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)

Imiquimod is an oral inducer of interferon (IFN) and several other proinflammatory cytokines and has been successfully used topically as an antiviral agent for the treatment of genital warts. We have investigated the molecular mechanisms by which imiquimod induces the expression of IFNs, IFN-stimulated genes (ISGs), and proinflammatory cytokines in vivo, using mice deficient in various components of the IFN signaling system. Mice deficient in the transcription factor interferon regulatory factor 1 (IRF-1) or in the serine/threonine protein kinase PKR responded normally to imiquimod, producing high levels of circulating IFN and induction of several ISGs. On the other hand, when mice deficient in STAT-1 were treated, a 32-fold reduction in the level of circulating IFN was observed, together with a lack of induction of 2-5 oligo adenylate synthetase (2-5 OAS) and IRF-1 genes. Interestingly, there was also a lack of induction of interleukin-6 (IL-6) gene expression, although tumor necrosis factor was induced and readily detected in serum. In mice deficient in the type I IFN receptor, imiquimod induced levels of IFN similar to those in control mice, but again, neither 2-5 OAS, IRF-1, nor IL-6 genes were induced in mutant mice. Our results suggest that STAT-1 plays a critical role in the mechanism of gene activation by imiquimod. Moreover, induction of IL-6 gene expression appears to be dependent on components of the IFN signaling cascade.
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PMID:The immune response modifier imiquimod requires STAT-1 for induction of interferon, interferon-stimulated genes, and interleukin-6. 1010 91

Interleukin-6 (IL-6)-type cytokines lead to growth arrest of human A375 melanoma cells. The present study demonstrates that this effect depends on the activation of STAT transcription factors. We observed a correlation between the extent of growth inhibition exerted by IL-6, IL-6 plus soluble IL-6 receptor or oncostatin M (OSM) and the intensities of STAT3 and STAT1 signals. A truncated chimeric receptor retaining only the membrane-proximal region of gp130, the common signal transducer of IL-6-type cytokines, did neither activate STATs nor mediate growth arrest of stable transfectants. These functions were restored by the addition of short STAT recruitment modules comprising critical tyrosine residues from gp130 (Y767, Y814). A receptor carrying tyrosine module Y759 of gp130 effectively mediated activation of the phosphatase SHP-2 but did not alter cell growth. Overexpression of dominant negative forms of STAT3 but not STAT1 abrogated the inhibitory effect of OSM and IL-6 in A375 cells. In addition, we have identified the cyclin-dependent kinase inhibitor p27/Kipl as a novel target to be regulated by IL-6-type cytokines. Stimulation-dependent upregulation of p27 mRNA occurred STAT3-dependently. Also p27 protein accumulated which coincided with the disappearance of hyperphosphorylated retinoblastoma protein in three human melanoma cell lines sensitive to IL-6-type cytokines.
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PMID:Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1. 1039 82

One of the major actions of interleukin-6 (IL-6) is the transcriptional activation of acute-phase plasma proteins (APP) genes in liver cells. Signaling by the IL-6 receptor is mediated through the signal transducing subunit gp130 and involves the activation of Janus-associated kinases (JAKs), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein (MAP) kinase. Functional analysis of gp130 in rat hepatoma cells by using transduced chimeric G-CSFR-gp130 receptor constructs demonstrates that SHP-2, the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase, acts as a negative regulator of the JAK/STAT signaling in part by downregulating JAK activity, thereby indirectly moderating the induction of STAT3-dependent APP genes. This study shows that in hepatoma cells, the recruitment and tyrosine phosphorylation of SHP-2, but not SHC, is the primary signaling event associated with the activation of MAP kinases (ERK1/2) by gp130. Overexpression of truncated SHP-2 that lacks Grb2-interacting sites, but not the full-length catalytically inactive SHP-2, reduces ERK activation by IL-6, confirming the signal-mediating role of SHP-2. Activation of ERK1/2 is correlated with induction of the immediate-early response genes. Stimulation of the c-fos, c-jun, and egr-1 genes is essentially absent in cells expressing gp130 with a Y759F mutation, which is unable to recruit SHP-2. Interestingly, both JAK/STAT and SHP-2 pathways regulate the induction of the junB gene. Moreover, disengagement of SHP-2 from gp130 signaling not only enhances APP gene induction but also further reduces cell proliferation, in part correlated with the attenuated expression of immediate-early response genes. These results suggest that IL-6 regulation of APP genes is affected by SHP-2 in two ways: SHP-2 acts as a phosphatase on the JAK/STAT pathway and serves as linker to the MAP kinase pathway, which in turn moderates APP production.
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PMID:Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells. 1040 24

We have previously demonstrated that interleukin-6 (IL-6) increases the levels of the heat shock protein 90 (Hsp90) and activates the Hsp90beta promoter via the IL-6-activated transcription factors NF-IL6 and STAT-3. In addition, interferon-gamma (IFN-gamma) treatment increases the levels of Hsp70 and Hsp90 and also enhances the activity of the Hsp70 and Hsp90beta promoters with these effects being dependent on activation of the STAT-1 transcription factor by IFN-gamma. The effect of IL-6/STAT-3 and IFN-gamma/STAT-1 was mediated via a short region of the Hsp70/Hsp90 promoters, which also mediates the effects of NF-IL6. This region also contains a binding site for the stress-activated transcription factor HSF-1. Furthermore, STAT-1 and HSF-1 interact with one another via a protein-protein interaction and produce a strong activation of transcription. In contrast, STAT-3 and HSF-1 antagonize one another and reduce the activation of both the Hsp70 and Hsp90 promoters. Thus, STAT-1 or STAT-3 activation alone or together results in the activation of Hsp promoters. However, STAT-1 or STAT-3 interact differently with HSF-1 to regulate Hsp promoter activity. These results indicate that STATs are able to moduate the Hsp70 and Hsp90 gene promoters and that these transcription factors are likely to play a very important role in Hsp gene activation by nonstressful stimuli and the integration of these responses with the stress response of these genes.
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PMID:Transcriptional regulation of the heat shock protein genes by STAT family transcription factors. 1044 Feb 32

The pleiotropic cytokine interleukin-6 (IL-6) induces acute phase protein expression in HepG2 human hepatoma cells and promotes the growth of mouse B9 hybridoma. The signaling cascades leading to these biological functions are only partially known. We analysed the involvement of MAPK homologues in IL-6 transduction pathways and found that interleukin-6 triggered activation of p38 stress-activated protein kinase (p38) but not of jun kinase. p38 activity was required for biological functions including acute phase protein secretion from HepG2 hepatoma and proliferation of B9 hybridoma cells. Using a reporter gene construct containing a 190 bp promoter fragment of the acute phase protein haptoglobin we found that p38 is involved in transcriptional activation of the haptoglobin promoter by STAT3 but not by NF-IL6. Thus, we present evidence for a role of p38 in IL-6 induced functions and a possible cross-talk between this MAPK homologue and the STAT pathway.
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PMID:Stress activated protein kinase p38 is involved in IL-6 induced transcriptional activation of STAT3. 1044 52

Interleukin-6 (IL-6) is involved in the pathophysiology of various diseases of the CNS. Because the molecular mechanism of action of this cytokine in human neurons is not well understood, we were interested in characterizing and defining a model system for IL-6-induced activation of signal transduction cascades, transcriptional activation, and protein synthesis in human neuronal cells. We show that IL-6 leads to transcriptional activation of signal transducer and activator of transcription 3 (STAT3) in human SH-SY5Y neuroblastoma cells. IL-6-induced activation and translocation of STAT3 and to a lesser degree STAT1 but not STAT5 are demonstrated. STAT3 is phosphorylated on Tyr705 and Ser727 residues on stimulation with IL-6, suggesting maximal activation of transcription. We also show IL-6-induced phosphorylation of p42/44 mitogen-activated protein (MAP) kinase, providing evidence for MAP kinase pathway activation. The physiological relevance of our results is confirmed by IL-6-induced phosphorylation of key signaling proteins of both STAT and MAP kinase pathway in rat primary hippocampal neurons. Furthermore, de novo protein synthesis on IL-6 activation is demonstrated.
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PMID:Interleukin-6 activates signal transducer and activator of transcription and mitogen-activated protein kinase signal transduction pathways and induces de novo protein synthesis in human neuronal cells. 1053 60

Heme oxygenase-1 (HO-1) is a stress protein, and its induction has been suggested to participate in defense mechanisms against agents that promote oxidative injury such as endotoxins and heme. We have shown that the inflammatory cytokines, interleukin-6 (IL-6) and heme-induced HO-1 gene expression, were suppressed by dexamethasone (Dex) in a sustained manner. We examined the mechanism by which the anti-inflammatory agent, Dex, inhibits IL-6 and heme-induced HO-1 expression in rabbit coronary endothelial cells. Endothelial cells treated with heme (10 microM) and IL-6 (25 ng/ml), increased HO-1 mRNA 15- and 60-fold, respectively. The activity of HO was increased 3-fold after such treatment. Although Dex failed to inhibit heme-mediated HO-1 mRNA and HO activity, it was able to reverse IL-6-stimulated HO activity. Several human HO-1 promoter-drive chloramphenicol acetyltransferase (CAT) constructs were examined to analyze IL-6 and Dex-mediated modulation of the HO-1 gene in endothelial cells. CAT assays revealed that the HO-1 promoter region between -180 and -1500 might contain a Dex-mediated negative regulator. Gel mobility shift assays using nuclear extracts from IL-6-treated endothelial cells showed a binding to the synthetic 21 base pairs of the HO-1 sequence that contains the putative STAT3 sequence. STAT3-specific probe inhibited nuclear binding protein to the putative HO-1-STAT3 sequence. This suggests that IL-6 induction of human HO-1 is mediated via the JAK-STAT pathway and that Dex inhibition of gene expression is carried out by activation of a transcriptional protein in competition with the STAT3 binding site.
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PMID:Negative regulation of human heme oxygenase in microvessel endothelial cells by dexamethasone. 1056 44

Oncostatin M (OSM), a cytokine first identified from activated monocytes and T lymphocytes, is one of the most potent autocrine growth factor for AIDS and Kaposi's sarcoma. Little is known about the effects of OSM on normal vascular cells. We thus exposed human aortic smooth muscle cells (hASMCs) to OSM, examined cell proliferation and morphology, and determined interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) expression. OSM had a weak antiproliferative effect. After a 4-day incubation with 100 ng/mL OSM, cell count decreased to 69+/-3% of control. However, OSM induced striking changes in hASMC morphology, characterized by a polyclonal shape, in contrast to the spindle morphological feature of control hASMCs. OSM stimulated the release of IL-6 by hASMCs in a dose-dependent way; after a 48-hour exposure, values were 8.5+/-0.7, 29.7+/-3.5, 50.9+/-4.4, and 73.8+/-7.6x10(3) U/mL (n=6) at OSM concentrations of 0, 1, 10, and 100 ng/mL, respectively. OSM induced marked expression of COX-2 protein and mRNA. Leukemia inhibitory factor had no effect on hASMCs, indicating that OSM effects on hASMCs were mediated by the OSM type II receptor and not by the leukemia inhibitory factor receptor. OSM used the JAK/STAT signaling pathway, as demonstrated by rapid phosphorylation of JAK1 and specific activation of STAT1. Interestingly, OSM acted in synergy with IL-1beta on IL-6 production and COX-2 expression. In conclusion, OSM is a novel regulator of human smooth muscle cell functions, acting in concert with IL-1beta, and OSM may play a role in major vascular diseases such as atherosclerosis.
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PMID:Oncostatin M induces interleukin-6 and cyclooxygenase-2 expression in human vascular smooth muscle cells : synergy with interleukin-1beta. 1059 Feb 38

In this paper, we demonstrated that in cultured rat hepatocytes cell swelling induced the activation of STAT1 and STAT3 proteins without any effect on STAT4, STAT5 and STAT6 proteins. Cell swelling induced an activation of STAT proteins through an increase in the phosphorylation of the tyrosine residue also phosphorylated by interleukin-6, but without any activation of JAK kinases. The signaling pathway by which cell swelling activated STAT1 and STAT3 is discussed.
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PMID:Cell swelling activates STAT1 and STAT3 proteins in cultured rat hepatocytes. 1060 54

We have studied the activation of signal transducers and activators of transcription (STATs) in trigeminal ganglion after intraperitoneal injection of lipopolysaccharide (LPS) and Interleukin-1beta (IL-1beta). Using electrophoretic mobility shift assays we have shown that STAT1 and STAT3 are activated within 1 to 2 h. of injection of either LPS or IL-1beta. Eight hours after LPS injection the DNA binding activity of these complexes is still elevated while induction by IL-1beta returns to baseline levels within 4 h. By immunohistochemistry, using an antibody specific for the tyrosine phosphorylated, activated form of STAT-1, we show that this induction occurs in sensory neurons. IL-6 may be important in this cascade since induction of STATs by IL-1beta is blocked in Interleukin-6 knock out mice.
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PMID:Systemic lipopolysaccharide and interleukin-1beta activate the interleukin 6: STAT intracellular signaling pathway in neurons of mouse trigeminal ganglion. 1068 16


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