UNIPROT:P05231 - FACTA Search

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

A variety of injuries, such as bacterial infection or ischemic tissue necrosis, induce systemic acute phase reaction expressed as fever, leukocytosis, release of several hormones, activation of clotting, complement and kinin forming pathways, and drastic increase of synthesis of certain plasma proteins. The reaction is triggered by 'alarm molecules', including free radicals, which activate several stress-sensitive protein kinases (ERK, p38, JNK) in macrophages and other responsive cells. These kinases phosphorylate, usually in a multi-step cascade, transcription factors belonging primarily to C/EBP, NF-kappa B and AP-1 families. Active transcription factors after translocation to nucleus interact with responsive elements in the gene promoters of acute-phase cytokines: tumor necrosis factor-alpha, interleukin-1 and interleukin-6. Enhanced transcription of these genes is usually followed by rapid translation and precursor protein processing leading to the release of biologically active cytokines. Fine tuning of the acute phase response appears to be regulated at all stages: primary signals, kinase cascades, transcription factors, mRNA stability and translation, cytokine precursor processing, secretion and bioavailability. This makes possible designing of specific inhibitors of cytokine synthesis as potential therapeutic drugs.
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PMID:Initiation of acute phase response and synthesis of cytokines. 895 Jan 92

We recently reported that insulin stimulation results in the serine phosphorylation of STAT3 (signal transducer and activator of transcription-3). In the present study, we identified serine 727 as the site of insulin-stimulated STAT3 serine phosphorylation. This phosphorylation event occurs independent of tyrosine phosphorylation. Furthermore, interleukin-6-induced tyrosine phosphorylation can occur independent of serine phosphorylation, demonstrating that these two phosphorylation pathways are mechanistically unrelated. Selective activation of the JNK and p38 family of mitogen-activated protein (MAP) kinases by anisomycin treatment did not result in the phosphorylation of STAT3. In contrast, activation of the ERK MAP kinase pathway with both insulin and osmotic shock resulted in the serine phosphorylation of STAT3. In addition, expression of a dominant-interfering Ras mutant (N17Ras) or treatment with the specific MEK inhibitor (PD98059) prevented the insulin stimulation of STAT3 serine phosphorylation. Blockade of ERK activation by expression of the MAP kinase phosphatase (MKP-1) had no effect on insulin-stimulated STAT3 serine phosphorylation. Together, these data demonstrate that the insulin-stimulated serine phosphorylation of STAT3 occurs by a MEK-dependent pathway that is independent of ERK activation.
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PMID:Signal transducer and activator of transcription-3 serine phosphorylation by insulin is mediated by a Ras/Raf/MEK-dependent pathway. 932 21

Recent studies have indicated that serine phosphorylation regulates the activities of STAT1 and STAT3. However, the kinase(s) responsible and the role of serine phosphorylation in STAT function remain unresolved. In the present studies, we examined the growth factor-dependent serine phosphorylation of STAT1 and STAT3. We provide in vitro and in vivo evidence that the ERK family of mitogen-activated protein (MAP) kinases, but not JNK or p38, specifically phosphorylate STAT3 at serine 727 in response to growth factors. Evidence for additional mitogen-regulated serine phosphorylation is also provided. STAT1 is a relatively poor substrate for all MAP kinases tested both in vitro and in vivo. STAT3 serine phosphorylation, not its tyrosine phosphorylation, results in retarded mobility of the STAT3 protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Importantly, serine 727 phosphorylation negatively modulates STAT3 tyrosine phosphorylation, which is required for dimer formation, nuclear translocation, and the DNA binding activity of this transcriptional regulator. Interestingly, the cytokine interleukin-6 also stimulates STAT3 serine phosphorylation, but in contrast to growth factors, this occurs by an ERK-independent process.
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PMID:STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. 934 14

Tumor necrosis factor alpha (TNF-alpha) is a cytokine implicated in the pathogenesis of numerous chronic and acute inflammatory conditions. We have previously shown that mouse Sertoli cells respond to TNF-alpha by increasing interleukin-6 production and intercellular adhesion molecule-1 (ICAM-1) expression (1). In this cell type TNF-alpha activates the mitogen-activated protein kinase (MAPK) pathways p42/p44 MAPK, JNK/SAPK, and p38, the last of which is responsible for interleukin-6 production (1). To determine which MAPK signaling pathway is required for TNF-alpha induction of ICAM-1 expression, we have utilized the protein kinase inhibitor dimethylaminopurine, demonstrating that treatment of Sertoli cells with such compound significantly reduced ICAM-1 expression and JNK/SAPK activation. Moreover, dimethylaminopurine treatment increased the expression of MAPK phosphatase-2, providing a possible mechanism of action of this compound. By using agonist antibodies to p55 and to p75 TNF-alpha receptors and both human and mouse TNF-alpha, we demonstrate that both TNF receptors are expressed and that only the p55 receptor is involved in ICAM-1 expression. The p55 receptor activates all of the three pathways, whereas p75 failed to activate any of the MAPKs. Altogether our results demonstrate that TNF-alpha up-regulates ICAM-1 expression through the activation of the JNK/SAPK transduction pathway mediated by the p55 receptor.
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PMID:Activation of Jun N-terminal kinase/stress-activated protein kinase pathway by tumor necrosis factor alpha leads to intercellular adhesion molecule-1 expression. 1050 45

Double-stranded RNA (dsRNA) accumulates in virus-infected mammalian cells and signals the activation of host defense pathways of the interferon system. We describe here a novel form of dsRNA-triggered signaling that leads to the stimulation of the p38 mitogen-activated protein kinase (p38 MAPK) and the c-Jun NH(2)-terminal kinase (JNK) and of their respective activators MKK3/6 and SEK1/MKK4. The dsRNA-dependent signaling to p38 MAPK was largely intact in cells lacking both RNase L and the dsRNA-activated protein kinase (PKR), i. e., the two best-characterized mediators of dsRNA-triggered antiviral responses. In contrast, activation of both MKK4 and JNK by dsRNA was greatly reduced in cells lacking RNase L (or lacking both RNase L and PKR) but was restored in these cells when introduction of dsRNA was followed by inhibition of ongoing protein synthesis or transcription. These results are consistent with the notion that the role of RNase L and PKR in the activation of MKK4 and JNK is the elimination, via inhibition of protein synthesis, of a labile negative regulator(s) of the signaling to JNK acting upstream of SEK1/MKK4. In the course of these studies, we identified a long-sought site of RNase L-mediated cleavage in the 28S rRNA, which could cause inhibition of translation, thus allowing the activation of JNK by dsRNA. We propose that p38 MAPK is a general participant in dsRNA-triggered cellular responses, whereas the activation of JNK might be restricted to cells with reduced rates of protein synthesis. Our studies demonstrate the existence of alternative (RNase L- and PKR-independent) dsRNA-triggered signaling pathways that lead to the stimulation of stress-activated MAPKs. Activation of p38 MAPK (but not of JNK) was demonstrated in mouse fibroblasts in response to infection with encephalomyocarditis virus (ECMV), a picornavirus that replicates through a dsRNA intermediate. Fibroblasts infected with EMCV (or treated with dsRNA) produced interleukin-6, an inflammatory and pyrogenic cytokine, in a p38 MAPK-dependent fashion. These findings suggest that stress-activated MAPKs participate in mediating inflammatory and febrile responses to viral infections.
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PMID:Activation of p38 mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase by double-stranded RNA and encephalomyocarditis virus: involvement of RNase L, protein kinase R, and alternative pathways. 1061 Dec 40

Cyclooxygenase-2 (COX-2), the enzyme primarily responsible for induced prostaglandin synthesis, is an immediate early gene induced by endotoxin in macrophages. We investigated the cis-acting elements of the COX-2 5'-flanking sequence, the transcription factors and signaling pathways responsible for transcriptional activation of the COX-2 gene in endotoxin-treated murine RAW 264.7 macrophages. Luciferase reporter constructs with alterations in presumptive cis-acting transcriptional regulatory elements demonstrate that the cyclic AMP-response element and two nuclear factor interleukin-6 (CCAAT/enhancer-binding protein (C/EBP)) sites of the COX-2 promoter are required for optimal endotoxin-dependent induction. In contrast, the E-box and NF-kappaB sites are not required for endotoxin-dependent induction. Inhibition of endotoxin-induced NF-kappaB activation by expression of an inhibitor-kappaB alpha mutant does not block endotoxin-dependent COX-2 reporter activity. Overexpression of c-Jun, C/EBPbeta, and C/EBPdelta enhances induction of the COX-2 reporter, while overexpression of cyclic AMP-response element-binding protein or "dominant negative" C/EBPbeta represses COX-2 induction. In addition, endotoxin rapidly and transiently elicits c-Jun phosphorylation in RAW 264.7 macrophages. Cotransfection of the COX-2 reporter with dominant negative expression vectors shows that endotoxin-induced COX-2 gene expression requires signaling through a Ras-independent pathway involving the adapter protein ECSIT and the signaling kinases MEKK1 and JNK. In contrast, endotoxin-induced COX-2 reporter activity is not blocked by overexpression of dominant-negative forms of Raf-1, ERK1, or ERK2.
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PMID:Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages. 1069 22

Cytokines are extracellular mediators that have been reported to affect neurotransmitter release and synaptic plasticity phenomena when applied in vitro. Most of these effects occur rapidly after the application of the cytokines and are presumably mediated through the activation of protein phosphorylation processes. While many cytokines have an inflammatory action, interleukin-6 (IL-6) has been found to have a neuroprotective effect against ischaemia lesions and glutamate excitotoxicity, and to increase neuronal survival in a variety of experimental conditions. In this paper, the functional effects of IL-6 on the spread of excitation visualized by dark-field/infrared videomicroscopy in rat cortical slices and on glutamate release from cortical synaptosomes were analysed and correlated with the activation of the STAT3, mitogen-activated protein kinase ERK (MAPK/ERK) and stress-activated protein kinase/cJun NH2-terminal kinase (SAPK/JNK) pathways. We have found that IL-6 depresses the spread of excitation and evoked glutamate release in the cerebral cortex, and that these effects are accompanied by a stimulation of STAT3 tyrosine phosphorylation, an inhibition of MAPK/ERK activity, a decreased phosphorylation of the presynaptic MAPK/ERK substrate synapsin I and no detectable effects on SAPK/JNK. The effects of IL-6 were effectively counteracted by treatment of the cortical slices with the tyrosine kinase inhibitor lavendustin A. The inhibitory effects of IL-6 on glutamate release and on the spread of excitation in the rat cerebral cortex indicate that the protective effect of IL-6 on neuronal survival could be mediated by a downregulation of neuronal activity, release of excitatory neurotransmitters and MAPK/ERK activity.
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PMID:Interleukin-6 inhibits neurotransmitter release and the spread of excitation in the rat cerebral cortex. 1076 53

Several cytokines have short-term effects on synaptic transmission and plasticity that are thought to be mediated by the activation of intracellular protein kinases. We have studied the effects of interleukin-6 (IL-6) on the expression of paired pulse facilitation (PPF), posttetanic potentiation (PTP), and long-term potentiation (LTP) in the CA1 region of the hippocampus as well as on the activation of the signal transducer and activator of transcription-3 (STAT3), the mitogen-activated protein kinase ERK (MAPK/ERK), and the stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK). IL-6 induced a marked and dose-dependent decrease in the expression of PTP and LTP that could be counteracted by the simultaneous treatment with the tyrosine kinase inhibitor lavendustin A (LavA) but did not significantly affect PPF. The IL-6-induced inhibition of PTP and LTP was accompanied by a simulation of STAT3 tyrosine phosphorylation and an inhibition of MAPK/ERK dual phosphorylation, in the absence of changes in the state of activation of SAPK/JNK. Both effects of IL-6 on STAT3 and MAPK/ERK activation were effectively counteracted by LavA treatment. The results indicate the tyrosine kinases and MAPK/ERK are involved in hippocampal synaptic plasticity and may represent preferential intracellular targets for the actions of IL-6 in the adult nervous system.
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PMID:The inhibitory effects of interleukin-6 on synaptic plasticity in the rat hippocampus are associated with an inhibition of mitogen-activated protein kinase ERK. 1089 38

Activation of signal transducer and activator of transcription 3 (STAT3) by interleukin-6 (IL-6) involves phosphorylation of Tyr-705 and Ser-727, both of which are critical for STAT3 transactivation. Here, we demonstrate that IL-6 activates Rac-1 and SEK-1/MKK-4 of the stress-activated protein kinase pathway, as well as protein kinase Cdelta (PKCdelta), as indicated by PKCdelta Thr-505 phosphorylation. However, JNK-1, the end point kinase of the stress-activated protein kinase pathway signal transduction cascade, is not activated by IL-6. PKCdelta was found to be associated with SEK-1/MKK-4 in unstimulated HepG2 cells but rapidly dissociates from SEK-1/MKK-4 upon IL-6 stimulation to become associated with STAT3. Inhibition of PKCdelta using rottlerin (6 microm) or by overexpression of dominant negative PKCdelta demonstrates that PKCdelta kinase activity is required for STAT3 Ser-727 phosphorylation and transactivation but not for STAT3 Tyr-705 phosphorylation or nuclear import. PKCdelta signals downstream of Rac-1 and SEK-1/MKK-4, because enhanced STAT3 transactivation induced by overexpression of constitutive active RacV12 was strongly abrogated by rottlerin, whereas IL-6-induced SEK-1/MKK-4 Thr-223 phosphorylation was not affected under these conditions. Studying the kinetics of STAT3 and PKCdelta phosphorylation in cytoplasmic and nuclear fractions revealed that STAT3 Tyr-705 phosphorylation and nuclear translocation precedes PKCdelta Thr-505 and STAT3 Ser-727 phosphorylation. Furthermore, the IL-6-induced PKCdelta Thr-505 and STAT3 Ser-727 phosphorylation were only observed in nuclear fractions of HepG2 cells. These results demonstrate that IL-6-induced STAT3 transactivation involves the sequential activation of Rac-1 and SEK-1/MKK-4, which leads to nuclear translocation of PKCdelta by release from a SEK-1/MKK-4-containing complex. Our results further indicate that PKCdelta-mediated STAT3 Ser-727 phosphorylation is mainly a nuclear event.
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PMID:Sequential activation of Rac-1, SEK-1/MKK-4, and protein kinase Cdelta is required for interleukin-6-induced STAT3 Ser-727 phosphorylation and transactivation. 1133 11

Many Fas-expressing cells do not undergo cell death upon Fas stimulation. In the normal human diploid cell line GM6112, the addition of soluble Fas ligand (sFasL) leads to morphological signs of cell death in less than 1% of cells. Treatment of serum-starved GM6112 fibroblasts with sFasL resulted in a rapid and transient phosphorylation of ERK1/2 without a significant increase in JNK and p38 activities. Unless co-treated with the protein synthesis inhibitor anisomycin, sFasL did not show gene-inducing activity in cells maintained in complete medium. However, when cells were serum-starved for 4 days, treatment with sFasL alone induced interleukin-6 gene expression and, less strongly, interleukin-8 gene expression. Sensitization of the gene-inducing activity by serum starvation correlated with NF-kappaB activation by sFasL. Furthermore, we found that the expression of FADD and caspase-8 was significantly reduced in serum-starved cells, whereas the level of cFLIP remained unchanged. Transfection of GM6112 cells with the antisense caspase-8 expression construct sensitized cells toward sFasL-induced NF-kappaB-dependent reporter activation. Our results support the notion that a change in the ratio of cFLIP and caspase-8 may be responsible for turning on the Fas-activated NF-kappaB pathway, which otherwise is supplanted by the death-inducing pathway.
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PMID:Non-apoptotic signaling pathways activated by soluble Fas ligand in serum-starved human fibroblasts. Mitogen-activated protein kinases and NF-kappaB-dependent gene expression. 1160 Apr 97

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