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

Signals propagated via the gp130 subunit of the interleukin-6 (IL-6)-type cytokine receptors mediate, among various cellular responses, proliferation of hematopoietic cells and induction of acute-phase plasma protein (APP) genes in hepatic cells. Hematopoietic growth control by gp130 is critically dependent on activation of both STAT3 and protein tyrosine phosphatase 2 (SHP-2). To investigate whether induction of APP genes has a similar requirement for SHP-2, we constructed two chimeric receptors, G-gp130 and G-gp130(Y2F), consisting of the transmembrane and cytoplasmic domains of gp130 harboring either a wild-type or a mutated SHP-2 binding site, respectively, fused to the extracellular domain of the granulocyte colony-stimulating factor (G-CSF) receptor. Rat hepatoma H-35 cells stably expressing the chimeric receptors were generated by retroviral transduction. Both chimeric receptors transmitted a G-CSF-induced signal characteristic of that triggered by IL-6 through the endogenous gp130 receptor; i.e., both activated the appropriate JAK, induced DNA binding activity by STAT1 and STAT3, and up-regulated expression of the target APP genes, those for alpha-fibrinogen and haptoglobin. Notwithstanding these similarities in the patterns of signaling responses elicited, mutation of the SHP-2 interaction site in G-gp130(Y2F) abrogated ligand-activated receptor recruitment of SHP-2 as expected. Moreover, the tyrosine phosphorylation state of the chimeric receptor, the associated JAK activity, and the induced DNA binding activity of STAT1 and STAT3 were maintained at elevated levels and for an extended period of time in G-gp130(Y2F)-expressing cells following G-CSF treatment compared to that in cells displaying the G-gp130 receptor. H-35 cells ectopically expressing G-gp130(Y2F) were also found to display an enhanced sensitivity to G-CSF and a higher level of induction of APP genes. Overexpression of the enzymatically inactive SHP-2 enhanced the signaling by the wild-type but not by the Y2F mutant G-gp130 receptor. These results indicate that gp130 signaling for APP gene induction in hepatic cells differs qualitatively from that controlling the proliferative response in hematopoietic cells in not being strictly dependent on SHP-2. The data further suggest that SHP-2 functions normally to attenuate gp130-mediated signaling in hepatic (and, perhaps, other) cells by moderating JAK action.
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PMID:Protein tyrosine phosphatase 2 (SHP-2) moderates signaling by gp130 but is not required for the induction of acute-phase plasma protein genes in hepatic cells. 948 69

STAT3 (signal transducer and activator of transcription 3) is a key transcription factor mediating the signals for a variety of cytokines, including interleukin-6 (IL-6). The Stat3 gene itself is activated by IL-6 signals. We show that the region of the signal-transducing subunit, gp130, essential for STAT3 activation, is also required for activation of the Stat3 gene. To elucidate the mechanisms activating the Stat3 gene, we identified an IL-6 response element (IL-6RE) in the Stat3 gene promoter containing both a low affinity STAT3-binding element and a cAMP-responsive element (CRE). Electrophoretic mobility shift assays showed that IL-6 induced a slowly migrating complex on the IL-6RE containing a STAT3 homodimer and an unidentified CRE-binding protein. With the combination of transient transfection assays using mutant Stat3 promoter-reporter constructs and electrophoretic mobility shift assays, we found that the formation of a slowly migrating complex was required for full activation of the Stat3 gene. Thus, STAT3 activates the Stat3 gene in cooperation with an unidentified CRE-binding protein. This regulatory mechanism is similar to that of the junB gene, which is activated by IL-6 through the junB IL-6RE, which contains a low affinity STAT3-binding site and a CRE-like site.
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PMID:Autoregulation of the Stat3 gene through cooperation with a cAMP-responsive element-binding protein. 949 31

Interferon regulatory factor-1 (IRF-1) is a cell growth inhibitor, induced by cytokines, which transactivates downstream effector genes. The role of IRF-1 in the antiproliferative effect of interleukin-6 (IL-6) was investigated using the A375 human melanoma cell line. IL-6 is a stronger inhibitor of A375 proliferation compared with interferon-gamma (IFNgamma). However, in contrast to IFNgamma, IL-6 triggered lower IRF-1 DNA binding activity and induced barely detectable IRF-1-dependent transactivation activity. Furthermore, although IFNgamma induces only activation of signal transducer and activator of transcription (STAT) 1, IL-6 activates mainly STAT3. These data suggest that IRF-1 plays a minor role in the antiproliferative effect of IL-6, which uses alternative signalling events to induce growth inhibition in A375 melanoma cells.
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PMID:Interferon-gamma and interleukin-6 inhibit proliferation in human melanoma cells by different signalling pathways. 950 73

The acute phase response is the answer of the organism to disturbances of its physiological homeostasis. It consists of a local and a systemic reaction. The latter is characterized by dramatic changes in the concentration of some plasma proteins called acute phase proteins. Interleukin-6 (IL-6) has been identified in vitro and in vivo as the major hepatocyte stimulating factor. Subsequently, additional hepatocyte stimulating factors, such as leukemia inhibitory factor, oncostatin-M, interleukin-11 and ciliary neurotrophic factor have been discovered. IL-t and related cytokines belong to the so-called alpha-helical cytokine family characterized by four antiparallel helices. IL-6 and IL-6-type cytokines exert their action via plasma membrane receptor complexes consisting of specific cytokine binding subunits and a common signal transducing protein gp130. In this presentation we focus on structure/function studies of IL-6, its receptor subunits gp80 and gp130, the internalization of the ligand/receptor complex and a recently elucidated signal transduction pathway. We have shown that protein tyrosine kinases of the JAK family are associated with the cytoplasmic domain of gp130 and are activated in response to IL-6. Subsequently, the transcription factors--named STATs (signal transducers and activators of transcription)--STAT1 alpha and STAT3 are transiently recruited to the cytoplasmic domain of gp130, where they become tyrosine phosphorylated by JAK kinases. In addition to the tyrosine phosphorylation we have observed that IL-6 also induces a serine phosphorylation of STAT3. This modification occurs with a delayed time-course as compared to the tyrosine phosphorylation and is inhibited by the protein kinase inhibitor H7. We propose that the STAT3 serine phosphorylation is required for transactivation of IL-6 target genes which is also inhibited by H7.
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PMID:Interleukin-6 and related cytokines: effect on the acute phase reaction. 955 28

Studies on the role of interleukin-6 (IL-6) in bone metabolism have been accumulating. However, its effects on osteoblasts are still unclear because the results are conflicting depending on the study models employed. We reasoned that these conflicting data are due to variable expression levels of membrane-bound IL-6 receptors (IL-6Rs). In the present study, we found that IL-6 in combination with soluble IL-6R (sIL-6R) consistently caused a marked elevation of alkaline phosphatase and a decrease in proliferation in the human osteoblastic cell line MG-63, which expressed no detectable membrane-bound IL-6R and failed to respond to IL-6. These effects of IL-6/sIL-6R were blocked by neutralizing antibodies to the IL-6 signal transducer gp130, suggesting an involvement of IL-6 signaling in the elicitation of the effects of IL-6/sIL-6R. Upon stimulation with IL-6/sIL-6R, the gp130, cytoplasmic Janus kinases JAK1 and JAK2 were tyrosine phosphorylated. Moreover, signal transducers and activators of transcription STAT1 and STAT3 were also tyrosine phosphorylated, translocated to the nucleus, and bound to the putative STAT-binding DNA elements. In addition, mitogen-activated protein (MAP) kinase was also activated in response to IL-6/sIL-6R These data demonstrate that sIL-6R may enhance the responsiveness of MG-63 cells to IL-6. Thus, IL-6 in collaboration with sIL-6R may modulate differentiation and proliferation of osteoblastic cells, presumably by activating two distinct signaling pathways of JAK-STAT and MAP kinase.
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PMID:Combination of interleukin-6 and soluble interleukin-6 receptors induces differentiation and activation of JAK-STAT and MAP kinase pathways in MG-63 human osteoblastic cells. 961 Jul 41

A noncovalently bound dimeric form of recombinant human IL-6 interleukin-6 (IL-6D) was shown to be an antagonist for IL-6 activity, in a STAT3 tyrosine phosphorylation assay using HepG2 cells, under conditions where it does not dissociate into monomeric IL-6 (IL-6M). The fluorescence from Trp157, the single tryptophan residue in the primary sequence of IL-6, is altered in IL-6D, where the wavelength maximum is blue-shifted by 3 nm and the emission intensity is reduced by 30%. These data suggest that Trp157 is close to, but not buried by, the dimer interface. Both IL-6D and IL-6M are compact molecules, as determined by sedimentation velocity analysis, and contain essentially identical levels of secondary and tertiary structure, as determined by far- and near-UV CD, respectively. IL-6D and IL-6M show the same susceptibility to limited proteolytic attack, and exhibit identical far-UV CD-monitored urea-denaturation profiles with the midpoint of denaturation occurring at 6.0 +/- 0.1 M urea. However, IL-6D was found to dissociate prior to the complete unfolding of the protein, with a midpoint of dissociation of 3 M urea, suggesting that dissociation and dimerization occur when the protein is in a partially unfolded state. Based on these results, we suggest that IL-6D is a metastable domain-swapped dimer, comprising two monomeric units where identical helices from each protein chain are swapped through the loop regions at the "top" of the protein (i.e., the region of the protein most distal from the N- and C-termini). Such an arrangement would account for the antagonistic activity of IL-6D. In this model, receptor binding site I, which comprises residues in the A/B loop and the C-terminus of the protein, is free to bind the IL-6 receptor. However, site III, which includes Trp157 and residues in the C/D loop and N-terminal end of helix D, and perhaps site II, which comprises residues in the A and C helices, are no longer able to bind the signal transducing component of the IL-6 receptor complex, gp130.
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PMID:Physicochemical characterization of an antagonistic human interleukin-6 dimer. 969 57

The transmembrane protein gp130 is a shared component of the receptor complexes for the interleukin-6 (IL-6)-type cytokines, which include IL-6, leukemia inhibitory factor (LIF) and oncostatin M (OSM). In addition to its role in the generation of high affinity receptors, gp130 is required for signal transduction by these cytokines. In the present study we have examined the role of the N-terminal located, extracellular immunoglobulin (Ig)-like module of gp130 in signal transduction by IL-6 and LIF. We have expressed wild-type human gp130 or three mutants in murine myeloid M1-UR21 cells that lack functional endogenous gp130 but express the IL-6 receptor (IL-6R) and the LIF receptor (LIFR). By measuring cellular responses, such as morphological changes upon differentiation, soft agar colony formation, and induction of tyrosine phosphorylation of the signal transducer and activator of transcription, STAT3, we show that signaling by IL-6, but not LIF, is significantly reduced by mutations in the Ig-like module of gp130. However, the binding of 125I-labeled IL-6 or LIF is not affected by these mutations. We also present evidence that the Ig-like module forms part of the epitope of an anti-gp130 monoclonal antibody that neutralizes the bioactivity of IL-6, but not of LIF or OSM. The data suggest that gp130-activation by IL-6 and LIF requires different regions of gp130, that the Ig-like module of gp130 may be required for IL-6-induced gp130 dimerization, and that the stoichiometry of the high affinity IL-6 receptor-complex differs from those of the receptor-complexes for LIF and OSM.
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PMID:The immunoglobulin-like module of gp130 is required for signaling by interleukin-6, but not by leukemia inhibitory factor. 971

We used KO mice lacking either TNF receptor 1 (TNFR-1) or receptor 2 (TNFR-2) to determine whether signaling at the start of liver regeneration after partial hepatectomy (PH) involves only one or both TNF receptors and to analyze in more detail the abnormalities caused by lack of TNFR-1 receptor, which is required for the initiation of liver regeneration. Lack of TNFR-2 had little effect on NF-kappaB and STAT3 binding, and no effect in interleukin-6 production after PH, but caused a delay in AP-1 and C/EBP binding and in the expression of c-jun and c-myc messenger RNA (mRNA). In contrast to mice lacking TNFR-1, which had deficient hepatocyte DNA synthesis and massive lipid accumulation in hepatocytes, TNFR-2 KO mice had normal liver structure and similar levels of hepatocyte DNA replication as those of wild type mice. We conclude that TNFR-1, but not TNFR-2, is necessary for liver regeneration, and that NF-kappaB and STAT3 binding are activated by signals transduced by TNFR-1. Inhibition of AP-1 and C/EBP binding and in the expression of c-jun and c-myc mRNA in the first 4 hours after PH, as well as the apparent lack of Fos in AP-1 complexes, had no effect on the timing or extent of DNA replication.
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PMID:Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor. 975 24

Stimulation of the interleukin-6 (IL-6) signalling pathway occurs via the IL-6 receptor-glycoprotein 130 (IL-6R-gp130) receptor complex and results in the regulation of acute-phase protein genes in liver cells. Ligand binding to the receptor complex leads to tyrosine phosphorylation and activation of Janus kinases (Jak), phosphorylation of the signal transducing subunit gp130, followed by recruitment and phosphorylation of the signal transducer and activator of transcription factors STAT3 and STAT1 and the src homology domain (SH2)-containing protein tyrosine phosphatase (SHP2). The tyrosine phosphorylated STAT factors dissociate from the receptor, dimerize and translocate to the nucleus where they bind to enhancer sequences of IL-6 target genes. Phosphorylated SHP2 is able to bind growth factor receptor bound protein (grb2) and thus might link the Jak/STAT pathway to the ras/raf/mitogen-activated protein kinase pathway. Here we present data on the dose-dependence, kinetics and kinase requirements for SHP2 phosphorylation after the activation of the signal transducer, gp130, of the IL-6-type family receptor complex. When human fibrosarcoma cell lines deficient in Jak1, Jak2 or tyrosine kinase 2 (Tyk2) were stimulated with IL-6-soluble IL-6R complexes it was found that only in Jak1-, but not in Jak 2- or Tyk2-deficient cells, SHP2 activation was greatly impaired. It is concluded that Jak1 is required for the tyrosine phosphorylation of SHP2. This phosphorylation depends on Tyr-759 in the cytoplasmatic domain of gp130, since a Tyr-759-->Phe exchange abrogates SHP2 activation and in turn leads to elevated and prolonged STAT3 and STAT1 activation as well as enhanced acute-phase protein gene induction. Therefore, SHP2 plays an important role in acute-phase gene regulation.
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PMID:Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression. 979 95

Signaling through tumor necrosis factor receptor type 1 (TNFR-1) using a pathway that involves nuclear factor kappaB (NF-kappaB), interleukin-6 (IL-6), and STAT3 is required for the initiation of liver regeneration. We have proposed that TNF primes hepatocytes to respond to the mitogenic effect of growth factors, but so far, there has been no experimental demonstration that TNF enhances growth factor responses of hepatocytes. To test this hypothesis, we infused hepatocyte growth factor (HGF) and transforming growth factor (TGF-) (40 microgram/24 h) directly into the portal vein of rats for 24 hours using osmotic pumps and determined whether TNF injection (5 microgram per rat) would significantly increase hepatocyte DNA labeling in these animals. All rats received 5-bromo-2'-deoxyuridine (BrdU) by intraperitoneal delivery during a 48-hour period (i.e., BrdU infusion continued for 24 hours after the end of growth factor administration). BrdU labeling in the liver was measured by both immunohistochemistry and flow cytometry, and the results obtained by these methods showed excellent concordance. The results demonstrate that TNF transiently activates NF-kappaB and STAT3 and increases the proliferative response of hepatocytes to HGF or TGF- by fourfold. Priming effects on hepatocyte DNA replication were also obtained with injection of lipopolysaccharide (LPS) and gadolinium chloride (GdCl3), agents that release TNF in the liver. Similarly to TNF, GdCl3 injection caused the activation of NF-kappaB and STAT3, reaching a maximum 8 to 12 hours after the injection. The results show that TNF acts as a primer to sensitize hepatocytes to the proliferative effects of growth factors and offers a mechanism to explain the initiation and progression phases of liver regeneration after partial hepatectomy (PH).
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PMID:Tumor necrosis factor primes hepatocytes for DNA replication in the rat. 979 5


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