DOCSLIB.ORG

A GPR40 Agonist GW9508 Suppresses CCL5, CCL17, And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A GPR40 Agonist GW9508 Suppresses CCL5, CCL17, And View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector ORIGINAL ARTICLE A GPR40 Agonist GW9508 Suppresses CCL5, CCL17, and CXCL10 Induction in Keratinocytes and Attenuates Cutaneous Immune Inflammation Tomoko Fujita1,2, Toshiyuki Matsuoka1,2, Tetsuya Honda3, Kenji Kabashima1,3, Takako Hirata1,2 and Shuh Narumiya1,2 G-protein coupled receptors (GPCR) exert diverse physiological functions, many of which are exploited therapeutically. The roles of GPCR in keratinocytes in immune response in the skin, however, remain poorly defined. In this study, we focused on Gi-coupled GPCR in keratinocytes and defined their actions in immunoactivation of cultured keratinocytes in vitro and immune reaction in the skin in vivo. We first activated HaCaT cells by tumor necrosis factor (TNF)-a and IFN-g and examined effects of various ligands for GPCR on production of CCL17 and CCL5. Agonists for Gi-coupled receptors, particularly GW9508 for GPR40, inhibited CCL17 and CCL5 expression in a pertussis toxin-sensitive manner. The inhibitory effect by GW9508 was abrogated by depletion of GPR40 with RNA interference. GW9508 further suppressed expression of IL-11, IL-24, and IL-33 induced in HaCaT cells by TNF-a and IFN-g. GW9508 also inhibited CCL5 and CXCL10 production by normal human epidermal keratinocytes. Administration of GW9508 topically to the skin in the challenging phase suppressed ear swelling in a repeated hapten application model and contact hypersensitivity with downregulation of CCL5 and CXCL10, respectively. Thus, in the skin, stimulation of Gi-coupled receptors attenuates induction of critical cytokines and chemokines by proinflammatory cytokines in keratinocytes and suppresses allergic inflammation in the skin. Journal of Investigative Dermatology (2011) 131, 1660–1667; doi:10.1038/jid.2011.123; published online 19 May 2011 INTRODUCTION such as taste or odor perception. Notably, about half of all G-proteins consisting of a, b, and g subunits are signal drugs currently used clinically target GPCR in various transducers and mediate actions of G-protein coupled systems from the central nervous system to the cardiovascular receptors (GPCR) with seven transmembrane domains in system. However, the role of GPCR in the immune system the plasma membrane (Neves et al., 2002). Each GPCR is remains obscure and their therapeutic application in this area coupled to either a different class of G-proteins, Gs, Gi, Gq, has been limited to those for chemokines and other or G12/13, or a combination thereof. Gsa activates adenylate chemotactic substances such as sphingosine-1-phosphate cyclase, and raises the intracellular concentration of cAMP. (Rosen et al., 2007). GPCR have been generally viewed as On the other hand, Gia inhibits adenylate cyclase and mediating immunosuppression through elevation of intra- decreases intracellular cAMP. Among more than 1,000 GPCR cellular cAMP in cells such as macrophages and T cells encoded by mammalian genomes, up to 400–500 GPCR (Nance and Sanders, 2007). However, contrary to this recognize neurotransmitters, hormones, and paracrine oversimplified view, recent studies have indicated that GPCR factors, whereas others are involved in sensory functions have diverse roles in immunity depending on the context of immune response. For example, we have recently shown that stimulation of the cAMP pathway by prostaglandin 1Center for Innovation in Immunoregulative Technology and Therapeutics, E receptors EP2 and EP4 exerts significant facilitation of Th17 2 Kyoto University, Kyoto, Japan; Department of Pharmacology, Faculty of expansion by regulating IL-23 expression by dendritic cells Medicine, Kyoto University, Kyoto, Japan and 3Department of Dermatology, Faculty of Medicine, Kyoto University, Kyoto, Japan and enhancing the IL-23-induced Th17 amplification Correspondence: Shuh Narumiya, Department of Pharmacology, Faculty of (Yao et al., 2009). These findings have questioned the simple Medicine, Kyoto University, Yoshida Konoecho, Kyoto, 606-8501 Japan. paradigm of the immunosuppression by cAMP and suggest E-mail: [email protected] that the action of a GPCR in the immune system has to be Abbreviations: AD, atopic dermatitis; CHS, contact hypersensitivity; GPCR, defined in the contexts of target cells and tissues, timing of G-protein coupled receptors; NHEK, normal human epidermal keratinocyte; stimulation, types of other combined stimuli, and output of PTX, pertussis toxin; QRT-PCR, quantitative RT-PCR; TNF, tumor necrosis factor; TNF-a þ IFN-g, TNF-a and IFN-g in combination the response at various levels. Received 17 November 2010; revised 24 February 2011; accepted 21 March The incidence and severity of allergic skin diseases such as 2011; published online 19 May 2011 contact hypersensitivity (CHS) and atopic dermatitis (AD) 1660 Journal of Investigative Dermatology (2011), Volume 131 & 2011 The Society for Investigative Dermatology T Fujita et al. A GPR40 Agonist Suppresses Skin Inflammation have increased extensively over the last 20 years in keratinocytes (NHEKs), and mouse models of AD and CHS, developed countries, and drugs targeted to these diseases and addressed these issues. are urgently demanded. In these allergic diseases, keratino- cytes have a crucial role in disease progression (Girolomoni RESULTS et al., 2004; Pastore et al., 2006). We previously reported that GPR40 agonist GW9508 suppresses CCL17 production through administration of an agonist of prostaglandin E receptor EP3, pertussis toxin-sensitive Gi protein a Gi-coupled receptor, attenuates allergic asthma (Kunikata We first used HaCaT human epidermal keratinocyte cell line. et al., 2005), CHS (Honda et al., 2009), and allergic Previous reports showed that HaCaT cells produce CCL17 in conjunctivitis (Ueta et al., 2009). Stimulation of cannabinoid response to stimulation with tumor necrosis factor (TNF)-a CB1 and CB2 receptors, both coupled to Gi, has also been or IFN-g alone, or TNF-a and IFN-g in combination shown to induce attenuation of DNFB-induced CHS (Karsak (TNF-a þ IFN-g; Saeki and Tamaki, 2006). We exploited this et al., 2007). Although EP3 is expressed on epithelial cells in finding and reproduced synergistic production of CCL17 by the airway and conjunctiva and keratinocytes in the skin TNF-a þ IFN-g in HaCaT cells, both at mRNA and protein and EP3 in these cells is suggested to mediate the above levels (Figure 1a). We also found that TNF-a and IFN-g therapeutic action, a direct proof of the involvement of synergistically enhance CCL5 production by HaCaT cells Gi-coupled receptors in keratinocytes in such action is (Figure 1b). CCL17 and CCL5 are produced by keratinocytes lacking. In this study, we first sought to define the actions in inflammatory states and have crucial roles in Th2-type of Gi-coupled receptors in cultured keratinocytes and then to immune responses such as AD (Pastore et al., 2006; Saeki analyze the effects of such pathway in elicitation of immune and Tamaki, 2006). To screen GPCR ligands that inhibit the inflammation in the skin. Here, we used HaCaT, a human TNF-a þ IFN-g-induced chemokine expression, we examined epidermal keratinocyte cell line, normal human epidermal the activity of compounds in the Tocriscreen Mini library in *** ** * * * ) 70 * 35 * ) 1,250 ** –1 125 –1 60 30 1,000 50 100 25 (a.u.) 40 75 (a.u.) 20 750 15 30 50 500 20 10 250 25 5 10 Ccl5/Gapdh Ccl17/Gapdh 0 CCL5 protein (pg ml 0 0 CCL17 protein (pg ml 0 None TNF-α IFN-γ TI None TNF-α IFN-γ TI None TNF-α IFN-γ TI None TNF-α IFN-γ TI 90 125 80 ) 70 ) –1 1,250 70 100 60 –1 1,000 (a.u.) 60 50 75 (a.u.) 50 *** *** 40 * 750 40 ** ** * ** 30 30 50 ** 500 20 20 25 Ccl17/Gapdh 250 10 Ccl5/Gapdh 10 CCL17 protein (pg ml 0 0 0 CCL5 protein (pg ml 0 TI TI+veh –8 –7 –6 TI TI+veh –8 –7 –6 TI TI+veh –8 –7 –6 TI TI+veh –8 –7 –6 TI + GW9508 (log[M]) TI + GW9508 (log [M]) TI + GW9508 (log [M]) TI + GW9508 (log [M]) 250 ** 70 *** 150 *** ) 1,250 200 60 * –1 * (a.u.) 50 1,000 150 100 ** 40 (a.u.) 750 100 ** 30 500 20 50 50 Ccl17/Gapdh 10 250 Ccl5/Gapdh 0 CCL17 protein (pg/ml) 0 0 CCL5 protein (pg ml TI+veh 0 1 10 TI+veh 0 1 10 0 TI+veh 0 1 10 TI+veh 0 1 10 μ –1 TI + 1 M GW9508 + PTX (ng ml ) TI + 1 μM GW9508 + PTX (ng ml–1) –1 TI + 1 μM GW9508 + PTX (ng ml ) TI + 1 μM GW9508 + PTX (ng ml–1) 150 *** 125 *** 100 (a.u.) 100 (a.u.) 75 50 50 25 Ccl5/Gapdh Ccl17/Gapdh 0 0 TI+veh –8 –7 –6 TI+veh –8 –7 –6 TI + forskolin (log[M]) TI + forskolin (log [M]) Figure 1. Inhibition by GW9508 of tumor necrosis factor (TNF)-a þ IFN-c-induced production of CCL17 and CCL5 in HaCaT cells. CCL17 (a) and CCL5 (b) production by TNF-a and/or IFN-g. Inhibitory effect of GW9508 on TNF-a þ IFN-g-induced CCL17 (c) and CCL5 (d) production. Effect of pertussis toxin (PTX) (e and f) and forskolin (g) on TNF-a þ IFN-g-induced CCL17 and CCL5 production. TI, TNF-a þ IFN-g; veh, vehicle. Quantitative real-time RT-PCR data are shown as arbitrary units (a.u.) where the value for unstimulated sample is set at 1. Results show a representative of three independent experiments. Data show mean±SEM (n ¼ 3). *Po0.05, **Po0.01, ***Po0.001 versus TI þ veh in (c–f). www.jidonline.org 1661 T Fujita et al. A GPR40 Agonist Suppresses Skin Inflammation this system with CCL17 as a parameter. This screening GPR40 (–) GPR120 (–) GAPDH (–) revealed that several agonists for putative Gi-coupled receptors, such as ST91 for a2 adrenergic receptor, GP1a and GP2a for CB2, 30-fluorobenzyl-spiperone for dopamine D2, and GW9508 for GPR40 potently suppressed the 1.0 TNF-a þ IFN-g-induced CCL17 production (Supplementary Table S1 online).
Load more

Recommended publications
  • C-X-C Motif Chemokine Ligand 10 Produced by Mouse Sertoli Cells in Response to Mumps Virus Infection Induces Male Germ Cell Apoptosis
    Citation: Cell Death and Disease (2017) 8, e3146; doi:10.1038/cddis.2017.560 OPEN Macmillan Publishers Limited, part of Springer Nature. www.nature.com/cddis Corrected: Correction C-X-C motif chemokine ligand 10 produced by mouse Sertoli cells in response to mumps virus infection induces male germ cell apoptosis Qian Jiang1, Fei Wang1, Lili Shi1, Xiang Zhao1, Maolei Gong1, Weihua Liu1, Chengyi Song2, Qihan Li3, Yongmei Chen1, Han Wu*,1,2 and Daishu Han*,1 Mumps virus (MuV) infection usually results in germ cell degeneration in the testis, which is an etiological factor for male infertility. However, the mechanisms by which MuV infection damages male germ cells remain unclear. The present study showed that C-X-C motif chemokine ligand 10 (CXCL10) is produced by mouse Sertoli cells in response to MuV infection, which induces germ cell apoptosis through the activation of caspase-3. CXC chemokine receptor 3 (CXCR3), a functional receptor of CXCL10, is constitutively expressed in male germ cells. Neutralizing antibodies against CXCR3 and an inhibitor of caspase-3 activation significantly inhibited CXCL10-induced male germ cell apoptosis. Furthermore, the tumor necrosis factor-α (TNF-α) upregulated CXCL10 production in Sertoli cells after MuV infection. The knockout of either CXCL10 or TNF-α reduced germ cell apoptosis in the co-cultures of germ cells and Sertoli cells in response to MuV infection. Local injection of MuV into the testes of mice confirmed the involvement of CXCL10 in germ cell apoptosis in vivo. These results provide novel insights into MuV-induced germ cell apoptosis in the testis.
    [Show full text]
  • Critical Role of CXCL4 in the Lung Pathogenesis of Influenza (H1N1) Respiratory Infection
    ARTICLES Critical role of CXCL4 in the lung pathogenesis of influenza (H1N1) respiratory infection L Guo1,3, K Feng1,3, YC Wang1,3, JJ Mei1,2, RT Ning1, HW Zheng1, JJ Wang1, GS Worthen2, X Wang1, J Song1,QHLi1 and LD Liu1 Annual epidemics and unexpected pandemics of influenza are threats to human health. Lung immune and inflammatory responses, such as those induced by respiratory infection influenza virus, determine the outcome of pulmonary pathogenesis. Platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) has an immunoregulatory role in inflammatory diseases. Here we show that CXCL4 is associated with pulmonary influenza infection and has a critical role in protecting mice from fatal H1N1 virus respiratory infection. CXCL4 knockout resulted in diminished viral clearance from the lung and decreased lung inflammation during early infection but more severe lung pathology relative to wild-type mice during late infection. Additionally, CXCL4 deficiency decreased leukocyte accumulation in the infected lung with markedly decreased neutrophil infiltration into the lung during early infection and extensive leukocyte, especially lymphocyte accumulation at the late infection stage. Loss of CXCL4 did not affect the activation of adaptive immune T and B lymphocytes during the late stage of lung infection. Further study revealed that CXCL4 deficiency inhibited neutrophil recruitment to the infected mouse lung. Thus the above results identify CXCL4 as a vital immunoregulatory chemokine essential for protecting mice against influenza A virus infection, especially as it affects the development of lung injury and neutrophil mobilization to the inflamed lung. INTRODUCTION necrosis factor (TNF)-a, interleukin (IL)-6, and IL-1b, to exert Influenza A virus (IAV) infections cause respiratory diseases in further antiviral innate immune effects.2 Meanwhile, the innate large populations worldwide every year and result in seasonal immune cells act as antigen-presenting cells and release influenza epidemics and unexpected pandemic.
    [Show full text]
  • Ncomms1239.Pdf
    ARTICLE Received 10 Nov 2010 | Accepted 15 Feb 2011 | Published 15 Mar 2011 DOI: 10.1038/ncomms1239 Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer Ole Audun Werner Haabeth1, Kristina Berg Lorvik1, Clara Hammarström2, Ian M. Donaldson3,4, Guttorm Haraldsen2, Bjarne Bogen1 & Alexandre Corthay1 The immune system can both promote and suppress cancer. Chronic inflammation and proinflammatory cytokines such as interleukin (IL)-1 and IL-6 are considered to be tumour promoting. In contrast, the exact nature of protective antitumour immunity remains obscure. Here, we quantify locally secreted cytokines during primary immune responses against myeloma and B-cell lymphoma in mice. Strikingly, successful cancer immunosurveillance mediated by tumour-specific CD4 + T cells is consistently associated with elevated local levels of both proinflammatory (IL-1α, IL-1β and IL-6) and T helper 1 (Th1)-associated cytokines (interferon-γ (IFN-γ), IL-2 and IL-12). Cancer eradication is achieved by a collaboration between tumour- specific Th1 cells and tumour-infiltrating, antigen-presenting macrophages. Th1 cells induce secretion of IL-1β and IL-6 by macrophages. Th1-derived IFN-γ is shown to render macrophages directly cytotoxic to cancer cells, and to induce macrophages to secrete the angiostatic chemokines CXCL9/MIG and CXCL10/IP-10. Thus, inflammation, when driven by tumour- specific Th1 cells, may prevent rather than promote cancer. 1 Centre for Immune Regulation, Institute of Immunology, University of Oslo and Oslo University Hospital Rikshospitalet, PO Box 4950 Nydalen, 0424 Oslo, Norway. 2 Department of Pathology, Institute of Pathology, Oslo University Hospital Rikshospitalet and University of Oslo, PO Box 4950 Nydalen, 0424 Oslo, Norway.
    [Show full text]
  • Establishment of HIV-1 Latency in Resting CD4+ T Cells Depends on Chemokine-Induced Changes in the Actin Cytoskeleton
    Establishment of HIV-1 latency in resting CD4+ T cells depends on chemokine-induced changes in the actin cytoskeleton Paul U. Camerona,b,c,1, Suha Salehb,1, Georgina Sallmannb, Ajantha Solomonb, Fiona Wightmanb, Vanessa A. Evansb, Genevieve Boucherd, Elias K. Haddadd,Rafick-Pierre Sekalyd, Andrew N. Harmane, Jenny L. Andersonf, Kate L. Jonesf, Johnson Makf,g, Anthony L. Cunninghame, Anthony Jaworowskib,c,f, and Sharon R. Lewina,b,f,2 aInfectious Diseases Unit, Alfred Hospital, Melbourne, Victoria 3004, Australia; Departments of bMedicine and cImmunology, Monash University, Melbourne 3004, Australia; dLaboratoire d’Immunologie, Centre de Recherche de Centre Hospitalier de L’Universitie de Montreal, Saint-Luc, Quebec, Canada; eWestmead Millenium Research Institute, Westmead 2145, Australia; fCentre for Virology, Burnet Institute, Melbourne 3004, Australia; and gDepartment of Biochemistry and Molecular Biology, Department of Microbiology, Monash University, Clayton 3800, Australia Edited by Malcolm A. Martin, National Institute of Allergy and Infectious Diseases, Bethesda, MD, and approved August 23, 2010 (received for review March 8, 2010) Eradication of HIV-1 with highly active antiretroviral therapy mokines, in addition to CXCR4 ligands may facilitate HIV-1 + (HAART) is not possible due to the persistence of long-lived, entry and integration in resting CD4 T cells and that this was latently infected resting memory CD4+ T cells. We now show that mediated via activation of actin. + HIV-1 latency can be established in resting CD4+ T cells infected We now show that the exposure of resting CD4 T cells to with HIV-1 after exposure to ligands for CCR7 (CCL19), CXCR3 the chemokines CCL19, CXCL10, and CCL20, all of which fi (CXCL9 and CXCL10), and CCR6 (CCL20) but not in unactivated regulate T-cell migration, allows for ef cient HIV-1 nuclear lo- + calization and integration of the HIV-1 provirus, that this oc- CD4 T cells.
    [Show full text]
  • Expression and Analysis of CXCL8 and CXCL10 Chemokines In
    erial D act is b ea o s c e y s M Mycobacterial Diseases Rawat et al., Mycobact Dis 2016, 6:2 DOI: 10.4172/2161-1068.1000208 ISSN: 2161-1068 Research an open access journal Expression and Analysis of CXCL8 and CXCL10 Chemokines in Human Skin Lesions Infected with M.leprae Krishan Dutta Rawat1, Mamta Chahar1, PVJ Reddy1, Nalini Srivastava2, U.D.Gupta1, M. Natrajan1, V.M. Katoch3, Kiran Katoch1 and D.S. Chauhan1* 1National JALMA Institute for Leprosy & Other Mycobacterial Diseases Tajganj, Agra, U.P, India 2SOS in Biotechnology, Jiwaji University, Gwalior, M.P, India. 3Department of Health Research, Indian Council of Medical Research, Ansari Nagar, New Delhi, India *Corresponding author: Chauhan DS, Microbiology & Molecular biology Lab, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, (ICMR) Tajganj, Agra-282001, Tel: (0562) 2331751-4; Fax: +91-562-2331755; E-mail: [email protected] Rec date: February 02, 2016; Acc date: May 19, 2016; Pub date: May 24, 2016 Copyright: © 2016 Rawat KD, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract This study is focused to analyze the expression profile of CXCL8 and CXCL10 chemokines genes and to address the contribution of these chemokines in late phase of M.leprae infection in human skin lesion samples. In this study skin biopsy samples from leprosy patients (n=35) were collected including BL-LL=12, BB=14, BT=8 and healthy volunteers (n=3).
    [Show full text]
  • Expression and Regulation of Chemokines in Murine and Human Type 1 Diabetes Suparna A
    ORIGINAL ARTICLE Expression and Regulation of Chemokines in Murine and Human Type 1 Diabetes Suparna A. Sarkar,1 Catherine E. Lee,1 Francisco Victorino,1,2 Tom T. Nguyen,1 Jay A. Walters,1 Adam Burrack,1,2 Jens Eberlein,1 Steven K. Hildemann,3 and Dirk Homann1,2,4 fl – More than one-half of the ~50 human chemokines have been in ammation (1 3), and multiple chemokines and chemokine associated with or implicated in the pathogenesis of type 1 receptors have emerged as pertinent contributors to the diabetes, yet their actual expression patterns in the islet environ- natural history of various autoimmune disorders, including ment of type 1 diabetic patients remain, at present, poorly defined. type 1 diabetes; potential biomarkers; and possible drug Here, we have integrated a human islet culture system, murine targets (4–8). In fact, work conducted over the past 20 models of virus-induced and spontaneous type 1 diabetes, and the years has implicated more than one-half of all human and/ histopathological examination of pancreata from diabetic organ or rodent chemokines in the pathogenesis of type 1 diabetes donors with the goal of providing a foundation for the informed and/or its complications, although much of the work pub- selection of potential therapeutic targets within the chemokine/ receptor family. Chemokine (C-C motif) ligand (CCL) 5 (CCL5), lished to date on human type 1 diabetes and chemokines CCL8, CCL22, chemokine (C-X-C motif) ligand (CXCL) 9 (CXCL9), remains limited to genetic association studies and che- CXCL10, and chemokine (C-X3-C motif) ligand (CX3CL) 1 (CX3CL1) mokine/receptor analyses in peripheral blood (9–23).
    [Show full text]
  • Human CXCL4/PF4 Immunoassay Quantikine
    Quantikine® ELISA Human CXCL4/PF4 Immunoassay Catalog Number DPF40 For the quantitative determination of human Platelet Factor 4 (PF4) concentrations in cell culture supernates, serum, and platelet-poor plasma. This package insert must be read in its entirety before using this product. For research use only. Not for use in diagnostic procedures. TABLE OF CONTENTS SECTION PAGE INTRODUCTION ....................................................................................................................................................................1 PRINCIPLE OF THE ASSAY ..................................................................................................................................................2 LIMITATIONS OF THE PROCEDURE ................................................................................................................................2 TECHNICAL HINTS ................................................................................................................................................................2 MATERIALS PROVIDED & STORAGE CONDITIONS ..................................................................................................3 OTHER SUPPLIES REQUIRED ............................................................................................................................................3 PRECAUTIONS ........................................................................................................................................................................4 SAMPLE
    [Show full text]
  • Baseline CXCL10 and CXCL13 Levels Are Predictive Biomarkers for Tumor Necrosis Factor Inhibitor Therapy in Patients with Moderat
    Han et al. Arthritis Research & Therapy (2016) 18:93 DOI 10.1186/s13075-016-0995-0 RESEARCH ARTICLE Open Access Baseline CXCL10 and CXCL13 levels are predictive biomarkers for tumor necrosis factor inhibitor therapy in patients with moderate to severe rheumatoid arthritis: a pilot, prospective study Bobby Kwanghoon Han1*, Igor Kuzin2, John P. Gaughan3, Nancy J. Olsen4 and Andrea Bottaro2 Abstract Background: TNF inhibitors have been used as a treatment for moderate to severe RA patients. However, reliable biomarkers that predict therapeutic response to TNF inhibitors are lacking. In this study, we investigated whether chemokines may represent useful biomarkers to predict the response to TNF inhibitor therapy in RA. Methods: RA patients (n = 29) who were initiating adalimumab or etanercept were recruited from the rheumatology clinics at Cooper University Hospital. RA patients were evaluated at baseline and 14 weeks after TNF inhibitor therapy, and serum levels of CXCL10, CXCL13, and CCL20 were measured by ELISA. Responders (n = 16) were defined as patients who had good or moderate response at week 14 by EULAR response criteria, and nonresponders (n = 13) were defined as having no response. Results: Responders had higher levels of baseline CXCL10 and CXCL13 compared to nonresponders (p =0.03 and 0.002 respectively). There was no difference in CCL20 levels. CXCL10 and CXCL13 were highly correlated with each other, and were higher in seropositive RA patients. CXCL10 and CXCL13 levels were decreased after TNF inhibitor therapy in responders. Baseline additive levels of CXCL10 + 13 were correlated with changes in DAS score at 14 weeks after TNF inhibitor therapy (r = 0.42, p = 0.03), and ROC curve analyses for predictive ability of CXCL10 + 13 showed an AUC of 0.83.
    [Show full text]
  • Glial Cell Activation, Recruitment, and Survival of B-Lineage Cells Following MCMV Brain Infection James R
    Lokensgard et al. Journal of Neuroinflammation (2016) 13:114 DOI 10.1186/s12974-016-0582-y RESEARCH Open Access Glial cell activation, recruitment, and survival of B-lineage cells following MCMV brain infection James R. Lokensgard*, Manohar B. Mutnal, Sujata Prasad, Wen Sheng and Shuxian Hu Abstract Background: Chemokines produced by reactive glia drive migration of immune cells and previous studies from our laboratory have demonstrated that CD19+ B cells infiltrate the brain. In this study, in vivo and in vitro experiments investigated the role of reactive glial cells in recruitment and survival of B-lineage cells in response to (murine cytomegalovirus) MCMV infection. Methods: Flow cytometric analysis was used to assess chemokine receptor expression on brain-infiltrating B cells. Real-time RT-PCR and ELISA were used to measure chemokine levels. Dual-immunohistochemical staining was used to co-localize chemokine production by reactive glia. Primary glial cell cultures and migration assays were used to examine chemokine-mediated recruitment. Astrocyte: B cell co-cultures were used to investigate survival and proliferation. Results: The chemokine receptors CXCR3, CXCR5, CCR5, and CCR7 were detected on CD19+ cells isolated from the brain during MCMV infection. In particular, CXCR3 was found to be elevated on an increasing number of cells over the time course of infection, and it was the primary chemokine receptor expressed at 60 days post infection Quite different expression kinetics were observed for CXCR5, CCR5, and CCR7, which were elevated on the highest number of cells early during infection and decreased by 14, 30, and 60 days post infection Correspondingly, elevated levels of CXCL9, CXCL10, and CXCL13, as well as CCL5, were found within the brains of infected animals, and only low levels of CCL3 and CCL19 were detected.
    [Show full text]
  • The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are
    viruses Article The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner Victoria Callahan 1, Seth Hawks 2, Matthew A. Crawford 3 , Caitlin W. Lehman 2 , Holly A. Morrison 2 , Hannah M. Ivester 4, Ivan Akhrymuk 2, Niloufar Boghdeh 1, Rafaela Flor 1, Carla V. Finkielstein 5 , Irving Coy Allen 2,6,7, James Weger-Lucarelli 2,7, Nisha Duggal 2,7, Molly A. Hughes 3 and Kylene Kehn-Hall 1,2,7,* 1 National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA; [email protected] (V.C.); [email protected] (N.B.); mfl[email protected] (R.F.) 2 Department of Biomedical Science and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA; [email protected] (S.H.); [email protected] (C.W.L.); [email protected] (H.A.M.); [email protected] (I.A.); [email protected] (I.C.A.); [email protected] (J.W.-L.); [email protected] (N.D.) 3 Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA; [email protected] (M.A.C.); [email protected] (M.A.H.) Citation: Callahan, V.; Hawks, S.; 4 Graduate Program in Translational Biology, Medicine and Health, Virginia Polytechnic Institute and State Crawford, M.A.; Lehman, C.W.; University, Roanoke, VA 24061, USA; [email protected] 5 Morrison, H.A.; Ivester, H.M.; Integrated Cellular Responses Laboratory, Department of Biological Sciences and Center for Drug Discovery, Akhrymuk, I.; Boghdeh, N.; Flor, R.; Fralin Biomedical Research Institute, Virginia Polytechnic Institute and State University, Roanoke, VA 24016, USA; fi[email protected] Finkielstein, C.V.; et al.
    [Show full text]
  • The Expression of CXCL10/CXCR3 and Effect of the Axis on the Function of T Lymphocyte Involved in Oral Lichen Planus
    Inflammation, Vol. 42, No. 3, June 2019 ( # 2018) DOI: 10.1007/s10753-018-0934-0 ORIGINAL ARTICLE The Expression of CXCL10/CXCR3 and Effect of the Axis on the Function of T Lymphocyte Involved in Oral Lichen Planus Jiaxiang Fang,1,2 Chen Wang,1,2 Chen Shen,3 Jing Shan,1,2 Xuewei Wang,1,2 Lin Liu,1,2 and Yuan Fan1,2,4 Abstract— The etiology of oral lichen planus (OLP) is still not clear. The purpose of this study was to explore the role of CXC chemokine receptor 3(CXCR3) and its ligand CXC motif chemokine 10(CXCL10) in the pathogenesis of OLP. We examined the expression of CXCR3 and CXCL10 in OLP patients and healthy controls by quantitative real-time PCR, Western blotting, ELISAs, and immunohistochemistry, respectively. Moreover, we detected the effects of CXCL10/CXCR3 axis on T lymphocyte migration, proliferation and apoptosis by Trans- well assays, CCK8 assays, and flow cytometry. We found that the expression of CXCR3 and CXCL10 was significantly increased in OLP patients. In addition, T lymphocyte migration rate of CXCL10 stimulation group was significantly higher than that of control and CXCR3 antagonist groups. After antagonizing CXCR3, the migration ability of T lymphocytes was significantly decreased, and regardless of whether CXCL10 was added in the upper chamber culture medium, the number of migrating cells was similar. The addition of CXCL10 stimulant could stimulate the proliferation of T lymphocytes, but there was no significant difference compared with control group. After antagonizing CXCR3, the proliferation rate of T lymphocytes was significantly reduced. However, there were no significant differences in the apoptosis rates of T lymphocytes between CXCL10 stimulation group, antagonist CXCR3 group, and control group.
    [Show full text]
  • Fas Ligand Promotes an Inducible TLR-Dependent Model of Cutaneous Lupus-Like Inflammation
    University of Massachusetts Medical School eScholarship@UMMS University of Massachusetts Medical School Faculty Publications 2018-06-11 Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus-like inflammation Purvi Mande University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/faculty_pubs Part of the Dermatology Commons, Immune System Diseases Commons, Immunity Commons, Immunopathology Commons, Rheumatology Commons, and the Skin and Connective Tissue Diseases Commons Repository Citation Mande P, Zirak B, Ko W, Taravati K, Bride KL, Brodeur TB, Deng AC, Dresser KA, Jiang Z, Ettinger R, Fitzgerald KA, Rosenblum MD, Harris JE, Marshak-Rothstein A. (2018). Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus-like inflammation. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1172/JCI98219. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1581 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in University of Massachusetts Medical School Faculty Publications by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Fas ligand promotes an inducible TLR- dependent model of cutaneous lupus–like inflammation Purvi Mande, … , John E. Harris, Ann Marshak-Rothstein J Clin Invest. 2018;128(7):2966-2978. https://doi.org/10.1172/JCI98219. Research Article Autoimmunity Dermatology Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9–/– autoimmune-prone strains paradoxically develop more severe disease.
    [Show full text]