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

The receptor for leukemia inhibitory factor (LIFR), in combination with the signal-transducing subunit for interleukin-6-type cytokine receptors, gp130, and LIF, activates transcription of acute-phase plasma protein genes in human and rat hepatoma cells and the vasoactive intestinal peptide gene in a human neuroblastoma cell line. To identify the regions within the cytoplasmic domain of LIFR that initiate signal transduction independently of gp130, we constructed a chimeric receptor by linking the extracellular domain of the granulocyte colony-stimulating factor receptor (G-CSFR) to the transmembrane and cytoplasmic domain of human LIFR. The function of the chimeric receptor protein in transcriptional activation was assessed by G-CSF-mediated stimulation of cotransfected cytokine-responsive reporter gene constructs in hepatoma and neuroblastoma cells. By using the full-length cytoplasmic domain and mutants with progressive carboxy-terminal deletions, internal deletions, or point mutations, we identified the first 150 amino acid residues of LIFR as the minimal region necessary for signaling. The signaling reaction appears to involve a cooperativity between the first 70-amino-acid region containing the two sequence motifs conserved among hematopoietin receptors (box 1 and box 2) and a critical sequence between residues 141 and 150 (box 3). Analogous analyses of the cytoplasmic domains of G-CSFR and gp130 indicated similar arrangements of functional domains in these receptor subunits and the requirement of a box 3-related motif for signaling.
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PMID:Multiple regions within the cytoplasmic domains of the leukemia inhibitory factor receptor and gp130 cooperate in signal transduction in hepatic and neuronal cells. 826 82

Interleukin-6 (IL-6), leukemia inhibitory factor, oncostatin M, interleukin-11, and ciliary neurotrophic factor bind to receptor complexes that share the signal transducer gp130. Upon binding, the ligands rapidly activate DNA binding of acute-phase response factor (APRF), a protein antigenically related to the p91 subunit of the interferon-stimulated gene factor-3 alpha (ISGF-3 alpha). These cytokines caused tyrosine phosphorylation of APRF and ISGF-3 alpha p91. Protein kinases of the Jak family were also rapidly tyrosine phosphorylated, and both APRF and Jak1 associated with gp130. These data indicate that Jak family protein kinases may participate in IL-6 signaling and that APRF may be activated in a complex with gp130.
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PMID:Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. 827 72

A recently defined family of cytokines, consisting of ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), and interleukin-6 (IL-6), utilize the Jak-Tyk family of cytoplasmic tyrosine kinases. The beta receptor components for this cytokine family, gp130 and LIF receptor beta, constitutively associate with Jak-Tyk kinases. Activation of these kinases occurs as a result of ligand-induced dimerization of the receptor beta components. Unlike other cytokine receptors studied to date, the receptors for the CNTF cytokine family utilize all known members of the Jak-Tyk family, but induce distinct patterns of Jak-Tyk phosphorylation in different cell lines.
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PMID:Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. 827 73

Neutralizing monoclonal antibodies specific for human interleukin-6 (IL-6) bind two distinct sites on the IL-6 protein (sites I and II). Their interference with IL-6 receptor binding suggested that site I is a receptor-binding site of IL-6, whereas site II is important for signal transduction. Mutagenesis of site II could therefore result in the isolation of IL-6 receptor antagonists. To test this hypothesis, a panel of IL-6 mutant proteins was constructed that did not bind to a site II-specific monoclonal antibody. One such site II mutant protein (with double substitution of Gln-160 with Glu and Thr-163 with Pro) was found to be an antagonist of human IL-6. It was inactive on human CESS cells, weakly active on human HepG2 cells, but active on mouse B9 cells. It could specifically antagonize the activity of wild-type IL-6 on CESS and HepG2 cells. The binding affinity of this variant for the 80-kDa IL-6 receptor was similar to that of wild-type IL-6. High affinity binding to CESS cells, however, was abolished, suggesting that the mutant protein is inactive because the complex of the 80-kDa IL-6 receptor and the mutant protein cannot associate with the signal transducer gp130. The human IL-6 antagonist protein may be potentially useful as a therapeutic agent.
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PMID:Development of a human interleukin-6 receptor antagonist. 827 83

The interleukin-6 (IL-6) signal is transduced through membrane-anchored gp130, which is associated with IL-6 receptor (IL-6R) in the presence of IL-6. Soluble forms of gp130 (sgp130) with molecular weights of 90 and 110 Kd were found in human serum. In the presence of recombinant IL-6 (rIL-6), serum sgp130 were capable of associating with serum sIL-6R. By the sandwich enzyme-linked immunosorbent assay, healthy human sera was shown to contain 390 +/- 72 ng/mL of sgp130. A mouse pro-B-cell line-derived transfectant, BAF-130, expressing human gp130 was used to examine the function of serum sgp130. When supplemented with rIL-6, human serum induced DNA synthesis in BAF-130 cells, whereas the serum deprived of sIL-6R did not. In contrast, the DNA synthesis induced in BAF-130 cells by rIL-6-supplemented serum was increased when the serum was deprived of sgp130. These results indicated that serum sgp130 could negatively regulate the IL-6 signal. Recently, gp130 has been shown to be involved in the signaling processes of oncostatin M, leukemia inhibitory factor, and ciliary neurotropic factor, in addition to those of IL-6. Recombinant sgp130 showed inhibitory effect on the biologic function of such cytokines. This work implies physiologic roles of naturally produced serum sgp130 in modulating signals through gp130.
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PMID:Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. 835 78

Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are cytokines that give rise to an identical set of tyrosine-phosphorylated proteins upon addition to responsive cells. One of these proteins is the interleukin-6 signal-transducing molecule gp130, which is required for signal transduction by both CNTF and LIF. Here we identify another prominent tyrosine-phosphorylated protein as LIF receptor (LIFR) beta, which was originally cloned as a LIF-binding protein. Cross-linking experiments with iodinated factors were carried out on a cell line responsive to CNTF and LIF, as well as on COS cells that were cotransfected with various combinations of gp130, LIFR beta, and CNTF receptor (CNTFR) alpha, the previously cloned CNTF-binding protein. These experiments reveal that LIF cross-links to LIFR beta alone, as well as to gp130 when it is coexpressed with LIFR beta. However, cross-linking of CNTF to LIFR beta and gp130 is only observed in the presence of CNTFR alpha. These and other data show that the two known LIF receptor components are recruited by CNTF and CNTFR alpha to form a trimeric CNTF receptor complex.
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PMID:Cross-linking identifies leukemia inhibitory factor-binding protein as a ciliary neurotrophic factor receptor component. 838 13

The ciliary neurotrophic factor (CNTF) receptor complex is shown here to include the CNTF binding protein (CNTFR alpha) as well as the components of the leukemia inhibitory factor (LIF) receptor, LIFR beta (the LIF binding protein) and gp130 [the signal transducer of interleukin-6 (IL-6)]. Thus, the conversion of a bipartite LIF receptor into a tripartite CNTF receptor apparently occurs by the addition of the specificity-conferring element CNTFR alpha. Both CNTF and LIF trigger the association of initially separate receptor components, which in turn results in tyrosine phosphorylation of receptor subunits. Unlike the IL-6 receptor complex in which homodimerization of gp130 appears to be critical for signal initiation, signaling by the CNTF and LIF receptor complexes depends on the heterodimerization of gp130 with LIFR beta. Ligand-induced dimerization of signal-transducing receptor components, also seen with receptor tyrosine kinases, may provide a general mechanism for the transmission of a signal across the cell membrane.
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PMID:LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. 839 97

cDNAs coding for the two receptor subunits of the interleukin-6 receptor have been stably expressed in Madine Darby canine kidney (MDCK) cells. The fate of the IL-6 binding protein (IL-6R) and of the signal transducing protein gp130 was studied independently. Both proteins were proteolytically cleaved from cells metabolically labeled with [35S]methionine/cysteine leading to the release of soluble receptor proteins of 55 kDa and 100 kDa, respectively. In contrast to the shedding of the IL-6R gp130 was inefficiently released from the cells and the process was not significantly stimulated by the phorbolester PMA. In addition we show that the soluble forms of the IL-6R and gp130 released by transfected cells can form a ternary complex with interleukin-6 indicating that such complexes also may occur in vivo.
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PMID:Differential shedding of the two subunits of the interleukin-6 receptor. 840 37

The ability to penetrate the dermal basement membrane and subsequently proliferate in the underlying mesenchyme is one of the key steps in malignant progression of human melanomas. We previously undertook studies aimed at assessing how normal dermal fibroblasts (one of the main cellular components of mesenchyme) may affect the growth of human melanoma cells and facilitate the overgrowth of malignant subpopulations (Cornil, I., D. Theodorescu, S. Man, M. Herlyn, J. Jambrosic, and R. S. Kerbel. 1991. Proc. Natl. Acad. Sci. USA. 88:6028-6032). We found that melanoma cell lines from early-stage (metastatically incompetent) lesions were growth inhibited whereas those from advanced-stage (metastatically competent) lesions were stimulated under the same conditions by co-culture with fibroblasts; conditioned medium from such cells gave the same result. Subsequent studies using biochemical purification and neutralizing antibodies revealed the inhibitory activity to be identical to interleukin-6 (IL-6). We now report that addition of purified recombinant human IL-6 resulted in a growth inhibition in vitro by G1/G0 arrest of early, but not advanced stage melanoma cells. Despite this alteration in response there was no significant difference in melanoma cell lines of varying malignancy in respect to their expression of genes encoding the IL-6 receptor, or gp130, the IL-6 signal transducer. Scatchard analysis also revealed similar [125I]IL-6 binding activities in both IL-6 sensitive and resistant groups. However, studies of IL-6 production indicated that five out eight IL-6 melanoma cell lines known to be resistant to exogenous IL-6-mediated growth inhibition constitutively expressed mRNA for IL-6; they also secreted bioactive IL-6 into culture medium. To assess the possible role of this endogenous IL-6 in melanoma cell growth, antisense oligonucleotides to the IL-6 gene were added to cultures of melanoma cells. This resulted in a significant growth inhibition only in cell lines that produced endogenous IL-6. In contrast, neutralizing antibodies to IL-6 were ineffective in causing such growth inhibition. This indicates that endogenous IL-6 may behave as a growth stimulator by an intracellular ("private") autocrine mechanism. Thus, a single cytokine, IL-6, can switch from behaving as a paracrine growth inhibitor to an autocrine growth stimulator within the same cell lineage during malignant tumor progression. Such a switch may contribute to the growth advantage of metastatically competent melanoma cells at the primary or distant organ sites and thereby facilitate progression of disease.
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PMID:Interleukin-6 undergoes transition from paracrine growth inhibitor to autocrine stimulator during human melanoma progression. 843 94

Recombinant human 125I-interleukin-6 (IL-6) was cross-linked with the homobifunctional reagent disuccinimidyl suberate to human hepatoma cells (HepG2). Three recombinant human 125I-IL-6-containing complexes of apparent molecular masses of 100, 120, and 200 kDa were immunoprecipitated with specific antibodies to human IL-6 or to the 80-kDa IL-6 receptor subunit. We show by immunoprecipitation, peptide mapping, and by the use of a cleavable heterobifunctional cross-linker (Denny-Jaffe reagent) that different polypeptides are involved in the formation of the 100- and 120-kDa IL-6-containing complexes. The molecular compositions of the 100- and 120-kDa cross-linked complexes were identified. The 100-kDa complex consisted of one ligand and one IL-6 receptor subunit, glycoprotein 80 (gp80), whereas the 120-kDa complex was found to be composed of one ligand and a polypeptide which was immunoprecipitable with the monoclonal antibody AM64 directed against gp130. Exposure of HepG2 cells to phorbol 12-myristate 13-acetate (PMA) or PMA-dexamethasone led to an increase in the 80-kDa IL-6 receptor mRNA and functional receptor protein. Whereas treatment of HepG2 cells with PMA led to an increase in the formation of gp80.gp130.IL-6 complexes determined by cross-linking, no corresponding increase in high affinity binding sites was found. The existence of a third IL-6 receptor subunit present in limiting amounts on HepG2 cells is proposed to explain this discrepancy. Evidence is presented that the 80-kDa IL-6 receptor up-regulation by PMA-dexamethasone is caused by the depletion of protein kinase C since the protein kinase C inhibitor staurosporine mimics the effect of PMA-dexamethasone.
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PMID:The hepatic interleukin-6 receptor. Studies on its structure and regulation by phorbol 12-myristate 13-acetate-dexamethasone. 844 Jul 9


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