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)

-Cardiotrophin-1, an interleukin-6-related cytokine, stimulates the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and induces cardiac myocyte hypertrophy. In this study, we demonstrate that cardiotrophin-1 induces cardiac myocyte hypertrophy in part by upregulation of a local renin-angiotensin system through the JAK/STAT pathway. We found that cardiotrophin-1 increased angiotensinogen mRNA expression in cardiac myocytes via STAT3 activation. Tyrosine phosphorylation of STAT3 by cardiotrophin-1 treatment resulted in STAT3 homodimer binding to the St-domain in the angiotensinogen gene promoter, which lead to promoter activation in a transient transfection assay. Cardiotrophin-1-induced STAT3 tyrosine phosphorylation and binding to the St-domain were suppressed by AG490, a specific JAK2 inhibitor, which also attenuated cardiotrophin-1-stimulated angiotensinogen promoter activity. Cardiotrophin-1 did not activate the angiotensinogen gene promoter that contained a substitution mutation within the St-domain. Finally, losartan, an angiotensin II type 1 receptor antagonist, significantly attenuated cardiotrophin-1-induced hypertrophy of neonatal rat cardiac myocytes. Angiotensin II is known to induce cardiac myocyte hypertrophy by activating the G-protein-coupled angiotensin II type 1 receptor. Our results suggest that upregulation of angiotensinogen and angiotensin II production contribute to cardiotrophin-1-induced cardiac myocyte hypertrophy and emphasize an important interaction between G-protein-coupled and cytokine receptors.
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PMID:Cardiotrophin-1 increases angiotensinogen mRNA in rat cardiac myocytes through STAT3 : an autocrine loop for hypertrophy. 1085 62

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

The interferons and interleukin-6 (IL-6) family cytokines exert their biological effects via Janus kinase and signal transducer and activator of transcription (JAK-STAT) signalling pathways. Our aim is to identify "novel" signalling molecules not previously implicated in JAK-mediated signalling. Phosphotyrosine profiles of either whole cell lysates, or subcellular fractions, of unstimulated and cytokine-treated cell lines have been analysed and ligand-inducible differences observed. Recombinant src homology 2 domains, biotinylated peptides corresponding to cytokine receptor intracellular domains, antiphosphotyrosine antibodies, anion exchange columns and 2-D phosphotyrosine profiling have been used to select cohorts of molecules that are tyrosine phosphorylated in response to cytokine treatment. Tyrosine phosphorylated proteins showing cytokine specificity or differential profiles in cell lines mutated in specific JAKs are being purified and identified by mass spectrometry.
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PMID:Phosphotyrosine profiling to identify novel components of interferon and interleukin 6-family cytokine signalling. 1167 83

The glycoprotein 130 (gp130) is the common signal transducing receptor chain of the interleukin-6 family of cytokines. Here we investigated the requirements for transfer of the information given by ligand binding to the cytoplasmic domain of gp130. It is demonstrated that the box 1/2 region has to be located membrane-proximally in order to bind and activate Janus kinases. To test the possible requirement of an alpha-helical orientation, we inserted 1-4 alanine residues into this juxtamembrane intracellular region. The insertion of one alanine results in a strongly reduced activation of STAT1 and STAT3, whereas insertion of three alanine residues leads to a stronger STAT activation. These results suggest that gp130-mediated activation of STATs is sensitive to rotational changes around the receptor axis perpendicular to the membrane. Surprisingly, insertion of 1, 2, 3, or 4 alanine residues into this juxtamembrane region leads to successive impairment but not abolishment of Janus kinase and receptor phosphorylation, supporting the finding of sensitivity of Janus kinases toward changes in distance of box 1/2 from the plasma membrane. We suggest a new model concerning the gp130 activation mode in which the relative orientation of the cytoplasmic regions seems to be critical for further signal transduction.
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PMID:Orientational constraints of the gp130 intracellular juxtamembrane domain for signaling. 1201 Oct 64

Glioblastoma multiforme (GBM), the most common and malignant central nervous system tumor in humans, is highly proliferative and resistant to apoptosis. Stat3, a latent transcription factor being activated by aberrant cytokine or growth factor signaling, acts as a suppressor of apoptosis in a number of cancer cells. Here we report that GBM tumors and cell lines contain high levels of constitutively activated Stat3 when compared with normal human astrocytes, white matter, and normal tissue adjacent to tumor. The persistent activation of Stat3 is in part, attributable to an autocrine action of interleukin-6 in the GBM cell line U251. Janus kinase inhibitor AG490 inhibits Stat3 activation with a concomitant reduction in steady-state levels of Bcl-X(L), Bcl-2 and Mcl-1 proteins and induces apoptosis in U251 cells as revealed by Poly (ADP-ribose) polymerase cleavage and Annexin-V staining. Expression of a dominant negative mutant Stat3 protein or treatment with AG490 markedly reduces the proliferation of U251 cells by inhibiting the constitutive activation of Stat3. These results provide evidence that constitutive activation of Stat3 contributes to the pathogenesis of glioblastoma by promoting both proliferation and survival of GBM cells. Therefore, targeting Stat3 signaling may provide a potential therapeutic intervention for GBM.
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PMID:Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. 1246 61

We investigated the effects of a chimeric protein (IL6RIL6 chimera) containing interleukin-6 (IL-6) fused to its soluble receptor (sIL-6R) on the proliferation and/or differentiation of rat oligodendrocyte progenitor cells (OPCs) and on oligodendrocyte survival. Exposure of OPCs to IL6RIL6 chimera for 48 h induced a dose-dependent decrease of bromodeoxyuridine (BrdU) incorporation. IL6RIL6 chimera treatment for 48 h also strongly increased the reduction of the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) by mitochondrial enzymes and enhanced oligodendrocyte staining with a mitochondrial fluorescent dye. A strong, dose-dependent increase in the number and length of processes immunostained for early (galactocerebroside) or late (myelin basic protein) oligodendrocyte differentiation markers was revealed after OPC treatment with IL6RIL6 chimera for 2-7 days, respectively. Moreover, treatment with IL6RIL6 chimera improved oligodendrocyte survival. The chimera-induced increase of oligodendrocyte arborization was mimicked, although with lower efficacy, by ciliary neurotrophic factor (CNTF) but not by IL-6 and was reduced in the presence of a gp130 soluble peptide which is able to inhibit the gp130-mediated signals of the IL-6/sIL-6R complex. Oligodendrocyte treatment with IL6RIL6 chimera for 30 min induced both signal transducer and the activator of transcription-1 (STAT-1) and STAT-3 phosphorylation and nuclear translocation. We conclude that, by interacting with membrane gp130 and possibly by activating Janus kinase/STAT pathways, IL6RIL6 chimera induces OPCs to differentiate into mature oligodendrocytes, promotes their survival, and could deserve investigation as a therapeutic strategy for enhancing remyelination.
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PMID:Soluble interleukin-6 (IL-6) receptor/IL-6 fusion protein enhances in vitro differentiation of purified rat oligodendroglial lineage cells. 1250 93

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

We established hepatitis C virus (HCV) core-expressing cells and investigated whether HCV core would modify the Janus kinase (JAK)-signal transducer and activator transcription factor (STAT) pathway under interleukin-6 (IL-6) and interferon (IFN)-gamma stimuli. Phosphorylation of JAK1/2 and STAT3, and STAT3-mediated transcription, were prevented by HCV core under IL-6 stimulation. In contrast, HCV core increased phosphorylation of JAK1/2 and STAT1 and STAT1-mediated transcription under IFN-gamma stimulation. Immunoprecipitation/Western blot analysis showed that HCV core could bind to JAK1/2. The PGYPWP sequences at codons 79-84 within HCV core were important for interaction with JAKs by in vitro binding analysis. In the reporter gene assay, HCV core-mediated suppression of JAK-STAT pathway under IL-6 stimulation was not observed by abrogation of PGYPWP sequence, suggesting that HCV core/JAK interaction may directly affect the signal transduction. In contrast, augmentation of JAK-STAT pathway was still seen by HCV core without functional PGYPWP sequence under IFN-gamma stimulation. Flow cytometric analysis revealed that HCV core up-regulated of IFN-gamma receptor 2 expression, which may be responsible for HCV core-mediated enhancement of JAK-STAT pathway under IFN-gamma stimulation. In conclusion, HCV core has different effects on the JAK-STAT pathway under IL-6 and IFN-gamma stimuli. This may be exerted by these two independent mechanisms.
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PMID:Hepatitis C virus core protein differently regulates the JAK-STAT signaling pathway under interleukin-6 and interferon-gamma stimuli. 1276 55

Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling is essential but not sufficient for full responses to the interferons (IFNs), most cytokines and some growth factors. The IFN-gamma and interleukin-6 (IL-6) response pathways have been used as model systems to investigate both the signals involved and their organisation. Activated STAT1 diffuses freely in the cytoplasmic and nuclear compartments of the cell providing a 'random walk' element in the IFN-gamma response. Completely foreign chimeric receptors and, remarkably, in the absence of STAT3, the endogenous IL-6 receptor can efficiently mediate an IFN-gamma-like response. Accordingly all of the signals required for an IFN-gamma response can be generated through physiological levels of a foreign ligand. JAK/STAT signalling, therefore, appears 'soft-wired', modular and highly flexible with substantial overlap between different response pathways. The data are consistent with a generic or 'core' set of signals from JAK/receptor complexes with 'add-on' modulation through specific receptor motifs. The cellular background likely profoundly affects the nature of the response.
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PMID:Of JAKs, STATs, blind watchmakers, jeeps and trains. 1282 28

The suppressor of cytokine signalling-1 (SOCS-1) gene is frequently silenced in human hepatocellular carcinoma by aberrant methylation. The aim of this study was to determine if SOCS-1 is inactivated in pancreatic ductal neoplasms, and to investigate if aberrant methylation of this gene affected the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. Aberrant methylation in the CpG island of the SOCS-1 gene was detected in six of 19 (31.6%) human pancreatic cancer cell lines using methylation-specific PCR, and was associated with a loss or reduction of gene expression in five of the six methylated cell lines. Thirteen of 60 pancreatic ductal adenocarcinomas (21.7%) and two of 34 intraductal papillary mucinous neoplasms (IPMNs) (5.9%) had methylated SOCS-1. In contrast, SOCS-1 methylation was not seen in pancreatic normal ductal epithelia (zero out of 15), in pancreatic intraepithelial neoplasia (PanINs) (zero out of 49) or in the IPMNs without infiltrating cancer (zero out of 20). 5-Aza-2'-deoxycytidine treatment of the SOCS-1-methylated pancreatic cancer cell lines led to restoration of SOCS-1 gene expression. Interleukin-6, which has been shown to act through the JAK/STAT pathway to increase cell growth, induced modest time and dose-dependent cell proliferation in a SOCS-1-methylated cell line (PL10, P=0.015) but not in two unmethylated cell lines. These results indicate that loss of SOCS-1 gene is associated with transcriptional silencing and may have growth-promoting effects, and that its methylation is a useful marker of pancreatic cancer.
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PMID:Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms. 1286 27


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