The Experts below are selected from a list of 9699 Experts worldwide ranked by ideXlab platform
Akihiko Yoshimura - One of the best experts on this subject based on the ideXlab platform.
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Negative Regulation of Cytokine Signaling in Immunity
Cold Spring Harbor perspectives in biology, 2018Co-Authors: Akihiko Yoshimura, Minako Ito, Shunsuke Chikuma, Takashi Akanuma, Hiroko NakatsukasaAbstract:Cytokines are key modulators of immunity. Most cytokines use the Janus kinase and signal transducers and activators of transcription (JAK-STAT) pathway to promote gene transcriptional regulation, but their signals must be attenuated by multiple mechanisms. These include the suppressors of cytokine signaling (SOCS) family of proteins, which represent a main negative regulation mechanism for the JAK-STAT pathway. Cytokine-inducible Src homology 2 (SH2)-containing protein (CIS), SOCS1, and SOCS3 proteins regulate cytokine signals that control the polarization of CD4+ T cells and the maturation of CD8+ T cells. SOCS proteins also regulate innate immune cells and are involved in tumorigenesis. This review summarizes recent progress on CIS, SOCS1, and SOCS3 in T cells and tumor immunity.
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suppressors of cytokine signaling potential immune checkpoint molecules for cancer immunotherapy
Cancer Science, 2017Co-Authors: Shunsuke Chikuma, Mitsuhiro Kanamori, Setsuko Miseomata, Akihiko YoshimuraAbstract:Inhibition of immune checkpoint molecules, PD-1 and CTLA4, has been shown to be a promising cancer treatment. PD-1 and CTLA4 inhibit TCR and co-stimulatory signals. The third T cell activation signal represents the signals from the cytokine receptors. The cytokine interferon-γ (IFNγ) plays an important role in anti-tumor immunity by activating cytotoxic T cells (CTLs). Most cytokines use the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and the suppressors of cytokine signaling (SOCS) family of proteins are major negative regulators of the JAK/STAT pathway. Among SOCS proteins, CIS, SOCS1, and SOCS3 proteins can be considered the third immunocheckpoint molecules since they regulate cytokine signals that control the polarization of CD4+ T cells and the maturation of CD8+ T cells. This review summarizes recent progress on CIS, SOCS1, and SOCS3 in terms of their anti-tumor immunity and potential applications.
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suppressors of cytokine signaling socs proteins and jak stat pathways regulation of t cell inflammation by socs1 and SOCS3
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Taiga Tamiya, Hideo Yasukawa, Ikko Kashiwagi, Reiko Takahashi, Akihiko YoshimuraAbstract:Various cytokines are involved in the regulation of the immune system and inflammation. Dysregulation of cytokine signaling can cause a variety of diseases, including allergy, autoimmune diseases, inflammation, and cancer. Most cytokines use the so-called janus kinase/signal transducer and activator of transcription pathway, and this pathway is negatively regulated by suppressors of cytokine signaling (SOCS) proteins. SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.
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SOCS proteins, cytokine signalling and immune regulation
Nature Reviews Immunology, 2007Co-Authors: Akihiko Yoshimura, Tetsuji Naka, Masato KuboAbstract:Suppressor of cytokine signalling (SOCS) proteins are inhibitors of cytokine signalling pathways. Studies have shown that SOCS proteins are key physiological regulators of both innate and adaptive immunity. These molecules positively and negatively regulate macrophage and dendritic-cell activation and are essential for T-cell development and differentiation. Evidence is also emerging of the involvement of SOCS proteins in diseases of the immune system. In this Review we bring together data from recent studies on SOCS proteins and their role in immunity, and propose a cohesive model of how cytokine signalling regulates immune-cell function. Suppressor of cytokine signalling (SOCS) proteins are inhibitors of the Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathways. SOCS1 also inhibits Toll-like receptor (TLR) signalling. SOCS3 determines the different responses induced by the inflammatory cytokine interleukin-6 (IL-6) and the anti-inflammatory cytokine IL-10. In dendritic cells (DCs), SOCS1 negatively regulates T helper 1 (T_H1)-cell induction by DCs, whereas SOCS3 regulates the balance between T_H2 and T_H3 cells. SOCS1 induced by microbes is an important mediator for interferon (IFN)-resistance. In T cells, SOCS1 is important for proper positive and negative selection and CD8^+ T-cell lineage determination because of the restriction of cytokine signalling during T-cell maturation. SOCS1 and SOCS3 regulate T_H-cell differentiation, including T_H1, T_H2, T_H17 and T_H3 cells. SOCS1 and SOCS3 expression levels correlate with human allergy and inflammatory diseases including inflammation-associated tumours. Overexpression or knockdown of SOCS proteins are therapeutic strategies for the treatment of autoimmune diseases and allergy and for the induction of antitumour immunity. In this Review, Akihiko Yoshimura and collegues discuss the most recent advances in our understanding of suppressor of cytokine signalling (SOCS) proteins in the regulation of immunity, their involvement in human diseases and the therapeutic implications of targeting this family of cytokine regulators.
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reciprocal regulation of socs 1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme
Clinical Cancer Research, 2007Co-Authors: Hong Zhou, Akihiko Yoshimura, Rika Miki, Mervi Eeva, Francesca Fike, David Seligson, Lu Yang, Michael A Teitell, Christina Jamieson, Nicholas A. CacalanoAbstract:Purpose: The expression of suppressors of cytokine signaling 1 ( SOCS1 ) and SOCS3 genes is dysregulated in several solid tumors, causing aberrant activation of cell growth and survival signaling pathways. In this study, we analyzed SOCS1 and SOCS3 gene expression in glioblastoma multiforme (GBM) and studied the role of each protein in GBM cell signaling and radiation resistance. Experimental Design: SOCS1 and SOCS3 gene expression was analyzed in 10 GBM cell lines by reverse transcription-PCR and Western blotting. SOCS3 expression was also studied in 12 primary GBM tissues by immunohistochemistry. The methylation status of the SOCS1 and SOCS3 loci was determined by methylation-specific PCR. Extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) activation in GBM cell lines overexpressing SOCS1 or lacking SOCS3 was determined by phosphorylated-specific Western blotting. Radiation responses in SOCS1-positive and SOCS3-deficient GBM cell lines and fibroblasts from wild-type and SOCS1 or SOCS3 knockout mice were studied in a clonogenic survival assay. Results: All GBM cell lines tested lacked SOCS1 expression, whereas GBM cell lines and primary GBM tumor samples constitutively expressed SOCS3. SOCS1 gene repression was linked to hypermethylation of the SOCS1 genetic locus in GBM cells. Reintroduction of SOCS1 or blocking SOCS3 expression sensitized cells to radiation and decreased the levels of activated ERK MAPKs in GBM cells. Conclusions: SOCS1 and SOCS3 are aberrantly expressed in GBM cell lines and primary tissues. Altered SOCS gene expression leads to increased cell signaling through the ERK-MAPK pathway and may play a role in disease pathogenesis by enhancing GBM radioresistance.
Jingyuan Fang - One of the best experts on this subject based on the ideXlab platform.
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trichostatin a a histone deacetylase inhibitor suppresses jak2 stat3 signaling via inducing the promoter associated histone acetylation of socs1 and SOCS3 in human colorectal cancer cells
Molecular Carcinogenesis, 2012Co-Authors: Hua Xiong, Wan Du, Yanjie Zhang, Jie Hong, Wenyu Su, Jieting Tang, Yingchao Wang, Rong Lu, Jingyuan FangAbstract:Aberrant janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling is involved in the oncogenesis of several cancers. Suppressors of cytokine signaling (SOCS) genes and SH2-containing protein tyrosine phosphatase 1 (SHP1) proteins, which are negative regulators of JAK/STAT signaling, have been reported to have tumor suppressor functions. However, in colorectal cancer (CRC) cells, the mechanisms that regulate SOCS and SHP1 genes, and the cause of abnormalities in the JAK/STAT signaling pathway, remain largely unknown. The present study shows that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, leads to the hyperacetylation of histones associated with the SOCS1 and SOCS3 promoters, but not the SHP1 promoter in CRC cells. This indicates that histone modifications are involved in the regulation of SOCS1 and SOCS3. Moreover, upregulation of SOCS1 and SOCS3 expression was achieved using TSA, which also significantly downregulated JAK2/STAT3 signaling in CRC cells. We also demonstrate that TSA suppresses the growth of CRC cells, and induces G1 cell cycle arrest and apoptosis through the regulation of downstream targets of JAK2/STAT3 signaling, including Bcl-2, survivin and p16ink4a. Therefore, our data demonstrate that TSA may induce SOCS1 and SOCS3 expression by inducing histone modifications and consequently inhibits JAK2/STAT3 signaling in CRC cells. These results also establish a mechanistic link between the inhibition of JAK2/STAT3 signaling and the anticancer action of TSA in CRC cells. Mol. Carcinog. © 2011 Wiley Periodicals, Inc.
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trichostatin a a histone deacetylase inhibitor suppresses jak2 stat3 signaling via inducing the promoter associated histone acetylation of socs1 and SOCS3 in human colorectal cancer cells
Molecular Carcinogenesis, 2012Co-Authors: Hua Xiong, Yanjie Zhang, Jie Hong, Jieting Tang, Yingchao Wang, Jingyuan FangAbstract:Aberrant janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling is involved in the oncogenesis of several cancers. Suppressors of cytokine signaling (SOCS) genes and SH2-containing protein tyrosine phosphatase 1 (SHP1) proteins, which are negative regulators of JAK/STAT signaling, have been reported to have tumor suppressor functions. However, in colorectal cancer (CRC) cells, the mechanisms that regulate SOCS and SHP1 genes, and the cause of abnormalities in the JAK/STAT signaling pathway, remain largely unknown. The present study shows that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, leads to the hyperacetylation of histones associated with the SOCS1 and SOCS3 promoters, but not the SHP1 promoter in CRC cells. This indicates that histone modifications are involved in the regulation of SOCS1 and SOCS3. Moreover, upregulation of SOCS1 and SOCS3 expression was achieved using TSA, which also significantly downregulated JAK2/STAT3 signaling in CRC cells. We also demonstrate that TSA suppresses the growth of CRC cells, and induces G1 cell cycle arrest and apoptosis through the regulation of downstream targets of JAK2/STAT3 signaling, including Bcl-2, survivin and p16(ink4a) . Therefore, our data demonstrate that TSA may induce SOCS1 and SOCS3 expression by inducing histone modifications and consequently inhibits JAK2/STAT3 signaling in CRC cells. These results also establish a mechanistic link between the inhibition of JAK2/STAT3 signaling and the anticancer action of TSA in CRC cells.
Hua Xiong - One of the best experts on this subject based on the ideXlab platform.
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trichostatin a a histone deacetylase inhibitor suppresses jak2 stat3 signaling via inducing the promoter associated histone acetylation of socs1 and SOCS3 in human colorectal cancer cells
Molecular Carcinogenesis, 2012Co-Authors: Hua Xiong, Wan Du, Yanjie Zhang, Jie Hong, Wenyu Su, Jieting Tang, Yingchao Wang, Rong Lu, Jingyuan FangAbstract:Aberrant janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling is involved in the oncogenesis of several cancers. Suppressors of cytokine signaling (SOCS) genes and SH2-containing protein tyrosine phosphatase 1 (SHP1) proteins, which are negative regulators of JAK/STAT signaling, have been reported to have tumor suppressor functions. However, in colorectal cancer (CRC) cells, the mechanisms that regulate SOCS and SHP1 genes, and the cause of abnormalities in the JAK/STAT signaling pathway, remain largely unknown. The present study shows that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, leads to the hyperacetylation of histones associated with the SOCS1 and SOCS3 promoters, but not the SHP1 promoter in CRC cells. This indicates that histone modifications are involved in the regulation of SOCS1 and SOCS3. Moreover, upregulation of SOCS1 and SOCS3 expression was achieved using TSA, which also significantly downregulated JAK2/STAT3 signaling in CRC cells. We also demonstrate that TSA suppresses the growth of CRC cells, and induces G1 cell cycle arrest and apoptosis through the regulation of downstream targets of JAK2/STAT3 signaling, including Bcl-2, survivin and p16ink4a. Therefore, our data demonstrate that TSA may induce SOCS1 and SOCS3 expression by inducing histone modifications and consequently inhibits JAK2/STAT3 signaling in CRC cells. These results also establish a mechanistic link between the inhibition of JAK2/STAT3 signaling and the anticancer action of TSA in CRC cells. Mol. Carcinog. © 2011 Wiley Periodicals, Inc.
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trichostatin a a histone deacetylase inhibitor suppresses jak2 stat3 signaling via inducing the promoter associated histone acetylation of socs1 and SOCS3 in human colorectal cancer cells
Molecular Carcinogenesis, 2012Co-Authors: Hua Xiong, Yanjie Zhang, Jie Hong, Jieting Tang, Yingchao Wang, Jingyuan FangAbstract:Aberrant janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling is involved in the oncogenesis of several cancers. Suppressors of cytokine signaling (SOCS) genes and SH2-containing protein tyrosine phosphatase 1 (SHP1) proteins, which are negative regulators of JAK/STAT signaling, have been reported to have tumor suppressor functions. However, in colorectal cancer (CRC) cells, the mechanisms that regulate SOCS and SHP1 genes, and the cause of abnormalities in the JAK/STAT signaling pathway, remain largely unknown. The present study shows that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, leads to the hyperacetylation of histones associated with the SOCS1 and SOCS3 promoters, but not the SHP1 promoter in CRC cells. This indicates that histone modifications are involved in the regulation of SOCS1 and SOCS3. Moreover, upregulation of SOCS1 and SOCS3 expression was achieved using TSA, which also significantly downregulated JAK2/STAT3 signaling in CRC cells. We also demonstrate that TSA suppresses the growth of CRC cells, and induces G1 cell cycle arrest and apoptosis through the regulation of downstream targets of JAK2/STAT3 signaling, including Bcl-2, survivin and p16(ink4a) . Therefore, our data demonstrate that TSA may induce SOCS1 and SOCS3 expression by inducing histone modifications and consequently inhibits JAK2/STAT3 signaling in CRC cells. These results also establish a mechanistic link between the inhibition of JAK2/STAT3 signaling and the anticancer action of TSA in CRC cells.
Masato Kubo - One of the best experts on this subject based on the ideXlab platform.
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SOCS proteins, cytokine signalling and immune regulation
Nature Reviews Immunology, 2007Co-Authors: Akihiko Yoshimura, Tetsuji Naka, Masato KuboAbstract:Suppressor of cytokine signalling (SOCS) proteins are inhibitors of cytokine signalling pathways. Studies have shown that SOCS proteins are key physiological regulators of both innate and adaptive immunity. These molecules positively and negatively regulate macrophage and dendritic-cell activation and are essential for T-cell development and differentiation. Evidence is also emerging of the involvement of SOCS proteins in diseases of the immune system. In this Review we bring together data from recent studies on SOCS proteins and their role in immunity, and propose a cohesive model of how cytokine signalling regulates immune-cell function. Suppressor of cytokine signalling (SOCS) proteins are inhibitors of the Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathways. SOCS1 also inhibits Toll-like receptor (TLR) signalling. SOCS3 determines the different responses induced by the inflammatory cytokine interleukin-6 (IL-6) and the anti-inflammatory cytokine IL-10. In dendritic cells (DCs), SOCS1 negatively regulates T helper 1 (T_H1)-cell induction by DCs, whereas SOCS3 regulates the balance between T_H2 and T_H3 cells. SOCS1 induced by microbes is an important mediator for interferon (IFN)-resistance. In T cells, SOCS1 is important for proper positive and negative selection and CD8^+ T-cell lineage determination because of the restriction of cytokine signalling during T-cell maturation. SOCS1 and SOCS3 regulate T_H-cell differentiation, including T_H1, T_H2, T_H17 and T_H3 cells. SOCS1 and SOCS3 expression levels correlate with human allergy and inflammatory diseases including inflammation-associated tumours. Overexpression or knockdown of SOCS proteins are therapeutic strategies for the treatment of autoimmune diseases and allergy and for the induction of antitumour immunity. In this Review, Akihiko Yoshimura and collegues discuss the most recent advances in our understanding of suppressor of cytokine signalling (SOCS) proteins in the regulation of immunity, their involvement in human diseases and the therapeutic implications of targeting this family of cytokine regulators.
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Role of endogenous inhibitors of cytokine signaling in allergic asthma.
Current medicinal chemistry, 2007Co-Authors: Hiromasa Inoue, Masato Kubo, Satoru Fukuyama, Koichiro Matsumoto, Akihiko YoshimuraAbstract:T helper 2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, play an important role in allergic immune disorders, such as bronchial asthma. These cytokines regulate diverse biological functions by binding to receptors at the cell surface to activate complex signal transduction pathways, including the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and the Ras-extracellular signal-regulated kinase (ERK) signaling pathways. The suppressor of cytokine signaling (SOCS) family proteins has been shown to regulate the JAK-STAT pathway, and the Sprouty-related EVH1-domain-containing protein (SPRED) family proteins regulate the Ras-ERK pathway. SOCS3 and SOCS5 are predominantly expressed in Th2 and Th1 cells, respectively, and they reciprocally inhibit the Th1 and Th2 differentiation processes. SOCS3 also has a role in Th3 differentiation. SPRED-1 is expressed in hematopoietic cells, including eosinophils, and negatively controls the eosinophil numbers and functions by modulating IL-5 signaling. Here, we discuss the role of SOCS and SPRED proteins in allergic asthma and explore the potential of these proteins as targets for therapeutic strategies in allergic asthma.
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Role of suppressor of cytokine signaling in ocular allergy.
Current opinion in allergy and clinical immunology, 2006Co-Authors: Masato Kubo, Akemi Ozaki, Shinya Tanaka, Mariko Okamoto, Atsuki FukushimaAbstract:Purpose of review The goal of this article is to evaluate developments in the knowledge of suppressor of cytokine signaling (SOCS) protein ocular allergy and the potential of SOCS proteins as targets for therapeutic strategies. Recent findings The family of proteins designated SOCS proteins plays an important role in Th2-mediated allergic responses through the control of the balance between Th1 and Th2 cells. SOCS3 and SOCS5 are predominantly expressed in Th2 and Th1 cells, respectively, and they reciprocally inhibit the Th1 and Th2 differentiation processes. SOCS3 is highly expressed at the disease site of allergic conjunctivitis, and T-cell-specific expression of SOCS3 deteriorates clinical and pathological features of allergic conjunctivitis. Reduction of the expression level or inhibition of function clearly reduces the severity of allergic conjunctivitis. On the other hand, constitutive expression of SOCS5, a specific inhibitor of IL-4 signaling, results in reduced eosinophil infiltration. Moreover, negative regulation of the Th2-mediated response by dominant-negative SOCS3 and SOCS5 reduced the incidence of allergic conjunctivitis in a mouse model. Summary The present article summarizes recent findings in terms of a role of SOCS protein as a negative regulator in ocular allergy and its clinical application.
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Suppressors of cytokine signaling and immunity
Nature immunology, 2003Co-Authors: Masato Kubo, Toshikatsu Hanada, Akihiko YoshimuraAbstract:The suppressors of cytokine signaling (SOCS) and cytokine-inducible SH2 protein are key physiological regulators of the immune system. Principally, SOCS1 and SOCS3 regulate T cells as well as antigen-presenting cells, including macrophages and dendritic cells. Here we review the function of SOCS1 and SOCS3 in innate and adaptive immunity, with particular emphasis on the relationship between immune regulation and SOCS.
Warren S. Alexander - One of the best experts on this subject based on the ideXlab platform.
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Rapid Inflammation in Mice Lacking Both SOCS1 and SOCS3 in Hematopoietic Cells.
PloS one, 2016Co-Authors: Takashi Ushiki, Nicos A. Nicola, Jian-guo Zhang, Nicholas D. Huntington, Stefan P Glaser, Hiu Kiu, Angela Georgiou, Donald Metcalf, Andrew W. Roberts, Warren S. AlexanderAbstract:The Suppressors of Cytokine Signalling (SOCS) proteins are negative regulators of cytokine signalling required to prevent excess cellular responses. SOCS1 and SOCS3 are essential to prevent inflammatory disease, SOCS1 by attenuating responses to IFNγ and gamma-common (γc) cytokines, and SOCS3 via regulation of G-CSF and IL-6 signalling. SOCS1 and SOCS3 show significant sequence homology and are the only SOCS proteins to possess a KIR domain. The possibility of overlapping or redundant functions was investigated in inflammatory disease via generation of mice lacking both SOCS1 and SOCS3 in hematopoietic cells. Loss of SOCS3 significantly accelerated the pathology and inflammatory disease characteristic of SOCS1 deficiency. We propose a model in which SOCS1 and SOCS3 operate independently to control specific cytokine responses and together modulate the proliferation and activation of lymphoid and myeloid cells to prevent rapid inflammatory disease.
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Key role of suppressor of cytokine signaling 3 in regulating gp130 cytokine-induced signaling and limiting chondrocyte responses during murine inflammatory arthritis.
Arthritis & Rheumatology, 2014Co-Authors: Xiao Liu, Warren S. Alexander, Sandra E Nicholson, Edmond M. Linossi, Ben A. Croker, Ian K. Campbell, Stephanie J. Gauci, Brett A. Tonkin, Nicole C. Walsh, Kate E. LawlorAbstract:Objective To examine the impact of the gp130 cytokine family on murine articular cartilage and to explore a potential regulatory role of suppressor of cytokine signaling 3 (SOCS-3) in murine chondrocytes. Methods In wild-type (WT) mouse chondrocytes, baseline receptor expression levels and gp130 cytokine–induced JAK/STAT signaling were determined by flow cytometry, and expression of SOCS-3 was assessed by quantitative polymerase chain reaction. The role of endogenous SOCS-3 was examined in cartilage explants and chondrocytes from mice with conditional deletion of SOCS3 driven by the Col2a1 promoter in vitro (SOCS3Δ/Δcol2) and from mice during CD4+ T cell–dependent inflammatory monarthritis. Bone erosions in the murine joints were analyzed by micro–computed tomography. Results On chondrocytes from WT mice, gp130 and the oncostatin M (OSM) receptor were strongly expressed, whereas the transmembrane interleukin-6 (IL-6) receptor was expressed at much lower levels. Compared to other gp130 cytokines, OSM was the most potent activator of the JAK/STAT pathway and of SOCS-3 induction. Treatment of SOCS3Δ/Δcol2 mouse cartilage explants and chondrocytes with gp130 cytokines prolonged JAK/STAT signaling, enhanced cartilage degradation, increased the expression of Adamts4, Adamts5, and RANKL, and elevated the production of IL-6, granulocyte colony-stimulating factor, CXCL1, and CCL2. SOCS3Δ/Δcol2 mice developed exacerbated inflammation and joint damage in response to gp130 cytokine injections, and these histopathologic features were also observed in mice with inflammatory monarthritis. Conclusion The results of this study highlight a key role for SOCS-3 in regulating chondrocyte responses during inflammatory arthritis. Within the gp130 cytokine family, OSM is a potent stimulus of chondrocyte responses, while IL-6 probably signals via trans-signaling. The gp130 cytokine–driven production of RANKL in chondrocytes may link chondrocyte activation and bone remodeling during inflammatory arthritis. Thus, these findings suggest that the inhibition of OSM might reduce the development and severity of structural joint damage during inflammatory arthritis.
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Regulation of multiple cytokine signalling pathways by SOCS3 is independent of SOCS2.
Growth factors (Chur Switzerland), 2009Co-Authors: Hiu Kiu, Douglas J. Hilton, Nicos A. Nicola, Warren S. Alexander, Christopher J. Greenhalgh, Anne L. Thaus, Andrew W. RobertsAbstract:Suppressor of cytokine signalling (SOCS) 3 is an essential regulator of cytokine signalling, and in turn its expression is tightly regulated. Data from overexpression studies in cell lines suggest that SOCS2 regulates SOCS3 protein degradation, by forming a molecular bridge to an E3 ubiquitin-ligase complex. Whether this regulation is relevant in primary cells is unknown. In this study, we utilized Socs2 − / − mice to examine the role of SOCS2 in modulating SOCS3 expression and degradation, and its impact on interleukin-2 (IL-2) and IL-6 signalling in primary haemopoietic cells. Both biochemical and biological analyses demonstrated unperturbed SOCS3 expression and cytokine signalling in the absence of SOCS2. Our results suggest that SOCS2 is not a physiological regulator of SOCS3 expression and action in primary haemopoietic cells.
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Perturbed thymopoiesis in vitro in the absence of suppressor of cytokine signalling 1 and 3.
Molecular immunology, 2008Co-Authors: Hayley A. Croom, Douglas J. Hilton, Warren S. Alexander, Andrew W. Roberts, David J. Izon, Mark M.w. Chong, David J. Curtis, Thomas W. H. Kay, Robyn StarrAbstract:Cytokine signals are central to the differentiation of thymocytes and their stepwise progression through defined developmental stages. The intensity and duration of cytokine signals are regulated by the suppressor of cytokine signalling (SOCS) proteins. A clear role for SOCS1 during the later stages of thymopoiesis has been established, but little is known about its role during early thymopoiesis, nor the function of its closest relative, SOCS3. Here, we find that both SOCS1 and SOCS3 are expressed during early thymopoiesis, with expression coincident during the double negative (DN)2 and DN3 stages. We examined thymocyte differentiation in vitro by co-culture of SOCS-deficient bone marrow cells with OP9 cells expressing the Notch ligand Delta-like1 (OP9-DL1). Cells lacking SOCS1 were retarded at the DN3:DN4 transition and appeared unable to differentiate into double positive (DP) thymocytes. Cells lacking both SOCS1 and SOCS3 were more severely affected, and displayed an earlier block in T cell differentiation at DN2, the stage at which expression of SOCS1 and SOCS3 coincides. This indicates that, in addition to their specific roles, SOCS1 and SOCS3 share overlapping roles during thymopoiesis. This is the first demonstration of functional redundancy within the SOCS family, and has uncovered a vital role for SOCS1 and SOCS3 during two important checkpoints in early T cell development.
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The comparative roles of suppressor of cytokine signaling-1 and -3 in the inhibition and desensitization of cytokine signaling.
The Journal of biological chemistry, 2006Co-Authors: Sam Wormald, Nicos A. Nicola, Jian-guo Zhang, Danielle L. Krebs, Lisa A. Mielke, Jeremy D. Silver, Warren S. Alexander, Terence P. Speed, Douglas J. HiltonAbstract:Abstract Negative feedback is a mechanism commonly employed in biological processes as a means of maintaining homeostasis. We have investigated the roles of suppressor of cytokine signaling (SOCS) proteins in regulating the kinetics of negative feedback in response to cytokine signaling. In mouse livers and bone marrow-derived macrophages, both interferon-γ (IFNγ) and interleukin-6 (IL-6) rapidly induced the tyrosine phosphorylation of signal transducer and activator of transcription-1 (STAT1) and STAT3. STAT3 tyrosine phosphorylation was bi-phasic in response to continuous IL-6 signaling. In macrophages lacking SOCS3, however, continuous IL-6 signaling induced uniformly high levels of STAT3 tyrosine phosphorylation, and early IL-6-inducible genes were inappropriately expressed at intermediate time points. SOCS3 therefore imposes bi-phasic kinetics upon IL-6 signaling. Compared with SOCS3 mRNA, Socs1 mRNA was induced relatively slowly, and SOCS1 simply attenuated the duration of IFNγ signaling. Surprisingly, heightened Socs1 mRNA expression but minimal STAT1 tyrosine phosphorylation was observed after prolonged stimulation with IFNγ, indicating that STAT1 may not play a large role in inducing Socs1 mRNA during steady-state IFNγ signaling. We also demonstrate that both SOCS1 and SOCS3 can desensitize primary bone marrow-derived macrophages to IFNγ and IL-6 signaling, respectively. Consistent with the kinetics with which Socs1 and SOCS3 mRNAs were induced, SOCS3 desensitized cells to IL-6 rapidly, whereas SOCS1-mediated desensitization to IFNγ occurred at later time points. The kinetics with which SOCS proteins are induced by cytokine may therefore be a parameter that is “hard-wired” into specific cytokine signaling pathways as a means of tailoring the kinetics with which cells become desensitized.
