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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogen-activated protein kinase (MAPK) signalling pathway serves to translocate information from activated plasma-membrane receptors to initiate nuclear transcriptional events. This cascade has recently been subdivided into two analogous pathways: the extracellular signal-regulated kinase (ERK) cascade, which preferentially signals mitogenesis, and the stress-activated protein kinase (SAPK) cascade, which is linked to growth arrest and/or cellular inflammation. In concurrent experiments utilizing rat glomerular mesangial cells (MCs), we demonstrate that growth factors or sphingosine activate ERK but not SAPK. In contrast, inflammatory cytokines or cell-permeable ceramide analogues activate SAPK but not ERK. Ceramide, but not sphingosine, induces interleukin-6 secretion, a marker of an inflamed phenotype. Moreover, ceramide can suppress growth factor- or sphingosine-induced ERK activation as well as proliferation. These studies implicate sphingolipid metabolites as opposing regulators of cell proliferation and inflammation through activation of separate kinase cascades.
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PMID:Sphingolipid metabolites differentially regulate extracellular signal-regulated kinase and stress-activated protein kinase cascades. 864 94

Native PC12 cells respond differentially to nerve growth factor (NGF) but not interleukin-6 (IL-6); PC12-E2 cells, a stable variant, respond to both stimuli (and more rapidly to NGF). Neither responds to epidermal growth factor (EGF). NGF primarily induces the RAS/extracellular signal-regulated kinase (ERK) pathway and IL-6 activates a JAK (Janus tyrosine kinase)/STAT (signal transducers and activators of transcription) response. EGF also stimulates RAS/ERK but in a transient manner. When either cell type is treated with combinations of NGF, EGF, and IL-6, at concentrations that produce modest or no response, a substantial augmentation of neurite outgrowth is observed. With PC12-E2 cells, a subthreshold concentration of IL-6 increases NGF response by approximately 2-3-fold after 1-2 days; the increase with EGF is more pronounced. Native PC12 cells show even greater synergistic effects with NGF and IL-6. The most dramatic effect was observed with low levels of EGF, where IL-6 increased the percentage of responsive cells from zero to approximately 60% after 3 days. In addition, two neural-specific transcripts, GAP-43 and SCG-10, are synergistically increased by the combinations of growth factors. Importantly, IL-6 does not enhance ERK phosphorylation in the presence of either NGF or EGF. In contrast, NGF and EGF, in the presence or absence of IL-6, cause mobility shifts of Stat3 that are consistent with serine phosphorylations. Although these modifications do not lead to activation and translocation by themselves, in the presence of the tyrosine phosphorylation induced by IL-6, they may play a role in the synergistic responses. These observations suggest a differentially regulated two-stage mechanism for the differentiative response of PC12 cells to NGF.
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PMID:Synergistic induction of neurite outgrowth by nerve growth factor or epidermal growth factor and interleukin-6 in PC12 cells. 866 31

Interleukin-6 (IL-6) is a pleiotropic cytokine, which is involved in inflammatory and immune responses, acute phase reactions, and hematopoiesis. In the mouse fibrosarcoma cell line L929, the nuclear factor (NF)-kappaB plays a crucial role in IL-6 gene expression mediated by tumor necrosis factor (TNF). The levels of the activated factor do not, however, correlate with the variations of IL-6 gene transcription; therefore, other factors and/or regulatory mechanisms presumably modulate the levels of IL-6 mRNA production. Upon analysis of various deletion and point-mutated variants of the human IL-6 gene promoter coupled to a reporter gene, we screened for possible cooperating transcription factors. Even the smallest deletion variant, containing almost exclusively a NF-kappaB-responsive sequence preceding the IL-6 minimal promoter, as well as a recombinant construction containing multiple kappaB-motifs, could still be stimulated with TNF. We observed that the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 was able to repress TNF-stimulated expression of the IL-6 gene, as well as of a kappaB-dependent reporter gene construct, without affecting the levels of NF-kappaB binding to DNA. Furthermore, we clearly show that, using a nuclear Gal4 "one-hybrid" system, the MAPK inhibitors SB203580 and PD0980589 have a direct repressive effect on the transactivation potential of the p65 kappaB subunit. Therefore, we conclude that, in addition to cytoplasmic activation and DNA binding of NF-kappaB, the p38 and extracellular signal-regulated kinase MAPK pathways act as necessary cooperative mechanisms to regulate TNF-induced IL-6 gene expression by modulating the transactivation machinery.
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PMID:p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-kappaB p65 transactivation mediated by tumor necrosis factor. 945 44

Gene activation and cellular differentiation induced by interleukin-6 (IL-6) and transcription factor Stat3 are suppressed by several factors, including ionomycin, granulocyte/macrophage-colony-stimulating factor, and phorbol 12-myristate 13-acetate (PMA), that block IL-6-induced Stat3 activation. These inhibitory agents activate mitogen activated protein kinases (MAPKs), and thus the role of MAPKs in the mechanism of inhibition of Stat3 activation was investigated. Inhibition of IL-6-induced Stat3 activation by PMA and ionomycin was rapid (within 5 min) and did not require new RNA or protein synthesis. Inhibition of Stat3 DNA-binding activity and tyrosine phosphorylation by PMA, ionomycin, and granulocyte/macrophage-colony-stimulating factor was reversed when activation of the extracellular signal-regulated kinase (ERK) group of MAPKs was blocked by using specific kinase inhibitors. Expression of constitutively active MEK1, the kinase that activates ERKs, or overexpression of ERK2, but not JNK1, inhibited Stat3 activation. Inhibition of Stat3 correlated with suppression of IL-6-induction of a signal transducer and activator of transcription (STAT)-dependent reporter gene. In contrast to IL-6, activation of Stat3 by interferon-alpha was not inhibited. MEKs and ERKs inhibited IL-6 activation of Stat3 harboring a mutation at serine-727, the major site for serine phosphorylation, similar to inhibition of wild-type Stat3, and inhibited Janus kinases Jak1 and Jak2 upstream of Stat3 in the Jak-STAT-signaling pathway. These results demonstrate an ERK-mediated mechanism for inhibiting IL-6-induced Jak-STAT signaling that is rapid and inducible, and thus differs from previously described mechanisms for downmodulation of the Jak-STAT pathway. This inhibitory pathway provides a molecular mechanism for the antagonism of Stat3-mediated IL-6 activity by factors that activate ERKs.
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PMID:Rapid inhibition of interleukin-6 signaling and Stat3 activation mediated by mitogen-activated protein kinases. 973 97

We have demonstrated that the ischemia-induced apoptosis of neurons in the CA1 region of the rat hippocampus was prevented by either intracerebroventricular or intravenous infusion of pituitary adenylate cyclase-activating polypeptide (PACAP). However, the molecular mechanisms underlying the anti-apoptotic effect of PACAP remain to be determined. Within 3-6 h after ischemia, the activities of members of the mitogen-activated protein (MAP) kinase family, including extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), and p38 were increased in the hippocampus. The ischemic stress had a potent influence on the MAP kinase family, especially on JNK/SAPK. PACAP inhibited the activation of JNK/SAPK after ischemic stress. Secretion of interleukin-6 (IL-6) into the cerebrospinal fluid was intensely stimulated after PACAP infusion. IL-6 inhibited the activation of JNK/SAPK, while it activated ERK. These observations suggest that PACAP and IL-6 act to inhibit the JNK/SAPK signaling pathway, thereby protecting neurons against apoptosis.
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PMID:PACAP protects hippocampal neurons against apoptosis: involvement of JNK/SAPK signaling pathway. 992 3

A critical feature of sepsis-induced acute lung injury is the release of cytokines from endotoxin (LPS)- stimulated alveolar macrophages (AM). LPS is also known to activate various members of the mitogen- activated protein kinase (MAPK) family in other types of cells. In this study, we evaluated whether multiple members of the MAPK family regulate cytokine gene expression in LPS-stimulated AM. We found that LPS activates both the extracellular signal-regulated kinase (Erk) and p38 kinases, and that this activation is augmented when the cells are cultured in serum. Inhibition of either the Erk (with PD98059) or p38 (with SB203580) kinase pathway resulted in only a partial reduction in cytokine (interleukin-6 and tumor necrosis factor) messenger RNA accumulation and cytokine release, whereas inhibition of both pathways simultaneously resulted in a decrease in cytokine gene expression to near-control levels. Nuclear run-on assays showed that the effect of these MAPK pathways on LPS-induced expression of the cytokine genes was attributable, at least in part, to regulation of gene transcription. These findings suggest that activation of both the Erk and p38 kinase pathways is necessary for optimal cytokine gene expression in LPS-stimulated human AM, and that the MAPK pathways play a critical role in the inflammatory response that occurs in sepsis-induced acute lung injury.
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PMID:Both Erk and p38 kinases are necessary for cytokine gene transcription. 1010 Oct 8

Leukemia inhibitory factor (LIF) signals via the heterodimeric receptor complex comprising the LIF receptor alpha subunit (LIFRalpha) and the common signal transducing subunit for interleukin-6 cytokine receptors, gp130. This study demonstrates that in different cell types, the level of LIFRalpha decreases during treatment with LIF or the closely related cytokine oncostatin M (OSM). Moreover, insulin and epidermal growth factor induce a similar LIFRalpha down-regulation. The regulated loss of LIFRalpha is specific since neither gp130 nor OSM receptor beta shows a comparable change in turnover. LIFRalpha down-regulation correlates with reduced cell responsiveness to LIF. Using protein kinase inhibitors and point mutations in LIFRalpha, we demonstrate that LIFRalpha down-regulation depends on activation of extracellular signal-regulated kinase 1/2 and phosphorylation of the cytoplasmic domain of LIFRalpha at serine 185. This modification appears to promote the endosomal/lysosomal pathway of the LIFRalpha. These results suggest that extracellular signal-regulated kinase-activating factors like OSM and growth factors have the potential to lower specifically LIF responsiveness in vivo by regulating LIFRalpha half-life.
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PMID:Stimulation of leukemia inhibitory factor receptor degradation by extracellular signal-regulated kinase. 1085 40

Priming with interfon (IFN)alpha enhanced the ability of the synthetic double-stranded RNA polyriboinosinic acid: polyribocytidilic acid (pI:C), but not interleukin-1 beta, to activate both p38 mitogen-activated kinase (MAPK) and extracellular signal-regulated kinase (ERK) signaling cascades. Activation by pI:C in IFN alpha-primed cells was delayed compared to activation with interleukin-1 beta, and this delay was followed by high, sustained activation of p38 MAPK and a modest elevation of ERK activation. Pharmacologic inhibition of either the ERK or the p38 MAPK pathway, using U0126 and SB203580, respectively, reduced interleukin-6 protein induction by at least 70%, and combined inhibition of both pathways fully blocked interleukin-6 protein expression and reduced interleukin-6 mRNA induction by more than 80%. In contrast, induction of double-stranded RNA-activated protein kinase (PKR) mRNA and protein by IFN alpha and/or pI:C was minimally affected by either inhibitor. Induction of interferon-regulatory factor-1 (IRF-1) by pI:C in IFN alpha primed cells was profoundly inhibited by U0126 but not by SB203580. Thus, IFN alpha priming enhances activation of p38 MAPK and ERK pathways by pI:C but not by interleukin-1 beta, thereby enhancing the expression of some, but not all, genes that are induced by pI:C.
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PMID:Multiple signaling cascades are differentially involved in gene induction by double stranded RNA in interferon-alpha-primed cells. 1123 Dec 89

Specific intracellular signals mediated by interleukin-6 (IL-6) receptor complexes, such as signal transducer and activator of transcription 3 (STAT 3) and extracellular signal-regulated kinase (ERK) 1/2, are considered to be responsible for inducing a variety of cellular responses. In multiple myeloma, IL-6 only enhanced the proliferation of CD45+ tumor cells that harbored the IL-6-independent activation of src family kinases even though STAT3 and ERK1/2 could be activated in response to IL-6 in both CD45+ and CD45(minus sign) cells. Furthermore, the IL-6-induced proliferation of CD45+ U266 myeloma cells was significantly suppressed by Lyn-specific antisense oligodeoxynucleotides or a selective src kinase inhibitor. These results indicate that the activation of both STAT3 and ERK1/2 is not enough for IL-6-induced proliferation of myeloma cell lines that require src family kinase activation independent of IL-6 stimulation. Thus, the activation of the src family kinases associated with CD45 expression is a prerequisite for the proliferation of myeloma cell lines by IL-6. We propose a mechanism for IL-6-induced cell proliferation that is strictly dependent upon the cellular context in myelomas.
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PMID:Requirements of src family kinase activity associated with CD45 for myeloma cell proliferation by interleukin-6. 1187 94

Analyses of mitogen-activated protein kinases (MAPKs) in a mouse hepatitis virus (MHV)-infected macrophage-derived J774.1 cell line showed activation of two MAPKs, p38 MAPK and c-Jun N-terminal kinase (JNK), but not of extracellular signal-regulated kinase (ERK). Activation of MAPKs was evident by 6 h postinfection. However, UV-irradiated MHV failed to activate MAPKs, which demonstrated that MHV replication was necessary for their activation. Several other MHV-permissive cell lines also showed activation of both p38 MAPK and JNK, which indicated that the MHV-induced stress-kinase activation was not restricted to any particular cell type. The upstream kinase responsible for activating MHV-induced p38 MAPK was the MAPK kinase 3. Experiments with a specific inhibitor of p38 MAPK, SB 203580, demonstrated that MHV-induced p38 MAPK activation resulted in the accumulation of interleukin-6 (IL-6) mRNAs and an increase in the production of IL-6, regardless of MHV-induced general host protein synthesis inhibition. Furthermore, MHV production was suppressed in SB 203580-treated cells, demonstrating that activated p38 MAPK played a role in MHV replication. The reduced MHV production in SB 203580-treated cells was, at least in part, due to a decrease in virus-specific protein synthesis and virus-specific mRNA accumulation. Interestingly, there was a transient increase in the amount of phosphorylation of the translation initiation factor 4E (eIF4E) in infected cells, and this eIF4E phosphorylation was p38 MAPK dependent; it is known that phosphorylated eIF4E enhances translation rates of cap-containing mRNAs. Furthermore, the upstream kinase responsible for eIF4E phosphorylation, MAPK-interacting kinase 1, was also phosphorylated and activated in response to MHV infection. Our data suggested that host cells, in response to MHV replication, activated p38 MAPK, which subsequently phosphorylated eIF4E to efficiently translate certain host proteins, including IL-6, during virus-induced severe host protein synthesis inhibition. MHV utilized this p38 MAPK-dependent increase in eIF4E phosphorylation to promote virus-specific protein synthesis and subsequent progeny virus production. Enhancement of virus-specific protein synthesis through virus-induced eIF4E activation has not been reported in any other viruses.
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PMID:Murine coronavirus replication-induced p38 mitogen-activated protein kinase activation promotes interleukin-6 production and virus replication in cultured cells. 1202 26


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