Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-6 signal transduction occurs when the liganded interleukin-6 receptor (IL-6R) interacts with glycoprotein (gp) 130. We hypothesized that synthetic peptides modeled from the extramembranous domain of the IL-6R may interfere with the IL-6-induced reaction between IL-6R and gp130 and may serve to elucidate the initial steps in IL-6 signal transduction. The capacity of such peptides to modulate two different IL-6 functions was evaluated: 1) IL-6-dependent B9 cell mitogenesis, and 2) IL-6-induced acute phase protein synthesis in HepG2 cells. A synthetic peptide, 249Y16T264, corresponding to residues 249-264, inhibited IL-6-dependent B9 proliferation and IL-6-induced acute phase protein up-regulation in HepG2 cells. Other peptides modeled from different regions of the IL-6R were not inhibitory. 249Y16T264 did not inhibit IL-6-independent HepG2 cell proliferation or total cellular protein synthesis. The inhibitory effect was reversible, indicating that the peptide was not cytotoxic. 249Y16T264 did not inhibit 125I-IL-6 binding in U266 cells. Delineation of this domain identified 249Y10R258 as the minimum effective sequence capable of inhibiting fibrinogen synthesis. Amino acid substitutions in 249Y10R258 obliterated the inhibitory effect on fibrinogen synthesis. In conclusion, a region of the extramembranous domain of the IL-6R has been identified that is involved in the regulation of IL-6 signal transmission. A synthetic peptide representing this region inhibits IL-6-dependent B9 cell mitogenesis and IL-6-stimulated acute phase response in HepG2 cells without affecting ligand binding.
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PMID:Identification of a regulatory domain of the interleukin-6 receptor. 751 15

Interleukin-6 (IL-6), leukemia inhibitory factor, oncostatin M, IL-11, and ciliary neurotrophic factor constitute the IL-6 family of cytokines and play important roles in hematopoiesis, immune response, and nervous system. The receptors for the IL-6 family of cytokines share gp130 through which signals are generated, although the cytoplasmic region of gp130 does not contain any catalytic domain. In this study we show that in addition to Jak family tyrosine kinase, the stimulation of gp130 by IL-6 plus soluble IL-6 receptor alpha induced the activation of Btk and Tec tyrosine kinases, whereas IL-3 and granulocyte colony-stimulating factor activated Tec but not Btk in a pro-B cell line. Furthermore, both Btk and Tec kinases were associated with gp130 without the ligand stimulation. Because Btk is a critical tyrosine kinase for B lymphopoiesis and Tec is considered to be involved in hematopoiesis, the results suggest the involvement of gp130-Btk-Tec signal pathway in early lymphohematopoiesis.
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PMID:Association and activation of Btk and Tec tyrosine kinases by gp130, a signal transducer of the interleukin-6 family of cytokines. 753 May

The synthesis of the human acute-phase alpha 1-acid glycoprotein (AGP) is primarily controlled by IL-6 and IL-1 in liver cells. In the present study, monoclonal antibodies against human gp80 interleukin-6 receptor (IL-6R) were utilized to study the role of the IL-6R in the control of the IL-6-induced AGP synthesis in the human hepatoma Hep3B cell line. Two of the 4 MAbs used in this study, M164 and M195, identified 2 different epitopes involved in IL-6 binding and two others, M91 and M182, recognized epitopes not involved in IL-6 binding. Dose-response experiments indicated that up to 55% of AGP synthesis was inhibited by 10(5) ng/ml of MAbs 164 or 195 when Hep3B cells were treated by IL-6 for 48h. Kinetics of the inhibition of AGP synthesis after addition of anti-IL-6R indicated that the decrease of the IL-6-induced AGP synthesis by Hep3B cells was obtained immediately after the addition of the anti-IL-6R MAbs. Of the two MAbs not involved in IL-6 binding, M91 was unable to interfere with the IL-6-induced AGP synthesis whereas, surprisingly, M182 decreased it by about 25%. Since M182 was also able to interfere with the proliferative response of an IL-6 dependent plasma cell line, our results suggested that M182 may be directed to a structure involved in the IL-6/IL-6R gp130 complex formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:IL-6-induced changes in synthesis of alpha 1-acid glycoprotein in human hepatoma Hep3B cells are distinctively regulated by monoclonal antibodies directed against different epitopes of IL-6 receptor (gp80). 753 7

The protein tyrosine kinases JAK1, JAK2 and Tyk2 and STATs (signal transducers and activators of transcription) 1 and 3 are activated in response to interleukin-6 (IL-6) in human fibrosarcoma cells. In mutant cells lacking JAK1, JAK2 or Tyk2, the absence of one kinase does not prevent activation of the others; activation does not, therefore, involve a sequential three-kinase cascade. In the absence of JAK1, the phosphorylation of the gp130 subunit of the IL-6 receptor and the activation of STATs 1 and 3 are greatly reduced. JAK1 is also necessary for the induction of IRF1 mRNA, thus establishing a requirement for the JAK/STAT pathway in the IL-6 response. JAK2 and Tyk2 although activated cannot, in the absence of JAK1, efficiently mediate activation of STATs 1 and 3. A kinase-negative mutant of JAK2 can, however, inhibit such activation, and ancillary roles for JAK2 and Tyk2 are not excluded. A major role for JAK1 and the nonequivalence of JAK1 and JAK2 in the IL-6 response pathway are, nevertheless, clearly established for these cells.
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PMID:A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. 753 14

gp130 is a signal-transducing subunit of receptors for the interleukin-6 (IL-6)-related cytokine subfamily including IL-6, leukemia inhibitory factor, oncostatin M, IL-11, and ciliary neurotrophic factor, indicating that gp130-mediated signals are involved in the immune response, hematopoiesis, inflammation, and endocrine and nervous system activity. We previously showed that gp130 stimulation rapidly activates Jak, Btk, and Tec tyrosine kinases, all of which constitutively associate with gp130. To further elucidate intracellular signal transduction through gp130, we examined the possible involvement of another nonreceptor tyrosine kinase, p92c-fes (Fes). We showed that gp130 stimulation rapidly induced tyrosine phosphorylation of Fes and actually activated its kinase activity in hematopoietic lineage cells. Furthermore, Fes associated with gp130 independently of ligand stimulation like Jak, Btk, and Tec tyrosine kinases. These results indicate that multiple nonreceptor tyrosine kinases are involved in the gp130-mediated signal transduction pathway. Because both gp130 and Fes are expressed not only in hematopoietic lineage cells but also in heart and nerve cells, Fes may play a role in signal transduction through gp130 in these tissues.
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PMID:Activation of Fes tyrosine kinase by gp130, an interleukin-6 family cytokine signal transducer, and their association. 753 9

By rational mutagenesis, receptor-specific functional analysis, and visualization of complex formation in solution, we identified individual amino acid side chains involved specifically in the interaction of ciliary neurotrophic factor (CNTF) with CNTFR alpha and not with the beta-components, gp130 and LIFR. In the crystal structure, the side chains of these residues, which are located in helix A, the AB loop, helix B, and helix D, are surface accessible and are clustered in space, thus constituting an epitope for CNTFR alpha. By the same analysis, a partial epitope for gp130 was also identified on the surface of helix A that faces away from the alpha-epitope. Superposition of the CNTF and growth hormone structures showed that the location of these epitopes on CNTF is analogous to the location of the first and second receptor epitopes on the surface of growth hormone. Further comparison with proposed binding sites for alpha- and beta-receptors on interleukin-6 and leukemia inhibitory factor indicated that this epitope topology is conserved among helical cytokines. In each case, epitope I is utilized by the specificity-conferring component, whereas epitopes II and III are used by accessory components. Thus, in addition to a common fold, helical cytokines share a conserved order of receptor epitopes that is function related.
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PMID:Localization of functional receptor epitopes on the structure of ciliary neurotrophic factor indicates a conserved, function-related epitope topography among helical cytokines. 753 96

Interleukin-6 (IL-6) interacts with a system of receptors, which include a 80-kDa IL-6-binding subunit (IL-6R) and a transducing element (gp130). The soluble form of IL-6R (sIL-6R) can bind its ligand and induce cellular responses by association with gp130, thus acting as an IL-6 agonist. We and others have previously shown that the responsiveness to IL-6 is different in hepatoma and human primary hepatocytes. We therefore compared the effects of sIL-6R on the two types of cells, and on the B9 hybridoma, another IL-6-sensitive cell line. Human primary hepatocytes, hepatoma cells PLC/PRF/5, and B9 cells were incubated with different concentrations of IL-6, sIL-6-R, or both. The hepatocyte culture supernatants were tested for their content of acute-phase proteins (APP). The proliferation of B9 cells was assessed by a colorimetric method. Results showed that sIL-6R alone markedly increased the production of APP by hepatoma cells in a dose-dependent manner, but affects only minimally primary hepatocytes and the proliferation of B9 cells. The combinations of IL-6R and its ligand enhanced the effects of Il-6 alone in both PLC/PRF/5 and B9 cells, but had no effect on primary hepatocytes. An immunohistochemical study indicated that the cell-surface expression of IL-6R was dramatically lower in hepatoma cells than in primary hepatocytes. In conclusion, our results show that the expression of IL-6R is low in the hepatoma cell PLC/PRF/5 when compared with primary hepatocytes and that this difference can, at least partly, explain their deficient responsiveness to IL-6. On the other hand, it appears that IL-6R expression by primary hepatocytes is sufficient and that circulating sIL-6R is unlikely to play a significant role in the modulation of IL6 effects.
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PMID:Soluble interleukin-6 receptor strongly increases the production of acute-phase protein by hepatoma cells but exerts minimal changes on human primary hepatocytes. 754 21

Interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) share a signal-transducing molecule called gp130. Previous studies showed that CNTF regulates fibrinogen gene expression in rat hepatocytes by competitive binding to the IL-6 receptor. This report explores the post ligand-binding events in the control of fibrinogen and early response gene production stimulated by IL-6 and CNTF in primary rat hepatocytes. Metabolic labeling, using [32P]orthophosphate or anti-phosphotyrosine antibody (Ab) blot experiments revealed that both IL-6 and CNTF induced tyrosine phosphorylation of gp130, and the Jak1 and Jak2 kinases in a dose- and time-dependent manner. Additional experiments revealed that only one of the early response genes, junb, but not c-myc or c-fos, was stimulated by the addition of either IL-6 or CNTF. These data suggest that activation of Jak kinases and stimulation of junb reflect a divergence of the IL-6/CNTF signaling pathway and further suggest that junb may participate in cytokine control of acute-phase protein production in the inflammatory response.
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PMID:Interleukin-6 and ciliary neurotrophic factor trigger janus kinase activation and early gene response in rat hepatocytes. 755 45

Transient transfection of expression vectors for various members of the hematopoietin receptor family and STAT proteins into COS-1 cells indicated that each receptor was capable of stimulating the DNA binding activity of STAT1, STAT3, and STAT5B. However, gp130 preferentially activated STAT1 and STAT3. Activation of STAT5B differed from that of the other two in that the box 3 sequence motif in the cytoplasmic domain of gp130 was not required. Moreover, STAT5B and STAT3 enhanced gene transcription via separate regulatory elements. This study has identified two potential signal transduction pathways by which hematopoietin receptors, including the interleukin-6 receptor, control transcription of acute phase plasma protein genes in hepatic cells.
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PMID:STAT3 and STAT5B are targets of two different signal pathways activated by hematopoietin receptors and control transcription via separate cytokine response elements. 755 77

A major limitation on the therapeutic use of cytokine antagonists is that the amount of cytokine to be neutralized in vivo is not presently known. We previously reported that anti-interleukin-6 (IL-6) monoclonal antibody (MoAb) administered to a patient with multiple myeloma (MM) induced high amounts of IL-6 to circulate in the form of monomeric immune complexes. Based on this observation, the present study developed a new methodology to estimate daily IL-6 production in 13 patients with MM or renal cancer who received anti-IL-6 MoAb. Treatment was considered effective when the production of C-reactive protein (CRP) was inhibited. The production of this acute-phase protein by hepatocytes is dependent on the activation of IL-6 gp130 transducer. Inhibition of tumor proliferation was also evaluated in patients with MM. In 7 of 13 patients whose CRP production was completely inhibited (> 96%) and who showed some antitumoral effects, whole-body IL-6 production in vivo was less than 18 micrograms/d (median, 5.7 micrograms/d; range, 0.5 to 17.5 micrograms/d). In the other 6 patients, subtotal inhibition of CRP production and a lack of antitumoral response were associated with high IL-6 production (median, 180 micrograms/d; range, 18 to 358 micrograms/d). These in vivo observations were consistent with mathematical modeling that predicted that anti-IL-6 MoAb treatment would be efficient only in low IL-6 producers. These data indicate the difficulty of neutralizing IL-6 with a single anti-IL-6 MoAb in vivo and call for new strategies to avoid accumulation of IL-6 in the form of stable immune complexes.
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PMID:Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments. 757 7


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