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

In B cell development, interleukin-6 (IL-6) induces terminal maturation of B lymphocytes into antibody producing plasma cells. Terminal differentiated B cells cell cycle arrest and death follows. In contrast, IL-6 acts as a growth factor for malignant myeloma plasma cells and in some cases protects them from therapeutic treatment. In this study, we examined two cell lines that show different responses to IL-6. Lymphoblastoid CESS cells respond to IL-6 by terminally differentiating into antibody producing plasma cells, cell cycle arrest, and undergo cell death. Continuous addition of IL-6 to these cells induces transient activation of STAT3, SHP-2 phosphorylation, and does not alter bcl-X(L) and c-myc expression. In contrast, the myeloma line ANBL6 proliferates when stimulated with IL-6 and this correlates with prolonged STAT3 activation and up-regulation of bcl-X(L) and c-myc. Interestingly, gp130-associated SHP-2 phosphorylation was detected in the IL-6-induced CESS cells but not myeloma cell lines. The data show a very distinct IL-6 signal transduction and kinetics in these cell lines and the distinct molecular events correlate closely to the cell fate of the lymphoblast and myeloma cell lines.
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PMID:Distinct IL-6 signal transduction leads to growth arrest and death in B cells or growth promotion and cell survival in myeloma cells. 1204 Apr 51

The expression of oncostatin M and leukemia inhibitory factor (LIF), JAK-STAT activators and members of the interleukin-6 family of cytokines, were examined in a series of primary ovarian carcinomas using immunohistochemistry. The malignant epithelial cells of all 29 ovarian carcinomas examined expressed oncostatin M; none expressed LIF. Oncostatin M can activate two related receptors, one consisting of a low-affinity LIF receptor subunit, LIFR beta, which forms a heterocomplex with the gp130 signal transducing protein and can recognize both oncostatin M and LIF, and a second heterocomplex consisting of a subunit that specifically recognizes oncostatin M, OSMR beta, and the gp130 protein. By immunohistochemistry, 25 of 25 ovarian carcinomas examined expressed the LIFR beta subunit in the malignant epithelial cells (all samples express gp130), and two-thirds the ovarian carcinomas studied expressed OSMR beta mRNA as determined by RT-PCR. Thus oncostatin M and its receptors are commonly coexpressed in malignant ovarian epithelial cells, and represent a potential autocrine loop in this tumor type. STAT3, of one the signaling proteins downstream of the oncostatin M/LIF receptors, was found in its phosphorylated, activated form (phosphotyrosine 705 STAT3) in the malignant epithelial cells of 17 of 23 ovarian carcinomas examined (74%) as determined by immunohistochemistry; this suggests that this protein is constitutively activated in most ovarian carcinomas, as it is in many other human malignancies. Recombinant human Oncostatin M (rhOSM) can induce the transient tyrosine 705 phosphorylation of STAT3 in serum-starved LIFR beta/OSMR beta expressing ovarian carcinoma cell lines, but does not alter cell growth and effects only a modest increase in the apoptotic rate in these cultured cells. Oncostatin M and its receptors may be part of a network of cytokine systems within ovarian carcinomas that may act to maintain STAT3 in its activated form, a phenomenon associated with the malignant phenotype.
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PMID:Coexpression of oncostatin M and its receptors and evidence for STAT3 activation in human ovarian carcinomas. 1206 40

Oncostatin M (OSM) is a glycoprotein cytokine that is produced by activated T-lymphocytes, monocytes, and macrophages. In a DNA synthesis assay, OSM reduced tritiated thymidine incorporation by 53% in Calu-1 lung carcinoma cells. Radiolabeled cDNAs from untreated Calu-1 cells and 30-h OSM-treated cells were used to probe duplicate nylon membrane cDNA expression arrays. This study revealed OSM-mediated expression of mRNAs encoding tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1). Northern blot analysis showed that the steady-state level of tPA mRNA is nearly undetectable in Calu-1 cells. Exposure of these cells to OSM for 30 h increased tPA mRNA expression by 20-fold and PAI-1 mRNA expression by 5-fold. Exposure of these cells to other gp130 receptor family cytokines, including leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and IL-11, do not significantly affect DNA synthesis or induction of tPA/PAI-1. Western blot studies demonstrated that OSM mediates a marked increase in secretion of the tPA protein. Secreted tPA was present in the conditioned medium almost exclusively as tPA/PAI-1 complexes. Inhibitor studies demonstrated that OSM-mediated induction of tPA and PAI-1 mRNAs is largely dependent upon activation of the MEK1/2 pathway. The JAK3/STAT3 pathway potentially serves a secondary role in these regulatory events.
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PMID:Oncostatin M induces tissue-type plasminogen activator and plasminogen activator inhibitor-1 in Calu-1 lung carcinoma cells. 1209 Jul 57

As the expression of cyclin D1 is induced during liver regeneration and also in hepatic tumor cells, cyclin D1 is likely to play an important role in the proliferation and transformation of hepatocytes. However, the role of cyclin D1 in liver development remains unknown. Here we show that the expression of D-type cyclins including cyclin D1, D2, and D3 is down-regulated along with liver development. In addition, oncostatin M (OSM), an interleukin-6 family cytokine, down-regulated the expression of cyclin D1 and D2 in a primary culture of fetal hepatocytes in which OSM induces hepatic differentiation. Ectopic expression of receptor mutants defective in the activation of either STAT3 or SHP-2/Ras indicated that the down-regulation of D1 and D2 cyclins by OSM was mediated by STAT3 but not by SHP-2/Ras. Consistently, expression of dominant negative STAT3 but not Ras relieved OSM-induced suppression of cyclin D expression. Activation of STAT3 in fetal hepatocytes of transgenic mice expressing the STAT3-estrogen receptor fusion protein by 4-hydroxytamoxifen resulted in the suppression of cyclin D1 and D2 expression. These results indicate that STAT3 activation is necessary and sufficient for down-regulation of D1 and D2 cyclins in fetal hepatocytes. Furthermore, STAT3-C, a constitutively active form of STAT3, suppressed transcription of the cyclin D1 promoter in fetal hepatocytes, whereas it activated the transcription in hepatic tumor cells, huH7 and HepG2. Thus, STAT3-mediated down-regulation of cyclin D expression is rather specific to fetal hepatocytes that are undergoing maturation processes including a reduction of their proliferation potential.
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PMID:STAT3 down-regulates the expression of cyclin D during liver development. 1214 85

Primary hippocampal neurons from newborn rats treated with glutamate showed clear excitotoxicity. This excitotoxicity could be reversed by treatment of the cells with cytokines of the interleukin-6 family. Stimulation of gp130 on hippocampal neurons resulted in tyrosine phosphorylation of STAT3 and activation of p42 and p44 MAP kinases. Receptors for the interleukin-6 type cytokines are active in membrane bound and soluble form. To address the question whether the neurotrophic effect of interleukin-6 type cytokines requires soluble cytokine receptors we used fusion proteins of interleukin-6 coupled to the soluble interleukin-6 receptor and ciliary neurotrophic factor coupled to the soluble ciliary neurotrophic factor receptor. Ciliary neurotrophic factor was as active as the cytokine-receptor fusion protein, indicating that hippocampal neurons express ciliary neurotrophic factor receptor on the cell surface. In contrast, interleukin-6 was only active at very high concentrations whereas the fusion protein of interleukin-6 coupled to the soluble interleukin-6 receptor (Hyper-IL-6) exhibited high neurotrophic activity at the same concentrations as ciliary neurotrophic factor. These data indicate that interleukin-6 receptor expression is very low on hippocampal neurons and that gp130 stimulation can be used to rescue hippocampal neurons from excitotoxicity.
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PMID:The effect of gp130 stimulation on glutamate-induced excitotoxicity in primary hippocampal neurons. 1215 Sep 83

The related members of the interleukin-6 (IL-6) family of cytokines, leukemia inhibitory factor (LIF), oncostatin M (OSM) and IL-6 are inflammatory mediators that control differentiated cell functions as well as proliferation. The cellular responsiveness to these cytokines is largely determined by the expression of the appropriate receptor proteins. The receptor expression profile for each cell type is established during differentiation and is often altered during oncogenic transformation. Since inhibition of histone deacetylases (HDAC) has the potential to re-activate epigenetically silenced genes, we asked whether inhibition of HDAC enhances the expression of IL-6 cytokine receptors and, thus, increase desirable cytokine responses. We demonstrate that treatment with FR901228 (FR), an HDAC inhibitor, increases the responsiveness to LIF in different cell types, including normal fibroblasts, epithelial cells, macrophages and splenocytes, as well as various tumor cell lines. Depending on the cell type, FR treatment also enhances the responsiveness to OSM and IL-6. These effects involve a transcriptional induction of the cytokine receptor subunits LIFRalpha, OSMRbeta, gp130, or the transcription factor STAT3. FR-specific induction of LIFRalpha occurs independently of de novo protein synthesis and cell proliferation and is mediated in part by the CBP/p300 coactivator. Chromatin immunoprecipitation experiments indicate that the expression of LIFRalpha and gp130 genes correlates with the level of acetylated histone 3 associated with the receptor promoter regions. The FR-stimulated expression of IL-6-type cytokine receptors in certain tumor cells also provided improved conditions for suppression of cell growth by taking advantage of the growth inhibitory effect of these cytokines.
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PMID:FR901228, an inhibitor of histone deacetylases, increases the cellular responsiveness to IL-6 type cytokines by enhancing the expression of receptor proteins. 1221 67

Interleukin-6 (IL-6) initiates STAT3 signaling in plasma membrane rafts with the subsequent transit of Tyr-phosphorylated STAT3 (PY-STAT3) through the cytoplasmic compartment to the nucleus in association with accessory proteins. We initially identified caveolin-1 (cav-1) as a candidate STAT3-associated accessory protein due to its co-localization with STAT3 and PY-STAT3 in flotation raft fractions, and heat shock protein 90 (HSP90) due to its inclusion in cytosolic STAT3-containing 200-400-kDa complexes. Subsequent immunomagnetic bead pullout assays showed that STAT3, PY-STAT3, cav-1, and HSP90 interacted in plasma membrane and cytoplasmic complexes derived from uninduced and stimulated Hep3B cells. This was a general property of STAT3 in that these interactions were also observed in alveolar epithelial type II-like cells, lung fibroblasts, and pulmonary arterial endothelial cells. Exposure of Hep3B cells to the raft disrupter methyl-beta-cyclodextrin for 1-10 min followed by IL-6 stimulation for 15 min preferentially inhibited the appearance of PY-STAT3 in the cav-1-enriched sedimentable cytoplasmic fraction, suggesting that these complexes may represent a trafficking intermediate immediately downstream from the raft. Because IL-6 is known to function in the body in the context of fever, the possibility that HSP90 may help preserve IL-6-induced STAT3 signaling at elevated temperature was investigated. Geldanamycin, an HSP90 inhibitor, markedly inhibited IL-6-stimulated STAT3 signaling in Hep3B hepatocytes cultured overnight at 39.5 degrees C as evaluated by DNA-shift assays, trafficking of PY-STAT3 to the nucleus, cross-precipitation of HSP90 by anti-STAT3 polyclonal antibody, and reporter/luciferase construct experiments. Taken together, the data show that IL-6/raft/STAT3 signaling is a chaperoned pathway that involves cav-1 and HSP90 as accessory proteins and suggest a mechanism for the preservation of this signaling during fever.
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PMID:Interactions of STAT3 with caveolin-1 and heat shock protein 90 in plasma membrane raft and cytosolic complexes. Preservation of cytokine signaling during fever. 1223 42

In the previous study, we demonstrated that the nuclear isoform of T-cell protein-tyrosine phosphatase (TC-PTP) dephosphorylated and deactivated signal transducer and activator of transcription 5a (STAT5a) and STAT5b, thereby negatively regulating prolactin (PRL)-mediated signaling pathway. In this study, we examined the involvement of the nuclear isoform of TC-PTP in interleukin-6 (IL-6)-mediated signaling pathway. IL-6 is a multifunctional cytokine that plays important roles in the immune system, hematopoiesis, and acute phase reactions, and has also implicated in IL-6-related diseases. Here, we demonstrate that IL-6-induced tyrosine-phosphorylation and activation of STAT3 were suppressed by overexpression of the nuclear isoform of TC-PTP in 293T cells. Tyrosine-phosphorylated STAT3 directly interacted with a substrate-trapping mutant of TC-PTP. Furthermore, retrovirus-mediated overexpression of the nuclear isoform of TC-PTP suppressed the IL-6-induced growth arrest of myeloid leukemia M1 cells. Endogenous TC-PTP complexed with STAT3 in the nucleus of M1 cells. These results strongly suggest that the nuclear isoform of TC-PTP may serve as a negative regulator of IL-6-mediated signaling pathway.
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PMID:The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation. 1235 25

Cytokine signaling generally occurs through receptors lacking tyrosine kinase activity. Aggregation of receptors leads to activation of receptor associated Janus kinases (Jaks) which in turn phosphorylate members of a family of transcription factors (STATs) that translocate to the nucleus and regulate gene expression. In the case of Interleukin-6 (IL-6), the consensus for signaling in B lineage cells has been that Jak1, Jak2 and Tyk2 are all phosphorylated upon ligand binding and participate in activation of downstream elements, in particular STAT3. In other cell types, Jak1 has been demonstrated to be absolutely required for IL-6 mediated activation of STAT3. In the present studies, we have identified a series of end stage B cell (plasma cell) lines that fail to express Jak1, but phosphorylate STAT3 in response to IL-6. No evidence was found for a requirement of other Jak family members in the activation of STAT3. STAT3 tyrosine phosphorylation was inhibited in a dose dependent manner by the MEK inhibitor U0126, but not by inhibitors of PI-3K or Src kinases. Moreover, STAT3 phosphorylation was similarly inhibited in lines expressing Jak1 wherein Jak1 was phosphorylated upon IL-6 stimulation and Jak1 phosphorylation was not inhibited by U0126. These results indicate that the MAPK pathway plays a critical role in IL-6 mediated tyrosine phosphorylation of STAT3 and suggests that Jak kinases may not be required in this cascade. Thus, it may be important to re-evaluate the role of Jak kinases in other cytokine signaling pathways as well.
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PMID:IL-6 mediated activation of STAT3 bypasses Janus kinases in terminally differentiated B lineage cells. 1236 Apr 5

Translocations involving the immunoglobulin heavy-chain switch region and fibroblast growth factor receptor 3 (FGFR3) are identified in 10% to 15% of patients with myeloma. In previous research we overexpressed FGFR3 or the constitutively active FGFR3-TD mutant in an interleukin-6 (IL-6)-dependent murine myeloma cell line, B9. FGFR3-enhanced IL-6 responsiveness increased phosphorylation of STAT3 and up-regulated Bcl-x(L). Since Bcl-x(L) was up-regulated, we have tested FGFR3-expressing B9 cells for chemotherapy sensitivity. FGFR3 expression did not alter sensitivity to melphalan or doxorubicin. In contrast, B9 cells overexpressing FGFR3 were resistant to treatment with dexamethasone, a phenomenon successfully reversed using a Bcl-x(L) antisense oligonucleotide. These data demonstrate that the overexpression of FGFR3 in B9 cells confers resistance to dexamethasone but not to anthracyclines or alkylating agents, at least in part through the up-regulation of Bcl-x(L). This finding has potential implications for the use of chemotherapy in t(4;14)-positive myeloma.
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PMID:Overexpression of the myeloma-associated oncogene fibroblast growth factor receptor 3 confers dexamethasone resistance. 1239 93


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