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

Trophoblast cells display a very unique capability: they physiologically invade into the surrounding tissue. This capability is widely associated with tumours, and, indeed, the invasive behaviour of both is rather similar. The imposing difference is that trophoblast cell invasion is temporally and locally controlled in contrast to unlimited tumour invasion. It initiates immediately after embryo implantation into the endometrium. Parallel to tumours, trophoblasts secrete proteases, such as matrix metalloproteinases, which dissolve the extracellular matrix and the surrounding tissue. Thereby, these proteases prepare and allow true invasion of trophoblasts. The invasive capacities of trophoblasts are positively and negatively regulated by numerous cytokines including leukaemia inhibitory factor (LIF), interleukin-6, hepatocyte growth factor, granulocyte macrophage-colony stimulating factor and others. They interact via specific receptors with the trophoblast cells, in which they activate intracellular signalling cascades. These will then induce expression of invasion relevant genes. One of these signalling pathways is the Janus kinase/signal transducers and activators of transcription (STAT) pathway. Especially phosphorylated STAT3 enhances invasiveness of tumours and trophoblast cells, where it is mainly activated by LIF. One of its most efficient physiological antagonists is suppressor of cytokine signalling 3. The balance of these two intracellular molecules seems to be a key regulator of tumour and trophoblast invasion.
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PMID:Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3). 1842 27

We previously reported that interleukin-6 (IL-6) was locally produced in the early period after intraperitoneal (i.p.) or subcutaneous carbon tetrachloride (CCl4) administration, but not after oral (p.o.) administration. In the present study, we focused on the up-regulation of stress-inducible proteins induced by IL-6 after i.p. CCl4 administration. The expression of heme oxygenase-1 (HO-1) (EC 1.14.99.3) mRNA and protein were induced more in rats administered CCl4 via the i.p. route, compared with the p.o. route; however, expression of heat shock protein (HSP) 72 and HSP90 mRNA were increased to similar extents in both experimental groups. The induction of HO-1 mRNA and protein after i.p. CCl4 administration were significantly reduced after pretreatment with anti-rat IL-6 antibody. Activation of the signal transducer and activator of transcription factor 3 (STAT3), which promotes HO-1 expression, peaked together with plasma levels of IL-6 after i.p. CCl4 administration, suggesting that hepatic HO-1 expression was increased by IL-6 via the Janus kinase/STAT3 pathway. The present data indicate that hepatic HO-1 is up-regulated by endogenously produced IL-6, in addition to its up-regulation by heme derived from cytochrome P450 which has already been reported in rats administered i.p. CCl4. The up-regulation of hepatic HO-1 expression may reduce the tissue injury to livers caused by CCl4.
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PMID:Up-regulation of hepatic heme oxygenase-1 expression by locally induced interleukin-6 in rats administered carbon tetrachloride intraperitoneally. 1854 52

Cytokine-induced suppressor of cytokine signaling (SOCS) proteins function as feedback inhibitors of cytokine receptor signaling by inhibiting the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signal transduction pathway. In this report, microtubule-associated protein 1S (MAP1), a member of the MAP1 family, was identified as a novel SOCS3 interacting protein. MAP1S could bind with microtubules and actin, and decorated and stabilized microtubules. A perinuclear co-localization was discovered between MAP1S and SOCS3. In MAP1S deficient macrophages, inhibition of SOCS3 on STAT3 phosphorylation can be partially hindered in the presence of interleukin-6 (IL-6) and lipopolysaccharide (LPS). The microtubule-depolymerizing drug nocodazole also disrupted the inhibitory activity of the SOCS3 protein. These results suggest that the interaction of SOCS3 with MAP1S and the integrity of the microtubule cytoskeleton play an important role in the negative regulation of SOCS3 on IL-6 signaling.
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PMID:The role of microtubule-associated protein 1S in SOCS3 regulation of IL-6 signaling. 1902 8

Cytokine interleukin-6 (IL-6) has been well shown to be elevated in brain injury and diseases. However, the significance of IL-6 production in such neuropathologic states remains controversial, and the intracellular signal-transduction pathways involved in the brain IL-6 action are primarily unclear. We previously indicated that exogenous IL-6 protected neurons against glutamate and N-methyl-d-aspartate (NMDA) attacks and the effects of IL-6 was blocked by anti-gp130 antibody. Here, we provide further evidence for the IL-6 neuroprotection and show signal molecules transducing the IL-6 message. The cerebellar granule neurons from postnatal 8-day infant rats were exposed to IL-6 for 8 days, and also pretreated chronically with Janus kinase (JAK) inhibitor AG490 and mitogen-activated protein kinase (MAPK) inhibitor PD98059. NMDA stimulated the cultured neurons for 30 min to induce neuronal injury and death. Cell counting kit-8 assay and Western blot were employed to measure neuronal vitality and cleaved caspase-3 expression, respectively. The chronic IL-6 exposure prevented the suppression of the neuronal vitality and the enhancement of the cleaved caspase-3 level induced by NMDA. The neuroprotective effect of IL-6 depended on IL-6 concentration and neuronal damaged degree. IL-6-induced STAT3 phosphorylation was inhibited by AG490 but not by PD98059; and IL-6-induced ERK1/2 activation was blocked by PD98059 but not by AG490. Either AG490 or PD98059 blocked the IL-6 protection against the NMDA-elicited neuronal vitality decrease and caspase-3 activation increase. These findings suggest that IL-6 protects neurons from NMDA-induced excitoxicity and the IL-6 neuroprotection may be transduced by both JAK/STAT3 and RAS/MAPK pathways.
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PMID:Neuroprotection of interleukin-6 against NMDA attack and its signal transduction by JAK and MAPK. 1906 39

Epidermal growth factor receptor (EGFR) is overexpressed in ovarian carcinomas, with direct or indirect activation of EGFR able to trigger tumour growth. We demonstrate significant activation of both signal transducer and activator of transcription (STAT)3 and its upstream activator Janus kinase (JAK)2, in high-grade ovarian carcinomas compared with normal ovaries and benign tumours. The association between STAT3 activation and migratory phenotype of ovarian cancer cells was investigated by EGF-induced epithelial-mesenchymal transition (EMT) in OVCA 433 and SKOV3 ovarian cancer cell lines. Ligand activation of EGFR induced a fibroblast-like morphology and migratory phenotype, consistent with the upregulation of mesenchyme-associated N-cadherin, vimentin and nuclear translocation of beta-catenin. This occurred concomitantly with activation of the downstream JAK2/STAT3 pathway. Both cell lines expressed interleukin-6 receptor (IL-6R), and treatment with EGF within 1 h resulted in a several-fold enhancement of mRNA expression of IL-6. Consistent with that, EGF treatment of both OVCA 433 and SKOV3 cell lines resulted in enhanced IL-6 production in the serum-free medium. Exogenous addition of IL-6 to OVCA 433 cells stimulated STAT3 activation and enhanced migration. Blocking antibodies against IL-6R inhibited IL-6 production and EGF- and IL-6-induced migration. Specific inhibition of STAT3 activation by JAK2-specific inhibitor AG490 blocked STAT3 phosphorylation, cell motility, induction of N-cadherin and vimentin expression and IL6 production. These data suggest that the activated status of STAT3 in high-grade ovarian carcinomas may occur directly through activation of EGFR or IL-6R or indirectly through induction of IL-6R signalling. Such activation of STAT3 suggests a rationale for a combination of anti-STAT3 and EGFR/IL-6R therapy to suppress the peritoneal spread of ovarian cancer.
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PMID:Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial-mesenchymal transition in ovarian carcinomas. 1908 23

Advances in our understanding of the cellular and molecular mechanisms in rheumatic disease fostered the advent of the targeted therapeutics era. Intense research activity continues to increase the number of potential targets at an accelerated pace. In this review, examples of promising targets and agents that are at various stages of clinical development are described. Cytokine inhibition remains at the forefront with the success of tumor necrosis factor blockers, and biologics that block interleukin-6 (IL-6), IL-17, IL-12, and IL-23 and other cytokines are on the horizon. After the success of rituximab and abatacept, other cell-targeted approaches that inhibit or deplete lymphocytes have moved forward, such as blocking BAFF/BLyS (B-cell activation factor of the tumor necrosis factor family/B-lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) or suppressing T-cell activation with costimulation molecule blockers. Small-molecule inhibitors might eventually challenge the dominance of biologics in the future. In addition to plasma membrane G protein-coupled chemokine receptors, small molecules can be designed to block intracellular enzymes that control signaling pathways. Inhibitors of tyrosine kinases expressed in lymphocytes, such as spleen tyrosine kinase and Janus kinase, are being tested in autoimmune diseases. Inactivation of the more broadly expressed mitogen-activated protein kinases could suppress inflammation driven by macrophages and mesenchymal cells. Targeting tyrosine kinases downstream of growth factor receptors might also reduce fibrosis in conditions like systemic sclerosis. The abundance of potential targets suggests that new and creative ways of evaluating safety and efficacy are needed.
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PMID:Garden of therapeutic delights: new targets in rheumatic diseases. 1923 66

The neuropoietic cytokine family includes interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF), among others. These cytokines have been shown to alter neural stem cell (NSC) self-renewal and progenitor cell division and differentiation, which could be mediated by the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway. Using neurospheres from the adult mouse subventricular zone (SVZ), we found that acute or chronic exposure to LIF or CNTF differentially affects sphere development and sphere growth. Both cytokines also favor the amplification of NSCs. Contrasting results were obtained with IL-6 or leptin, although both cytokines also activate the JAK/STAT pathway. Stimulating NSC self-renewal in vivo could be of therapeutic interest for treating neurodegeneration. When applied to the adult mouse brain, chronic LIF stimulates NSC self-renewal but prevents the emergence of more differentiated progeny. On the other hand, acute LIF treatment stimulates SVZ regeneration, most likely through an increase in NSCs. These results reveal that cytokine effects could vary as a function of exposure duration and suggest that, in the search for strategies to promote brain repair, in vivo acute LIF treatment could promote cell replacement.
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PMID:Cytokine control of adult neural stem cells. 1923 27

It was shown recently that synovial fibroblast transformation into adipocytes reduced the expression of interleukin-6 (IL-6) and IL-8. However, the synovial fibroblast adipogenesis was inhibited in inflammatory conditions induced by the tumor necrosis factor-alpha (TNF-alpha). Furthermore, adipogenesis is often accompanied by leptin production, a proinflammatory adipokine in rheumatic diseases. In this study, we tested the phytohormone genistein for adipogenic and anti-inflammatory properties on human synovial fibroblasts. Results showed that genistein was able to transform synovial fibroblasts into adipocytes that expressed perilipin-A and produced adiponectin, but not leptin. Furthermore, genistein enhanced glucocorticoid-mediated synovial fibroblast adipogenesis and, in parallel, downregulated glucocorticoid-induced leptin and leptin receptor. Endogenous and TNF-alpha-induced expressions of IL-6, IL-8, p38, p65 and C/EBP-beta were also downregulated by genistein, showing its anti-inflammatory properties. Peroxisome proliferator- activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, had a synergic effect on genistein-induced adipogenesis, whereas the non-active tyrosine kinase inhibitor, daidzein, had a significantly inferior adipogenic activity than genistein. The Janus kinase-2 tyrosine kinase inhibitor, AG 490, mimicked the anti-leptin effect of genistein. These results showed that genistein-induced adipogenesis involves PPAR-gamma induction and tyrosine kinase inhibition. In conclusion, genistein, alone or coupled with glucocorticoids, have both adipogenic and anti-inflammatory effects on synovial fibroblasts.
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PMID:Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts. 1943 61

Cadmium, mercury and rotenone are environmental pollutants whose neurotoxic mechanisms are not fully understood. We have shown previously that exposure of nerve cells to these agents produces oxidative stress which reversibly blocks growth factor and cytokine-mediated Janus kinase (Jak)/signal transducer and activator of transcription (STAT) signaling. Here we determined a critical role for mitochondrial dysfunction in inhibiting Jak/STAT activity in human BE(2)-C neuroblastoma cells. Exposure of BE(2)-C cells to the heavy metals CdCl(2) and HgCl(2) and to the mitochondrial complex I inhibitor rotenone inhibited interleukin-6, interferon-gamma and ciliary neurotrophic factor-mediated Jak/STAT signaling, reduced Jak1 and Jak2 auto-phosphorylation and induced Jak tyrosine nitration. However, identical exposure of HepG2 hepatoma cells produced no inhibition of these cytokine responses. In contrast, mitochondria in both BE(2)-C and HepG2 cells showed reduced mitochondrial membrane potential and increased superoxide production after exposure to CdCl(2), HgCl(2) and rotenone. Further, in an in vitro Jak auto-phosphorylation assay Jak2 isolated from either BE(2)-C or HepG2 cells was equally inhibited by mitochondria made dysfunctional by treatment with CdCl(2), HgCl(2) and rotenone. Each of these pro-oxidant effects was reversed by the mitochondrial antioxidant alpha-lipoic acid. The actions of cadmium were also blocked by the mitochondrial complex III bypass agent, 2,6-dichloroindophenol. Therefore, in BE(2)-C cells CdCl(2), HgCl(2) and rotenone disrupt mitochondria to increase intracellular ROS, which directly inhibits neuronal Jak tyrosine kinase activity. Non-neuronal cells such as HepG2 cells that are resistant to oxidative stress-mediated inhibition of cytokine signaling possess some as yet unknown mechanism that protects Jak kinases from oxidative insults. Pro-oxidant-induced mitochondrial dysfunction resulting in selective neuronal Jak inhibition provides a potential mechanism for environmental agents to promote neurodegeneration.
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PMID:Environmental toxicants inhibit neuronal Jak tyrosine kinase by mitochondrial disruption. 1963 91

We have shown that tyrosine kinases and mitogen-activated protein kinases mediate angiotensin II (Ang II) effects in cultured rat astrocytes. In this study, we investigated whether Ang II induces Janus kinase (JAK) 2, signal transducer and activators of transcription (STAT) 3 phosphorylation, and interleukin-6 (IL-6) secretion in cultured brainstem rat astrocytes. Ang II increased JAK2 phosphorylation in a time- and dose-dependent manner. Maximal phosphorylation of 1.7+/-0.4 fold above basal was observed at 15 min with 100 nM Ang II. Losartan (10 microM), an AT(1) receptor blocker, inhibited Ang II-mediated JAK2 phosphorylation, while 10 microM PD123319, an AT(2) receptor blocker, was ineffective. The JAK2 inhibitor, AG490 (50 microM), prevented Ang II JAK2 phosphorylation. Ang II also stimulated STAT3 in a concentration- and time-dependent manner. Maximal phosphorylation of 0.8+/-0.11 above basal was observed at 15 min with 100 nM Ang II. Treatment with AG490 reduced Ang II phosphorylation of STAT3 and Ang II-induced astrocyte growth suggesting that JAK2 is an upstream signal in these Ang II effects. Ang II also stimulated IL-6 secretion from brainstem astrocytes in a concentration- and time-dependent manner. Maximal IL-6 secretion of 0.7+/-0.2 above basal was observed with 100 nM Ang II after 48 h of treatment. Losartan decreased Ang II-induced IL-6 secretion while PD123319 was ineffective. Interestingly, AG490 reduced Ang II-stimulated IL-6 secretion. Our study showed for the first time that Ang II induced JAK2/STAT3 phosphorylation and IL-6 secretion through activation of the Ang II AT(1) receptor in brainstem astrocytes. In addition, Ang II stimulated IL-6 secretion and astrocyte growth through the JAK2 pathway in brainstem astrocytes. These results provide new insights into pro-inflammatory and mitogenic signaling mechanisms of Ang II in astrocytes.
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PMID:Angiotensin II activates JAK2/STAT3 pathway and induces interleukin-6 production in cultured rat brainstem astrocytes. 1974 27


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