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)

Interleukin-6 is involved in the regulation of many biological activities such as gene expression, cell proliferation, and differentiation. The control of the termination of cytokine signaling is as important as the regulation of initiation of signal transduction pathways. Three families of proteins involved in the down-regulation of cytokine signaling have been described recently: (i) SH2 domain-containing protein-tyrosine phosphatases (SHP), (ii) suppressors of cytokine signaling (SOCS), and (iii) protein inhibitors of activated STATs (PIAS). We have analyzed the interplay of two inhibitors in the signal transduction pathway of interleukin-6 and demonstrate that the tyrosine phosphatase SHP2 and SOCS3 do not act independently but are functionally linked. The activation of one inhibitor modulates the activity of the other; Inhibition of SHP2 activation leads to increased SOCS3-mRNA levels, whereas increased expression of SOCS3 results in a reduction of SHP2 phosphorylation after activation of the interleukin-6 signal transduction pathway. Furthermore, we show that tyrosine 759 in gp130 is essential for both SHP2 and SOCS3 but not for SOCS1 to exert their inhibitory activities on interleukin-6 signal transduction. Besides SHP2, SOCS3 also interacts with the Tyr(P)-759 peptide of gp130. Taken together, our results suggest differences in the function of SOCS1 and SOCS3 and a link between SHP2 and SOCS3.
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PMID:SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130. 1077 83

Recently, constitutive activation of JAK kinases (JAKs) and/or signal transducers and activators of transcription (STATs) has been reported in growing numbers of human cancer cells as well as oncogene-transformed cells. JAB/SOCS-1 has been shown to be an intrinsic JAK tyrosine kinase inhibitor and to suppress the cytokine-dependent JAK-STAT pathway. In this report, we investigated the effect of ectopic expression of JAB on v-Src-induced JAK-STAT activation. Forced expression of JAB in v-Src-transformed NIH3T3 cells neither suppressed phosphorylation of STAT3 and JAK1/JAK2 nor blocked STAT3-reporter gene activation. Colony forming assay also showed that JAB did not suppress v-Src-induced transformation of NIH3T3 cells, while dominant negative STAT3 suppressed it. In contrast, JAB could downregulate phosphorylation of STAT1 and STAT3 induced by interferon gamma (IFNgamma) and interleukin-6 (IL-6) plus soluble IL6 receptor (sIL-6R), respectively. Furthermore, in vitro kinase assay indicated that JAB suppressed hyperactivation of JAK1/JAK2 and JAK1 induced by IFNgamma and IL-6 plus sIL-6R respectively, but not v-Src-induced basal JAK1/JAK2 activity. Nevertheless, both JAK1/JAK2 activated by v-Src and that activated by IL-6 plus sIL-6R could similarly bind JAB. These results clearly demonstrate that JAB distinguishes cytokine-induced JAK-STAT signaling from v-Src-induced one and can not suppress the transformation with v-Src.
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PMID:The JAK-inhibitor, JAB/SOCS-1 selectively inhibits cytokine-induced, but not v-Src induced JAK-STAT activation. 1103 30

CIS (cytokine-inducible SH2 protein), SOCS (suppressor of cytokine signaling), or SSI (signal transducers and activators of transcription [STAT]-induced STAT inhibitor) proteins are a family of cytokine-inducible negative regulators of cytokine signaling via Janus kinase (JAK)-STAT pathways. Given the evidence that the JAK-STAT pathway plays a critical role in the cardiovascular system, the primary objective of this study was to assess the effects of the CIS family on JAK-STAT signaling in the cardiovascular system in rats treated with cardiotrophin-1 (CT-1), an interleukin-6 family of cytokines. Intravenous injection of 20 microgram/kg body weight of CT-1 induced a transient, marked increase in STAT3 activation in various tissues, including heart and lung, and subsequent upregulation of 2 members of the CIS family, JAK-binding protein (JAB)/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3, in the same tissues. It was also observed that CIS3 was directly associated with JAK2 in vivo. Pretreatment with the same dose of CT-1 60 minutes before significantly attenuated the STAT3 activation induced by a second injection of CT-1. We previously reported that intravenous injection of CT-1 results in the nitric oxide (NO)-dependent hypotension accompanied by the induction of inducible NO synthase mRNA. In rats pretreated with CT-1, the induction of inducible NO synthase mRNA or hypotension by subsequent CT-1 injection was not observed. Forced expression of JAB or CIS3, but not other CISs, directly blocked CT-1-induced STAT3 activation in 293 cells. These results suggest that JAB and CIS3 serve as endogenous inhibitors of CT-1-mediated JAK-STAT signaling in the cardiovascular system in vivo.
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PMID:Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp130 resistance in cardiovascular system in rat treated with cardiotrophin-1 in vivo. 1130 96

A new family of cytokine-inducible proteins, termed "suppressors of cytokine signaling" (SOCS), was discovered recently; these proteins function as negative regulators of signaling pathways involved in the cellular actions of many cytokines, growth factors, and hormones. Gene manipulation studies in mice point to the central importance of individual SOCS proteins in maintaining homeostasis by limiting cellular responses to specific cytokines or growth factors in a variety of different physiological systems. Cytokines modulate a wide variety of biological responses in the CNS, so members of the SOCS family might play crucial roles in regulating intracellular signaling by these effectors in both normal and disease states. Although to date studies of the neurobiology of the SOCS family have been limited, we know that many SOCS genes are constitutively expressed in the developing and adult brain, whereas the expression of others, particularly the SOCS1 and SOCS3 genes, can be highly regulated. Furthermore, roles for the SOCS are now evident in the modulation of neuroimmunoendocrine functions affected by a variety of cytokines, including leptin and members of the growth hormone and the interleukin-6/gp130 superfamilies. Overall, these findings point to the SOCS as likely crucial negative modulators in the temporal and spatial regulation and intensity of cytokine signaling and therefore actions in the CNS.
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PMID:Cytokine signaling in the brain: putting a SOCS in it? 1183 8

The suppressor of cytokine signaling (SOCS) family of proteins has been implicated in the negative regulation of several cytokine pathways, particularly the receptor-associated tyrosine kinase/signal transducer and activator of transcription (Jak/STAT) pathways of transcriptional activation. SOCS-1 (also known as JAB and SSI-1) inhibits signaling by many cytokines. Because of the previously observed hypermethylation-associated inactivation of SOCS-1 in hepatocellular carcinoma and the critical role of interleukin-6 (IL-6) as a survival factor in multiple myeloma (MM), we examined CpG island methylation of the SOCS-1 gene in MM cell lines and primary MM samples. Aberrant SOCS-1 methylation was found in the IL-6-dependent MM cell lines U266 and XG1, which correlated with transcriptional silencing. Treatment of these cell lines with the demethylating agent 5-aza-2'-deoxycytidine (DAC) up-regulated SOCS-1 expression. Methylation-associated inactivation of SOCS-1 in hematopoietic cell lines correlated with greater sensitivity to the chemical JAK inhibitor AG490. Using methylation-specific polymerase chain reaction (MSP), we found that SOCS-1 is hypermethylated in 62.9% (23/35) of MM patient samples. In contrast, methylation analysis of malignant lymphomas of various histologies revealed SOCS-1 hypermethylation in only 3.2% (2/62), and there was no methylation of SOCS-1 in normal peripheral blood leukocytes or bone marrow cells. We conclude that SOCS-1 is frequently inactivated by hypermethylation in MM patients. Silencing of the SOCS-1 gene may impair negative regulation of the Jak/STAT pathway and therefore result in greater responsiveness to cytokines, thus supporting survival and expansion of MM cells.
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PMID:SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. 1290 Mar 55

MUP/hIL-6 transgenic mice overexpressing human interleukin-6 (IL-6) are growth-retarded. As documented here, the major transcriptional factor constitutively activated by IL-6 in the MUP/hIL6 transgenic mice was signal transducer and transactivator 3 (STAT3). Since STAT3 has been implicated in the expression of negative regulators of GH signaling, the suppressors of cytokine signaling (SOCS) genes, we have in this study examined the expression of SOCS1, SOCS2, SOCS3, and CIS genes. We found a large, 5-fold increase in SOCS3 mRNA in the liver, brain, skeletal muscle, and the lung of the MUP/hIL-6 transgenic mice. SOCS genes are thought to inhibit activation of transcriptional factor STAT5 by GH. Despite the induction of SOCS3 mRNA, STAT5 was activated in growth-retarded transgenic mice in response to elevated endogenous GH serum levels. The significance of activation of STAT3 and STAT5 transcription factors for cell proliferation and growth impairment in this mouse model is therefore discussed.
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PMID:Growth impairment in IL-6-overexpressing transgenic mice is associated with induction of SOCS3 mRNA. 1255 79

The suppressor of cytokine signaling/cytokine-inducible SH2 containing proteins are cytokine inducible and are negative regulators of the signal transducers and activators of the transcription signaling pathway. We investigated the mechanism regulating signal transducers and activators of transcription and the suppressor of cytokine signaling/cytokine-inducible SH2 containing protein family in keratinocytes, one of the major target cells for cytokines. Suppressor of cytokine signaling 1 mRNA was upregulated 3 h post-interferon gamma, and a 8.1-fold increase in the suppressor of cytokine signaling 1 mRNA occurred 48 h post-interferon gamma. The suppressor of cytokine signaling 3 mRNA was also upregulated from 1 h post-interferon gamma, and a 6.7-fold increase in the suppressor of cytokine signaling 3/cytokine-inducible SH2 containing protein 3 mRNA occurred between 6 and 12 h post-interferon gamma. Interleukin-6 exposure for 1 h enhanced the expression of the suppressor of cytokine signaling 3/cytokine-inducible SH2 containing protein 3 mRNA, but the suppressor of cytokine signaling 1/JAB mRNA was not induced by interleukin-6. Interleukin-4 upregulated the suppressor of cytokine signaling 1/JAB and cytokine-inducible SH2 containing protein 1 mRNA, with 3.4-fold and 5.1-fold increases in mRNA observed at 1 h post-interleukin-4, respectively. In contrast, epidermal growth factor, which phosphorylates signal transducers and activators of transcription 3, did not influence the level of the suppressor of cytokine signaling/cytokine-inducible SH2 containing protein family mRNA expression. Transfection of an adenovirus vector expressing the suppressor of cytokine signaling 1/JAB completely inhibited interferon gamma-dependent signal transducers and activators of transcription 1 phosphorylation and interleukin-4-dependent signal transducers and activators of transcription 6 phosphorylation. Transfection of adenovirus vector expressing the suppressor of cytokine signaling 1/JAB did not inhibit interleukin-6-dependent signal transducers and activators of transcription 3 phosphorylation-several reports show that the suppressor of cytokine signaling 1/JAB is a potent inhibitor of signal transducers and activators of transcription 3 signaling in the myeloid leukemia M1 cell. Transfection of the adenovirus vector expressing suppressor of cytokine signaling 3/cytokine-inducible SH2 containing protein 3 completely inhibited interleukin-6-dependent signal transducers and activators of transcription 3 phosphorylation and partially inhibited interferon gamma-dependent signal transducers and activators of transcription 1 phosphorylation. Transfection of the adenovirus vector expressing suppressor of cytokine signaling 3/cytokine-inducible SH2 containing protein 3, however, did not inhibit interleukin-4-dependent signal transducers and activators of transcription 6 phosphorylation. Transfection of the adenovirus vector expressing cytokine-inducible SH2 containing protein 1 had no effect on signal transducers and activators of transcription 1, 3, and 6 signaling in normal keratinocytes. Therefore, the relationship between signal transducers and activators of transcription and suppressor of cytokine signaling is unique in the keratinocytes, and the suppressor of cytokine signaling regulates cytokine signals in these cells.
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PMID:Suppressor of cytokine signaling 1/JAB and suppressor of cytokine signaling 3/cytokine-inducible SH2 containing protein 3 negatively regulate the signal transducers and activators of transcription signaling pathway in normal human epidermal keratinocytes. 1264 19

Members of the suppressor of cytokine signaling (SOCS) family are potentially key physiological negative regulators of interleukin-6 (IL-6) signaling. To examine whether SOCS3 is involved in regulating this signaling, we have used conditional gene targeting to generate mice lacking Socs3 in the liver or in macrophages. We show that Socs3 deficiency results in prolonged activation of signal transducer and activator of transcription 1 (STAT1) and STAT3 after IL-6 stimulation but normal activation of STAT1 after stimulation with interferon-gamma (IFN-gamma). Conversely, IL-6-induced STAT activation is normal in Socs1-deficient cells, whereas STAT1 activation induced by IFN-gamma is prolonged. Microarray analysis shows that the pattern of gene expression induced by IL-6 in Socs3-deficient livers mimics that induced by IFN-gamma. Our data indicate that SOCS3 and SOCS1 have reciprocal functions in IL-6 and IFN-gamma regulation and imply that SOCS3 has a role in preventing IFN-gamma-like responses in cells stimulated by IL-6.
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PMID:SOCS3 negatively regulates IL-6 signaling in vivo. 1277 70

Leptin and its receptors have been shown to be expressed in several tissues, suggesting that this protein might be effective not only at the CNS level but also peripherally. We have previously reported that leptin and its long form receptor are expressed in the mouse mammary epithelial cell line HC11. In this study, we report a specific relationship among leptin, prolactin (PRL), interleukin-6 (IL-6), and tumor necrosis-alpha (TNF-alpha) in the modulation of the suppressor of cytokine signaling 1 (SOCS-1). Furthermore, we show that leptin and PRL are able to effectively enhance SOCS-1 gene expression in the HC11 cell line. Finally, high concentrations of leptin (100 nM) and/or PRL significantly (p<0.05) reduce the inhibitory effect of IL-6 (10 and 100 ng/ml) and TNF-alpha (10 and 100 ng/ml) on beta-casein gene expression in HC11 cells transfected with pbetacCAT, a chimeric rat-beta casein gene promoter-cloramphenicol acetyl transferase (CAT) gene construct. These results provide evidence that leptin may be an important mediator in regulating mammary gland growth and development and that this role may be related to the immune factors that are involved in inflammation.
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PMID:Leptin and prolactin modulate the expression of SOCS-1 in association with interleukin-6 and tumor necrosis factor-alpha in mammary cells: a role in differentiated secretory epithelium. 1525 87

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


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