Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Suppressor of cytokine signaling (SOCS) proteins are feedback inhibitors of the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathway. SOCS3 is upregulated by several signals in macrophages and has been implicated as a regulator of various signaling pathways. Here we show that phosphorylation of STAT3 is prolonged in mouse Socs3-deficient macrophages after stimulation with interleukin-6 (IL-6) but not IL-10, indicating that SOCS3 specifically affects signaling mediated by IL-6 and gp130. IL-6 induces a wider transcriptional response in Socs3-deficient macrophages than in wild-type cells; this response is dominated by interferon (IFN)-regulated genes owing to an excess of STAT1 phosphorylation. Thus, SOCS3 functions to control the quality of the response to IL-6 and prevents the activation of an IFN-induced program of gene expression.
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PMID:SOCS3 regulates the plasticity of gp130 signaling. 1277 70

Members of the interleukin-6 (IL-6) family of cytokines exert their biological effects via binding to their cognate ligand-binding receptor subunit on a target cell. The subsequent recruitment of the common signal transducer glycoprotein 130 and activation of the JAK/STAT and SHP-2/Ras/mitogen-activated protein kinase (MAPK) pathways are responsible for the majority of cellular responses elicited by IL-6 cytokines. Several types of experiments suggest that the Src family of kinases (SFK) also participates in IL-6 family cytokine-mediated signaling events. SYF cells, which lack expression of SFKs Src, Yes, and Fyn, were used to determine the role of SFKs in IL-6 family cytokine signaling and gene induction. SYF and wild type (WT) control fibroblasts displayed similar activation of signaling intermediates following stimulation with leukemia inhibitory factor (LIF). LIF-stimulated tyrosine phosphorylation of SHP-2 and subsequent activation of MAPK in SYF cells were identical to that seen in LIF-stimulated WT cells. Both LIF-stimulated tyrosine phosphorylation of STAT1 and STAT3, as well as LIF-stimulated DNA binding activity of STAT-containing nuclear complexes were indistinguishable when compared in SYF and WT cells. In addition, the phosphatidylinositol 3-kinase-sensitive Akt kinase and p38 MAPK were activated by LIF in both SYF and WT cells. Furthermore, LIF-stimulated expression of c-fos, egr-1, and suppressor of cytokine signaling-3 was retained in SYF cells. The IL-6 family cytokine oncostatin M was also capable of activating MAPK, STAT3, STAT1, Akt, and p38 in both WT and SYF cells. These results demonstrate that IL-6 family cytokines can activate a full repertoire of signaling pathways and induce gene expression independent of SFKs.
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PMID:Src family kinase-independent signal transduction and gene induction by leukemia inhibitory factor. 1276 51

Our previous study has shown that lipophilic 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors of statins can inhibit interferon-gamma-induced inducible nitric oxide synthase gene expression in RAW264.7 macrophages. In this study, we showed that lovastatin and fluvastatin are able to upregulate the mRNA expression of the suppressor of cytokine signaling-3 (SOCS-3) gene. This effect is specific for SOCS-3 and could be blocked by mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, while it was not affected by inhibitors of protein kinase C and A, mitogen-activated protein/extracellular signal-regulated kinase kinase, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, Src, Raf and Rho kinase. SOCS-3 expression results in the inhibition of interferon-gamma-, interleukin-6- and macrophage colony-stimulating factor-elicited signal transducer and activator of transcription phosphorylation, suggesting a novel anti-inflammatory mechanism of statins to down-modulate the functions of interferon-gamma-activated macrophages.
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PMID:Statins induce suppressor of cytokine signaling-3 in macrophages. 1464 48

Signal transducer and activator of transcription 3 (STAT3) has been reported to be activated by interleukin-6 receptor (IL-6R) or epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinomas (HNSCC), which may have important implications for responsiveness to therapeutics targeted at EGFR, IL-6R, or intermediary kinases. Suppressor of cytokine signaling-1 (SOCS-1) has been implicated recently in the negative regulation of IL-6R/Janus-activated kinase (JAK)-mediated activation of STAT3, suggesting that SOCS-1 could affect alternative activation of STAT3 by EGFR, IL-6R, and associated kinases. We investigated whether epigenetic modification of SOCS-1 affects STAT3 activation in response to IL-6R-, EGFR-, JAK-, or mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-mediated signal activation. STAT3 was predominantly activated by IL-6R via Jak1/Jak2 in HNSCC lines UMSCC-9 and UMSCC-38 in association with transcriptional silencing of SOCS-1 by hypermethylation. In UMSCC-11A cells with unmethylated SOCS-1, STAT3 activation was regulated by both EGFR and IL-6R via a JAK-independent pathway involving MEK. Pharmacologic inhibitors of JAK and MEK and expression of SOCS-1 following demethylation or transient transfection inhibited STAT3 activation and cell proliferation and induced cell apoptosis in corresponding cell lines. Hypermethylation of SOCS-1 was found in about one-third of human HNSCC tissues, making it a potentially relevant marker for STAT-targeted therapy in HNSCC patients. We conclude that SOCS-1 methylation status can differentially affect STAT3 activation by IL-6R and EGFR through JAK or MEK in different HNSCC and response to pharmacologic antagonists. Identifying the potential factors and the regulatory pathways in STAT3 activation has important implications for the development and selection of molecularly targeted therapy in HNSCC.
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PMID:Epigenetic modification of SOCS-1 differentially regulates STAT3 activation in response to interleukin-6 receptor and epidermal growth factor receptor signaling through JAK and/or MEK in head and neck squamous cell carcinomas. 1643 58

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-gamma (IFNgamma) 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 IFNgamma signaling. Surprisingly, heightened Socs1 mRNA expression but minimal STAT1 tyrosine phosphorylation was observed after prolonged stimulation with IFNgamma, indicating that STAT1 may not play a large role in inducing Socs1 mRNA during steady-state IFNgamma signaling. We also demonstrate that both SOCS1 and SOCS3 can desensitize primary bone marrow-derived macrophages to IFNgamma 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 IFNgamma 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.
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PMID:The comparative roles of suppressor of cytokine signaling-1 and -3 in the inhibition and desensitization of cytokine signaling. 1647 83

Cytokines are important mediators of cardiac disease. Accumulating evidence indicates that members of the interleukin-6 family of cytokines promote cardiac hypertrophy through the activation of the Janus kinase-signal transducer and activator of transcription (Jak/STAT) pathway. Aberrant Jak/STAT signaling may promote progression from hypertrophy to heart failure. Suppressor of cytokine signaling (SOCS) proteins are underexplored, negative regulators of Jak/STAT signaling. SOCS proteins may also interact with other inflammatory pathways known to affect cardiac function. A better understanding of the therapeutic potential of these proteins may lead to the controlled progression of heart failure and the limitation of myocardial depression. This review summarizes the cardiophysiological effect of the IL-6 cytokine family, outlines the mechanistic pathway of Jak/STAT signaling, explores the regulatory role of SOCS proteins in the heart, and discusses the potential of using SOCS proteins clinically.
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PMID:Jak/STAT/SOCS signaling circuits and associated cytokine-mediated inflammation and hypertrophy in the heart. 1691 47

Interleukin-6, levels of which are elevated in prostate cancer, activates different signal transduction pathways including that of Janus kinases/signal transducer and activator of transcription (STAT)3. However, phosphorylation of STAT3 has been reported to be associated with either stimulatory or inhibitory effects on cellular proliferation. To better understand the mechanisms of STAT3 regulation in benign and malignant prostate, we have investigated the role of suppressor of cytokine signaling (SOCS)-3. Cell lines that did not express phosphorylated STAT3 were found to be SOCS-3-positive. SOCS-3 was re-expressed in LNCaP cells after treatment with a demethylating agent. SOCS-3 immunohistochemistry revealed a negative or weak reaction in benign areas, whereas its expression was detected in tumor tissue. To investigate the involvement of SOCS-3 in regulation of cellular events, we incubated cancer cells with a cAMP derivative. This treatment yielded higher SOCS-3 levels, reduced [3H]thymidine incorporation, and increased percentage of apoptotic cells. However, down-regulation of SOCS-3 by a short interfering RNA approach resulted in inhibition of proliferation and an increased apoptotic rate. Collectively, our results show that SOCS-3 antagonizes regulation of cellular events by cAMP and is expressed in human prostate cancer.
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PMID:Suppressor of cytokine signaling-3 antagonizes cAMP effects on proliferation and apoptosis and is expressed in human prostate cancer. 1714 81

Proinflammatory cytokines are known to impair intestinal barrier function and to activate signaling pathways, whereas heat shock responses prevent cytokine-induced mucosal damage. We hypothesized that heat shock response blocks the effects of proinflammatory cytokines by regulating nitric oxide (NO) production and the activities of the Janus kinase/signal transducer and activator of transcription (STAT) pathway. A monolayer of Caco-2 cells were pretreated with sodium arsenite (SA, 500 micromol/L) for 1 h, followed by a 1-h recovery, and then stimulated with a cytokine mixture (cytomix: tumor necrosis factor alpha [10 ng/mL], interferon beta [1000 U/mL], and interleukin [IL] 1beta [1 ng/mL]) for 24 h. The permeability of horseradish peroxidase and fluorescein isothiocyanate-conjugated Dextran and transepithelial resistance and potential difference were measured in Ussing chambers. Interleukin-6, IL-8, NO, inducible NO synthase mRNA, STAT activity, and suppressor of cytokine signaling (SOCS) expression were measured in medium or cell lysates. Cytomix resulted in increased epithelial permeability of both fluorescein isothiocyanate-conjugated Dextran and horseradish peroxidase; whereas treatment of Caco-2 cells with SA 500 micromol/L blocked the cytomix-induced permeability changes. In addition, SA treatment decreased cytomix-induced NO production and inducible NO synthase mRNA expression and decreased the levels of STAT1, STAT3, SOCS1, and SOCS3. The SA treatment also decreased cytomix-induced IL-6 and IL-8 production in a dose-dependent manner. In conclusion, cytomix increased epithelial permeability, which is associated with increased NO and STAT activities. The SA treatment ameliorated cytomix-induced permeability, possibly through the downregulation of the NO and Janus kinase/STAT pathways.
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PMID:Heat shock stress ameliorates cytokine mixture-induced permeability by downregulating the nitric oxide and signal transducer and activator of transcription pathways in Caco-2 cells. 1722 93

Thiazolidinediones (TZDs) are synthetic agonists of the ligand-activated transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). TZDs are known to curtail inflammation associated with peripheral organ ischemia. As inflammation precipitates the neuronal death after stroke, we tested the efficacy of TZDs in preventing brain damage following transient middle cerebral artery occlusion (MCAO) in adult rodents. As hypertension and diabetes complicate the stroke outcome, we also evaluated the efficacy of TZDs in hypertensive rats and type-2 diabetic mice subjected to transient MCAO. Pre-treatment as well as post-treatment with TZDs rosiglitazone and pioglitazone significantly decreased the infarct volume and neurological deficits in normotensive, normoglycemic, hypertensive and hyperglycemic rodents. Rosiglitazone neuroprotection was not enhanced by retinoic acid x receptor agonist 9-cis-retinoic acid, but was prevented by PPARgamma antagonist GW9662. Rosiglitazone significantly decreased the post-ischemic intercellular adhesion molecule-1 expression and extravasation of macrophages and neutrophils into brain. Rosiglitazone treatment curtailed the post-ischemic expression of the pro-inflammatory genes interleukin-1beta, interleukin-6, macrophage inflammatory protein-1alpha, monocyte chemoattractant protein-1, cyclooxygenase-2, inducible nitric oxide synthase, early growth response-1, CCAAT/enhancer binding protein-beta and nuclear factor-kappa B, and increased the expression of the anti-oxidant enzymes catalase and copper/zinc-superoxide dismutase. Rosiglitazone also increased the expression of the anti-inflammatory gene suppressor of cytokine signaling-3 and prevented the phosphorylation of the transcription factor signal transducer and activator of transcription-3 after focal ischemia. Thus, PPARgamma activation with TZDs might be a potent therapeutic option for preventing inflammation and neuronal damage after stroke with promise in diabetic and hypertensive subjects.
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PMID:Peroxisome proliferator-activated receptor-gamma agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents. 1739 60

Granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) play key roles in regulating emergency granulopoiesis and inflammation, and are both negatively regulated by the inducible intracellular protein suppressor of cytokine signaling-3 (Socs3). Mice with Socs3 deleted specifically in hematopoietic cells succumb to severe neutrophil and macrophage-driven inflammation by 1 year of age, and responses to G-CSF are grossly exacerbated. In order to determine which elements of cellular responses to cytokines require Socs3, we have examined the differentiative and proliferative capacity of hematopoietic progenitor cells stimulated by G-CSF and IL-6. The differentiation of Socs3-deficient progenitor cells is skewed toward macrophage production in response to G-CSF or IL-6, whereas wild-type progenitor cells produce mainly neutrophils. The proliferative capacity of Socs3-deficient progenitor cells is greatly enhanced in response to G-CSF at all concentrations, but only at low concentrations for IL-6. Strikingly, synergistic responses to costimulation with stem cell factor and IL-6 (but not G-CSF) are lost at higher concentrations in Socs3-deficient progenitor cells. Cytokine-induced expression of transcriptional regulators including cebpb, Ets2, Bcl3, c-Myc, Jun, and Fosl2 are differentially regulated in Socs3-deficient cells. The tight regulation by Socs3 of signal transducer and activator of transcription 3 phosphorylation and gene transcription after cytokine receptor ligation significantly influences the fate of myeloid progenitor cells.
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PMID:Socs3 maintains the specificity of biological responses to cytokine signals during granulocyte and macrophage differentiation. 1840 Mar 61


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