The Experts below are selected from a list of 21786 Experts worldwide ranked by ideXlab platform
Richard F Loeser - One of the best experts on this subject based on the ideXlab platform.
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interleukin 7 stimulates secretion of s100a4 by activating the jak stat Signaling Pathway in human articular chondrocytes
Arthritis & Rheumatism, 2009Co-Authors: Raghunatha R Yammani, David L Long, Richard F LoeserAbstract:Objective S100A4 has been shown to be increased in osteoarthritic (OA) cartilage and to stimulate chondrocytes to produce matrix metalloproteinase 13 (MMP-13) through activation of the receptor for advanced glycation end products (RAGE). The aim of this study was to examine the mechanism of S100A4 secretion by chondrocytes. Methods Human articular chondrocytes isolated from ankle cartilage were stimulated with 10 ng/ml of interleukin-1β (IL-1β), IL-6, IL-7, or IL-8. Cells were pretreated with either a JAK-3 inhibitor, brefeldin A, or cycloheximide. Immunoblotting with phospho-specific antibodies was used to determine the activation of Signaling proteins. Secretion of S100A4 was measured in conditioned media by immunoblotting, and MMP-13 was measured by enzyme-linked immunosorbent assay. Results Chondrocyte secretion of S100A4 was observed after treatment with IL-6 or IL-8 but was much greater in cultures treated with equal amounts of IL-7 and was not observed after treatment with IL-1β. IL-7 activated the JAK/STAT Pathway, with increased phosphorylation of JAK-3 and STAT-3, leading to increased production of S100A4 and MMP-13. Overexpression of a dominant-negative RAGE construct inhibited the IL-7–mediated production of MMP-13. Pretreatment of chondrocytes with a JAK-3 inhibitor or with cycloheximide blocked the IL-7–mediated secretion of S100A4, but pretreatment with brefeldin A did not. Conclusion IL-7 stimulates chondrocyte secretion of S100A4 via activation of JAK/STAT Signaling, and then S100A4 acts in an autocrine manner to stimulate MMP-13 production via RAGE. Since both IL-7 and S100A4 are up-regulated in OA cartilage and can stimulate MMP-13 production by chondrocytes, this Signaling Pathway could contribute to cartilage destruction during the development of OA.
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interleukin 7 stimulates secretion of s100a4 by activating the jak stat Signaling Pathway in human articular chondrocytes
Arthritis & Rheumatism, 2009Co-Authors: Raghunatha R Yammani, David L Long, Richard F LoeserAbstract:Objective S100A4 has been shown to be increased in osteoarthritic (OA) cartilage and to stimulate chondrocytes to produce matrix metalloproteinase 13 (MMP-13) through activation of the receptor for advanced glycation end products (RAGE). The aim of this study was to examine the mechanism of S100A4 secretion by chondrocytes. Methods Human articular chondrocytes isolated from ankle cartilage were stimulated with 10 ng/ml of interleukin-1β (IL-1β), IL-6, IL-7, or IL-8. Cells were pretreated with either a JAK-3 inhibitor, brefeldin A, or cycloheximide. Immunoblotting with phospho-specific antibodies was used to determine the activation of Signaling proteins. Secretion of S100A4 was measured in conditioned media by immunoblotting, and MMP-13 was measured by enzyme-linked immunosorbent assay. Results Chondrocyte secretion of S100A4 was observed after treatment with IL-6 or IL-8 but was much greater in cultures treated with equal amounts of IL-7 and was not observed after treatment with IL-1β. IL-7 activated the JAK/STAT Pathway, with increased phosphorylation of JAK-3 and STAT-3, leading to increased production of S100A4 and MMP-13. Overexpression of a dominant-negative RAGE construct inhibited the IL-7–mediated production of MMP-13. Pretreatment of chondrocytes with a JAK-3 inhibitor or with cycloheximide blocked the IL-7–mediated secretion of S100A4, but pretreatment with brefeldin A did not. Conclusion IL-7 stimulates chondrocyte secretion of S100A4 via activation of JAK/STAT Signaling, and then S100A4 acts in an autocrine manner to stimulate MMP-13 production via RAGE. Since both IL-7 and S100A4 are up-regulated in OA cartilage and can stimulate MMP-13 production by chondrocytes, this Signaling Pathway could contribute to cartilage destruction during the development of OA.
Raghunatha R Yammani - One of the best experts on this subject based on the ideXlab platform.
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interleukin 7 stimulates secretion of s100a4 by activating the jak stat Signaling Pathway in human articular chondrocytes
Arthritis & Rheumatism, 2009Co-Authors: Raghunatha R Yammani, David L Long, Richard F LoeserAbstract:Objective S100A4 has been shown to be increased in osteoarthritic (OA) cartilage and to stimulate chondrocytes to produce matrix metalloproteinase 13 (MMP-13) through activation of the receptor for advanced glycation end products (RAGE). The aim of this study was to examine the mechanism of S100A4 secretion by chondrocytes. Methods Human articular chondrocytes isolated from ankle cartilage were stimulated with 10 ng/ml of interleukin-1β (IL-1β), IL-6, IL-7, or IL-8. Cells were pretreated with either a JAK-3 inhibitor, brefeldin A, or cycloheximide. Immunoblotting with phospho-specific antibodies was used to determine the activation of Signaling proteins. Secretion of S100A4 was measured in conditioned media by immunoblotting, and MMP-13 was measured by enzyme-linked immunosorbent assay. Results Chondrocyte secretion of S100A4 was observed after treatment with IL-6 or IL-8 but was much greater in cultures treated with equal amounts of IL-7 and was not observed after treatment with IL-1β. IL-7 activated the JAK/STAT Pathway, with increased phosphorylation of JAK-3 and STAT-3, leading to increased production of S100A4 and MMP-13. Overexpression of a dominant-negative RAGE construct inhibited the IL-7–mediated production of MMP-13. Pretreatment of chondrocytes with a JAK-3 inhibitor or with cycloheximide blocked the IL-7–mediated secretion of S100A4, but pretreatment with brefeldin A did not. Conclusion IL-7 stimulates chondrocyte secretion of S100A4 via activation of JAK/STAT Signaling, and then S100A4 acts in an autocrine manner to stimulate MMP-13 production via RAGE. Since both IL-7 and S100A4 are up-regulated in OA cartilage and can stimulate MMP-13 production by chondrocytes, this Signaling Pathway could contribute to cartilage destruction during the development of OA.
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interleukin 7 stimulates secretion of s100a4 by activating the jak stat Signaling Pathway in human articular chondrocytes
Arthritis & Rheumatism, 2009Co-Authors: Raghunatha R Yammani, David L Long, Richard F LoeserAbstract:Objective S100A4 has been shown to be increased in osteoarthritic (OA) cartilage and to stimulate chondrocytes to produce matrix metalloproteinase 13 (MMP-13) through activation of the receptor for advanced glycation end products (RAGE). The aim of this study was to examine the mechanism of S100A4 secretion by chondrocytes. Methods Human articular chondrocytes isolated from ankle cartilage were stimulated with 10 ng/ml of interleukin-1β (IL-1β), IL-6, IL-7, or IL-8. Cells were pretreated with either a JAK-3 inhibitor, brefeldin A, or cycloheximide. Immunoblotting with phospho-specific antibodies was used to determine the activation of Signaling proteins. Secretion of S100A4 was measured in conditioned media by immunoblotting, and MMP-13 was measured by enzyme-linked immunosorbent assay. Results Chondrocyte secretion of S100A4 was observed after treatment with IL-6 or IL-8 but was much greater in cultures treated with equal amounts of IL-7 and was not observed after treatment with IL-1β. IL-7 activated the JAK/STAT Pathway, with increased phosphorylation of JAK-3 and STAT-3, leading to increased production of S100A4 and MMP-13. Overexpression of a dominant-negative RAGE construct inhibited the IL-7–mediated production of MMP-13. Pretreatment of chondrocytes with a JAK-3 inhibitor or with cycloheximide blocked the IL-7–mediated secretion of S100A4, but pretreatment with brefeldin A did not. Conclusion IL-7 stimulates chondrocyte secretion of S100A4 via activation of JAK/STAT Signaling, and then S100A4 acts in an autocrine manner to stimulate MMP-13 production via RAGE. Since both IL-7 and S100A4 are up-regulated in OA cartilage and can stimulate MMP-13 production by chondrocytes, this Signaling Pathway could contribute to cartilage destruction during the development of OA.
Lionel B Ivashkiv - One of the best experts on this subject based on the ideXlab platform.
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cross regulation of Signaling Pathways by interferon γ implications for immune responses and autoimmune diseases
Immunity, 2009Co-Authors: Lionel B IvashkivAbstract:Interferon-γ (IFN-γ) is an important mediator of immunity and inflammation that utilizes the JAK-STAT Signaling Pathway to activate the STAT1 transcription factor. Many functions of IFN-γ have been ascribed to direct STAT1-mediated induction of immune effector genes, but recently it has become clear that key IFN-γ functions are mediated by cross-regulation of cellular responses to other cytokines and inflammatory factors. Here, we review mechanisms by which IFN-γ and STAT1 regulate Signaling by Toll-like receptors, inflammatory factors, tissue-destructive cytokines, anti-inflammatory cytokines, and cytokines that activate opposing STATs. These Signaling mechanisms reveal insights about how IFN-γ regulates macrophage activation, inflammation, tissue remodeling, and helper and regulatory T cell differentiation and how Th1 and Th17 cell responses are integrated in autoimmune diseases.
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jak stat Signaling Pathways in cells of the immune system
Reviews in immunogenetics, 2000Co-Authors: Lionel B IvashkivAbstract:Abstract Many, if not most, cytokines important for immune responses utilize the JAK-STAT Signaling Pathway. Jaks are receptor-associated protein tyrosine kinases, and STATs are latent cytoplasmic transcription factors that are activated by tyrosine phosphorylation. STATs play critical, nonredundant roles in mediating cellular transcriptional responses to cytokines, and in cell activation, survival and proliferation. The roles of Jaks and STATs in immune responses have been elucidated by analysis of induction of STAT target genes, and of mice rendered deficient in Jak and STAT genes. Cytokine Signaling is modulated by crosstalk between the JAK-STAT Pathway and Pathways triggered by other major immune receptors, such as antigen receptors and receptors for inflammatory cytokines. Tight regulation of cytokine Signaling is required for homeostasis, and several constitutive and inducible mechanisms for downregulation of JAK-STAT Signaling have been described.
Limin Chen - One of the best experts on this subject based on the ideXlab platform.
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2 5 oligoadenylate synthetase 2 oas2 inhibits zika virus replication through activation of type ι ifn Signaling Pathway
Viruses, 2020Co-Authors: Xinzhong Liao, He Xie, Kai Ren, Wenyu Lin, Xiaoqiong Duan, Chunhui Yang, Limin ChenAbstract:Background: 2′, 5′-oligoadenylate synthetase 2 (OAS2) has been known as an antiviral interferon-stimulated gene (ISG). However, the role of OAS2 on Zika virus (ZIKV) replication is still unknown. In this study, we sought to explore the effect of OAS2 on ZIKV replication and its underlying mechanism. Methods: We performed RNA-Seq in A549 cells with or without ZIKV infection. OAS2 or RIG-I was overexpressed by plasmid transfection or knocked down by siRNA in A549 cells. Expression levels of mRNA and protein of selected genes were detected by RT-qPCR and Western Blot, respectively. Interferon stimulated response element (ISRE) activity was examined by dual luciferase assay. Results: We found that ZIKV infection induced OAS2 expression through a RIG-I-dependent Pathway. OAS2 overexpression inhibited ZIKV replication, while OAS2 knockdown increased ZIKV replication. We observed that OAS2 inhibited ZIKV replication through enhanced IFNβ expression, leading to the activation of the Jak/STAT Signaling Pathway. Conclusion: ZIKV infection induced OAS2 expression, which in turn exerted its anti-ZIKV activities through the IFN-activated Jak/STAT Signaling Pathway.
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isg12a inhibits hcv replication and potentiates the anti hcv activity of ifn α through activation of the jak stat Signaling Pathway independent of autophagy and apoptosis
Virus Research, 2017Co-Authors: Yanzhao Chen, Baihai Jiao, Zhebin Zheng, Shilin Li, Limin ChenAbstract:Abstract Interferon stimulated (sensitive) genes (ISGs) are the effector molecules downstream of type I/III interferon (IFN) Signaling Pathways in host innate immunity. ISG12a can be induced by IFN-α. Although ISG12a has been reported to inhibit the replication of HCV, the exact mechanism remains to be determined. In this study, we investigated the possible mechanisms of ISG12a anti- HCV property by exploring the production of type I IFN and the activation of Janus kinase/signal transducer and activator of transcription (Jak/STAT) Signaling Pathway, apoptosis and autophagy in Huh7.5.1 cells transiently transfected with ISG12a over-expression plasmid. Interestingly, we found that ISG12a inhibited HCV replication in both Con1b replicon and the HCV JFH1-based cell culture system and potentiated the anti-HCV activity of IFN-α. ISG12a promoted the production of IFN α/β and activated the type I IFN Signaling Pathway as shown by increased p-STAT1 level, higher Interferon sensitive response element (ISRE) activity and up-regulated ISG levels. However, ISG12a over-expression did not affect cell autophagy and apoptosis. Data from our current study collectively indicated that ISG12a inhibited HCV replication and potentiated the anti-HCV activity of IFN-α possibly through induced production of type I IFNs and activation of Jak/STAT Signaling Pathway independent of autophagy and cell apoptosis.
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type iii interferon induces distinct socs1 expression pattern that contributes to delayed but prolonged activation of jak stat Signaling Pathway implications for treatment non response in hcv patients
PLOS ONE, 2015Co-Authors: Bing Liu, Shan Chen, Yujuan Guan, Limin ChenAbstract:Suppressor of cytokine Signaling 1 (SOCS1) has long been thought to block type I interferon Signaling. However, IFN-λ, a type III IFN with limited receptor expression in hepatic cells, efficiently inhibits HCV (Hepatitis C virus) replication in vivo with potentially less side effects than IFN-α. Previous studies demonstrated that type I and type III activated Janus kinase/signal transducer and activator of transcription (Jak/STAT) Signaling Pathway differently, with delayed but prolonged activation by IFN-λ stimulation compared to IFNα/β. However, the molecular mechanisms underlying this observation is not well understood. Here, we found that there are distinct differences in SOCS1 expression patterns in Huh-7.5.1 cells following stimulation with IFN-α and IFN-λ. IFN-λ induced a faster but shorter expression of SOCS1. Furthermore, we confirmed that SOCS1 over-expression abrogates anti-HCV effect of both IFN-α and IFN-λ, leading to increased HCV RNA replication in both HCV replicon cells and JFH1 HCV culture system. In line with this, SOCS1 over-expression inhibited STAT1 phosphorylation, attenuated IFN-stimulated response elements (ISRE) reporter activity, and blocked IFN-stimulated genes (ISGs) expression. Finally, we measured SOCS1 mRNA expression levels in peripheral blood mononuclear cells (PBMCs) with or without IFN-α treatment from 48 chronic hepatitis C patients and we found the baseline SOCS1 expression levels are higher in treatment non-responders than in responders before IFN-α treatment. Taken together, SOCS1 acts as a suppressor for both type I and type III IFNs and is negatively associated with sustained virological response (SVR) to IFN-based therapy in patients with HCV. More importantly, faster but shorter induction of SOCS1 by IFN-λ may contribute to delayed but prolonged activation of IFN Signaling and ISG expression kinetics by type III IFN.
William L Jorgensen - One of the best experts on this subject based on the ideXlab platform.
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selective janus kinase 2 jak2 pseudokinase ligands with a diaminotriazole core
Journal of Medicinal Chemistry, 2020Co-Authors: M E Liosi, David E Puleo, Ana S Newton, Joseph Schlessinger, S G Krimmer, Thomas K Dawson, Kara J Cutrona, Yoshihisa Suzuki, William L JorgensenAbstract:Janus kinases (JAKs) are non-receptor tyrosine kinases that are essential components of the JAK-STAT Signaling Pathway. Associated aberrant Signaling is responsible for many forms of cancer and disorders of the immune system. The present focus is on the discovery of molecules that may regulate the activity of JAK2 by selective binding to the JAK2 pseudokinase domain, JH2. Specifically, the Val617Phe mutation in JH2 stimulates the activity of the adjacent kinase domain (JH1) resulting in myeloproliferative disorders. Starting from a non-selective screening hit, we have achieved the goal of discovering molecules that preferentially bind to the ATP binding site in JH2 instead of JH1. We report the design and synthesis of the compounds and binding results for the JH1, JH2, and JH2 V617F domains, as well as five crystal structures for JH2 complexes. Testing with a selective and non-selective JH2 binder on the autophosphorylation of wild-type and V617F JAK2 is also contrasted.
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identification and characterization of jak2 pseudokinase domain small molecule binders
ACS Medicinal Chemistry Letters, 2017Co-Authors: David E Puleo, Kaury Kucera, Henrik Hammaren, Daniela Ungureanu, Ana S Newton, Olli Silvennoinen, William L Jorgensen, Joseph SchlessingerAbstract:Janus kinases (JAKs) regulate hematopoiesis via the cytokine-mediated JAK-STAT Signaling Pathway. JAKs contain tandem C-terminal pseudokinase (JH2) and tyrosine kinase (JH1) domains. The JAK2 pseudokinase domain adopts a protein kinase fold and, despite its pseudokinase designation, binds ATP with micromolar affinity. Recent evidence shows that displacing ATP from the JAK2 JH2 domain alters the hyperactivation state of the oncogenic JAK2 V617F protein while sparing the wild type JAK2 protein. In this study, small molecule binders of JAK2 JH2 were identified via an in vitro screen. Top hits were characterized using biophysical and structural approaches. Development of pseudokinase-selective compounds may offer novel pharmacological opportunities for treating cancers driven by JAK2 V617F and other oncogenic JAK mutants.
