 chemokine were analyzed in the surgically obtained disc specimens from C-HNP (n = 13 and L-HNP (n = 13 by real-time polymerase chain reaction (PCR. The localization of CX3CL1/CX3CR1 chemokine in the disc of C-HNP and L-HNP patients was determined using immunohistochemical study. Blood samples from patients with C-HNP and L-HNP patients were stained for CX3CR1 with flow cytometric analysis. Results: The CX3CL1 positive cell ratio in the discs was observed in both groups by immunohistochemical study. CX3CR1 was strongly expressed on endothelial cells in C-spine disc, but sparely expressed in L-spine disc. There was greater CX3CR1 mRNA expression in C-HNP patients than in L-HNP patients as quantified by reversal transcription-PCR (P = 0.010. CX3CR1 positive cell frequencies and CX3CR1 expression levels were increased in CD4 (+ T-cells and natural killer (NK cells from patients with C-HNP (P = 0.210 and P = 0.040. Conclusions: This study identified that increases in CX3CL1 and CX3CR1-expressing cells are significantly related to pathomechanism of HNP for the first time. Especially, CD4 (+ T-cells and NK cells expressing CX3CR1 may play an important role in developing C-HNP.

  18. Elevated Urinary T Helper 1 Chemokine Levels in Newly Diagnosed Hypertensive Obese Children

    Science.gov (United States)

    Övünç Hacıhamdioğlu, Duygu; Zeybek, Cengiz; Gök, Faysal; Pekel, Aysel; Muşabak, Uğur

    2015-01-01

    Objective: Increasing evidence suggests that T helper (Th) cells play a significant role in the pathogenesis of hypertension. The aim of this study was to evaluate the effect of obesity and anti-hypertensive treatment on urinary Th1 chemokines. Methods: The study groups consisted of three types of patients: hypertensive obese, healthy, and non-hypertensive obese. Pre-treatment and post-treatment samples of the hypertensive obese group and one sample from the other two groups were evaluated for urinary chemokine: regulated on activation, normal T cell expressed and secreted (RANTES), interferon-gamma-inducible protein 10 (IP10), and monokine induced by interferon-gamma (MIG). In the hypertensive obese group, urine microalbumin: creatinine ratio was examined before and after treatment. We recommended lifestyle changes to all patients. Captopril was started in those who could not be controlled with lifestyle changes and those who had stage 2 hypertension. Results: Twenty-four hypertensive obese (mean age 13.1), 27 healthy (mean age 11.2) and 22 non-hypertensive obese (mean age 11.5) children were investigated. The pre-treatment urine albumin: creatinine ratio was positively correlated with pre-treatment MIG levels (r=0.41, phypertensive and non-hypertensive obese group than in the controls. The urinary IP10 and MIG levels were higher in the pre-treatment hypertensive obese group than in the non-hypertensive obese. Comparison of the pre- and post-treatment values indicated significant decreases in RANTES, IP10, and MIG levels in the hypertensive obese group (phypertensive children before the onset of clinical indicators of target organ damage. Urinary RANTES seemed to be affected by both hypertension and obesity, and urinary IP10 and MIG seemed to be affected predominantly by hypertension. PMID:26831550

  19. Platelets as a Novel Source of Pro-Inflammatory Chemokine CXCL14

    Directory of Open Access Journals (Sweden)

    Alexander Witte

    2017-03-01

    Full Text Available Objective: Platelets are a major source of chemokines. Here, we demonstrate for the first time that platelets express significant amounts of CXCL14 and disclose powerful effects of platelet-derived CXCL14 on monocyte and endothelial migration. Methods: The expression of CXCL14 in platelets and in the supernatant of activated platelets was analysed by immunoblotting, ELISA, and flow cytometry. The effect of platelet-derived CXCL14 on monocyte migration was evaluated using a modified Boyden chamber. The effect of CXCL14 on monocyte phagocytosis was tested by using fluorochrome-labelled E.coli particles. The effect of platelet-derived CXCL14 on endothelial migration was explored by the use of an endothelial scratch assay. Results: Hitherto unrecognized expression of CXCL14 in human and murine platelets was uncovered by immunoblotting. Activation with platelet agonists such as adenosine-di-phosphate (ADP, collagen-related peptide (CRP, or thrombin-receptor activating peptide (TRAP, increased CXCL14 surface expression (flow cytometry and release into the supernatant (immunoblotting, ELISA. Since CXCL14 is known to be chemotactic for CD14+ monocytes, we investigated the chemotactic potential of platelet-derived CXCL14 on human monocytes. Activated platelet supernatant induced monocyte migration, which was counteracted upon neutralization of platelet-derived CXCL14 as compared to IgG control. Blocking of the chemokine receptor CXCR4, but not CXCR7, reduced the number of migratory monocytes towards recombinant CXCL14, suggesting the involvement of CXCR4 in the CXCL14-directed monocyte chemotaxis. Recombinant CXCL14 enhanced the phagocytic uptake of E.coli particles by monocytes. In scratch assays with cultured endothelial cells (HUVECs, platelet-derived CXCL14 counteracted the pro-angiogenic effects of VEGF, supporting its previously recognized angiostatic potential. Conclusions: Platelets are a relevant source of CXCL14. Platelet-derived CXCL14 at the

  20. COPD promotes migration of A549 lung cancer cells: the role of chemokine CCL21

    Directory of Open Access Journals (Sweden)

    Kuźnar-Kamińska B

    2016-05-01

    Full Text Available Barbara Kuźnar-Kamińska,1 Justyna Mikuła-Pietrasik,2 Patrycja Sosińska,2 Krzysztof Książek,2 Halina Batura-Gabryel1 1Department of Pulmonology, Allergology and Respiratory Oncology, 2Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland Abstract: Patients with COPD develop lung cancer more frequently than healthy smokers. At the same time, molecular mediators promoting various aspects of cancer cell progression are still elusive. In this report, we examined whether COPD can be coupled with increased migration of non-small-cell lung cancer cells A549 and, if so, whether this effect may be related to altered production and activity of chemokines CCL21, CXCL5, and CXCL12. The study showed that the migration of A549 cells through the polycarbonate membrane and basement membrane extract toward a chemotactic gradient elicited by serum from patients with COPD was markedly higher as compared with serum from healthy donors. The concentration of CCL21 and CXCL12, but not CXCL5, in serum from patients with COPD was also increased. Experiments in which CCL21- and CXCL12-dependent signaling was blocked revealed that increased migration of the cancer cells upon treatment with serum from patients with COPD was mediated exclusively by CCL21. Collectively, our results indicate that COPD may contribute to the progression of lung cancer via CCL21-dependent intensification of cancer cell migration. Keywords: chemokines, COPD, lung cancer, migration