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)

Gp130 cytokine receptor is involved in the formation of multimeric functional receptors for interleukin-6 (IL-6), IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor, and cardiotrophin-1. Cloning of the epitope recognized by an OSM-neutralizing anti-gp130 monoclonal antibody identified a portion of gp130 receptor localized in the EF loop of the cytokine binding domain. Site-directed mutagenesis of the corresponding region was carried out by alanine substitution of residues 186-198. To generate type 1 or type 2 OSM receptors, gp130 mutants were expressed together with either LIF receptor beta or OSM receptor beta. When positions Val-189/Tyr-190 and Phe-191/Val-192 were alanine-substituted, Scatchard analyses indicated a complete abrogation of OSM binding to both type receptors. Interestingly, binding of LIF to type 1 receptor was not affected, corroborating the notion that in this case gp130 mostly behaves as a converter protein rather than a binding receptor. The present study demonstrates that positions 189-192 of gp130 cytokine binding domain are essential for OSM binding to both gp130/LIF receptor beta and gp130/OSM receptor beta heterocomplexes.
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PMID:Identification of a gp130 cytokine receptor critical site involved in oncostatin M response. 1068 48

The development of culture systems that facilitate ex vivo maintenance and expansion of transplantable hematopoietic stem cells (HSCs) is vital to stem cell research. Establishment of such culture systems will have significant impact on ex vivo manipulation and expansion of transplantable stem cells in clinical applications such as gene therapy, tumor cell purging, and stem cell transplantation. We have recently developed a stromal-based culture system that facilitates ex vivo expansion of transplantable human HSCs. In this stromal-based culture system, 2 major contributors to the ex vivo stem cell expansion are the addition of leukemia inhibitory factor (LIF) and the AC6.21 stromal cells. Because the action of LIF is indirect and mediated by stromal cells, we hypothesized that LIF binds to the LIF receptor on AC6.21 stromal cells, leading to up-regulated production of stem cell expansion promoting factor (SCEPF) and/or down-regulated production of stem cell expansion inhibitory factor (SCEIF). Here we demonstrate a secreted SCEPF activity in the conditioned media of LIF-treated AC6.21 stromal cell cultures (SCM-LIF). The magnitude of ex vivo stem cell expansion depends on the concentration of the secreted SCEPF activity in the SCM-LIF. Furthermore, we have ruled out the contribution of 6 known early-acting cytokines, including interleukin-3, interleukin-6, granulocyte macrophage colony-stimulating factor, stem cell factor, flt3 ligand, and thrombopoietin, to this SCEPF activity. Although further studies are required to characterize this secreted SCEPF activity and to determine whether this secreted SCEPF activity is mediated by a single factor or by multiple growth factors, our results demonstrate that stromal cells are not required for this secreted SCEPF activity to facilitate ex vivo stem cell expansion. (Blood. 2000;95:1957-1966)
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PMID:A secreted and LIF-mediated stromal cell-derived activity that promotes ex vivo expansion of human hematopoietic stem cells. 1096 Feb 42

Ciliary neurotrophic factor (CNTF) is expressed in glial cells within the central and peripheral nervous systems. CNTF stimulates gene expression, cell survival or differentiation in a variety of neuronal cell types such as sensory, sympathetic, ciliary and motor neurons. In addition, effects of CNTF on oligodendrocytes as well as denervated and intact skeletal muscle have been documented. CNTF itself lacks a classical signal peptide sequence of a secreted protein, but is thought to convey its cytoprotective effects after release from adult glial cells by some mechanism induced by injury. Interestingly, mice that are homozygous for an inactivated CNTF gene develop normally and initially thrive. Only later in adulthood do they exhibit a mild loss of motor neurons with resulting muscle weakness, leading to the suggestion that CNTF is not essential for neural development, but instead acts in response to injury or other stresses. The CNTF receptor complex is most closely related to, and shares subunits with the receptor complexes for interleukin-6 and leukemia inhibitory factor. The specificity conferring alpha subunit of the CNTF complex (CNTFR alpha), is extremely well conserved across species, and has a distribution localized predominantly to the nervous system and skeletal muscle. CNTFR alpha lacks a conventional transmembrane domain and is thought to be anchored to the cell membrane by a glycosyl-phosphatidylinositol linkage. Mice lacking CNTFR alpha die perinatally, perhaps indicating the existence of a second developmentally important CNTF-like ligand. Signal transduction by CNTF requires that it bind first to CNTFR alpha, permitting the recruitment of gp130 and LIFR beta, forming a tripartite receptor complex. CNTF-induced heterodimerization of the beta receptor subunits leads to tyrosine phosphorylation (through constitutively associated JAKs), and the activated receptor provides docking sites for SH2-containing signaling molecules, such as STAT proteins. Activated STATs dimerize and translocate to the nucleus to bind specific DNA sequences, resulting in enhanced transcription of responsive genes. The neuroprotective effects of CNTF have been demonstrated in a number of in vitro cell models as well as in vivo in mutant mouse strains which exhibit motor neuron degeneration. Intracerebral administration of CNTF and CNTF analogs has also been shown to protect striatal output neurons in rodent and primate models of Huntington's disease. Treatment of humans and animals with CNTF is also known to induce weight loss characterized by a preferential loss of body fat. When administered systemically, CNTF activates downstream signaling molecules such as STAT-3 in areas of the hypothalamus which regulate food intake. In addition to its neuronal actions, CNTF and analogs have been shown to act on non-neuronal cells such as glia, hepatocytes, skeletal muscle, embryonic stem cells and bone marrow stromal cells.
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PMID:The ciliary neurotrophic factor and its receptor, CNTFR alpha. 1081 68

Leukaemia inhibitory factor (LIF) and interleukin-6 (IL-6) are candidate embryo-maternal signalling molecules which are present within the uterine luminal micro-environment. We examined the relative expression of the mRNAs encoding LIF and IL-6, as well as the LIF-binding subunit (LIFR-beta) of the LIF receptor and, as a potential downstream cytokine-responsive gene, beta(2)-microglobulin (beta(2)m), in porcine peri-implantation conceptuses, and in placenta and endometrium during early and mid-pregnancy. Peri-implantation spherical and filamentous conceptuses expressed LIFR-beta and beta(2)m mRNAs with no LIF mRNA present. Rapid development in days 11/12 spherical conceptuses to the filamentous stage was accompanied by transiently increased IL-6 gene expression. The corresponding endometrium, in contrast, expressed LIF in addition to these other mRNAs. LIFR-beta, IL-6 and beta(2)m, but not LIF mRNAs, were expressed in the Jag-1 cell line, an in vitro model for porcine day 14 trophoblast. The greatest steady-state amounts of LIF, LIFR-beta and IL-6 mRNAs in both the endometrium and placenta were evident at the post-implantation stages (days 30 and 60>day 18 of pregnancy). Treatment of porcine endometrial explants with human recombinant (hr)LIF or hrIL-6 resulted in no change in, or diminished, the presence of endometrial beta(2)m mRNA, respectively. Addition of LIF to peri-implantation conceptus explant cultures, in contrast, induced beta(2)m mRNA synthesis. These results highlight the potential importance of both the endometrium and placenta as sources, as well as targets, of these cytokines throughout pregnancy. Cytokine modulation of beta(2)m, a known in vitro mitogen, may constitute one mechanism for local control of trophoblast and endometrial proliferation.
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PMID:Pregnancy-dependent expression of leukaemia inhibitory factor (LIF), LIF receptor-beta and interleukin-6 (IL-6) messenger ribonucleic acids in the porcine female reproductive tract. 1083 69

The related cytokines, interleukin-6 (IL-6), oncostatin M (OSM), and leukemia inhibitory factor (LIF) direct the formation of specific heteromeric receptor complexes to achieve signaling. Each complex includes the common signal-transducing subunit gp130. OSM and LIF also recruit the signaling competent, but structurally distinct OSMRbeta and LIFRalpha subunits, respectively. To test the hypothesis that the particularly prominent cell regulation by OSM is due to signals contributed by OSMRbeta, we introduced stable expression of human or mouse OSMRbeta in rat hepatoma cells which have endogenous receptors for IL-6 and LIF, but not OSM. Both mouse and human OSM engaged gp130 with their respective OSMRbeta subunits, but only human OSM also acted through LIFR. Signaling by OSMRbeta-containing receptors was characterized by highest activation of STAT5 and ERK, recruitment of the insulin receptor substrate and Jun-N-terminal kinase pathways, and induction of a characteristic pattern of acute phase proteins. Since LIF together with LIFRalpha appear to form a more stable complex with gp130 than OSM with gp130 and OSMRbeta, co-activation of LIFR and OSMR resulted in a predominant LIF-like response. These results suggest that signaling by IL-6 cytokines is not identical, and that a hierarchical order of cytokine receptor action exists in which LIFR ranks as dominant member.
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PMID:Receptor subunit-specific action of oncostatin M in hepatic cells and its modulation by leukemia inhibitory factor. 1085 24

Leukemia inhibitory factor (LIF) signals via the heterodimeric receptor complex comprising the LIF receptor alpha subunit (LIFRalpha) and the common signal transducing subunit for interleukin-6 cytokine receptors, gp130. This study demonstrates that in different cell types, the level of LIFRalpha decreases during treatment with LIF or the closely related cytokine oncostatin M (OSM). Moreover, insulin and epidermal growth factor induce a similar LIFRalpha down-regulation. The regulated loss of LIFRalpha is specific since neither gp130 nor OSM receptor beta shows a comparable change in turnover. LIFRalpha down-regulation correlates with reduced cell responsiveness to LIF. Using protein kinase inhibitors and point mutations in LIFRalpha, we demonstrate that LIFRalpha down-regulation depends on activation of extracellular signal-regulated kinase 1/2 and phosphorylation of the cytoplasmic domain of LIFRalpha at serine 185. This modification appears to promote the endosomal/lysosomal pathway of the LIFRalpha. These results suggest that extracellular signal-regulated kinase-activating factors like OSM and growth factors have the potential to lower specifically LIF responsiveness in vivo by regulating LIFRalpha half-life.
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PMID:Stimulation of leukemia inhibitory factor receptor degradation by extracellular signal-regulated kinase. 1085 40

The biological actions of interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF) are mediated via respective functional receptor complexes consisting of a common signal-transducing component, gp130, and other specific receptor components, IL-6 receptor alpha (IL-6R), LIF receptor beta (LIFR), and CNTF receptor alpha (CNTFR). IL-6, LIF, and CNTF are implicated in skeletal muscle regeneration. However, the cell populations that express these receptor components in regenerating muscles are unknown. Using in situ hybridization histochemistry, we examined spatiotemporal expression patterns of gp130, IL-6R, LIFR, and CNTFR mRNAs in regenerating muscles after muscle contusion. At the early stages of regeneration (from 3 hr to Day 2 post contusion), significant signals for gp130 and LIFR mRNAs were detected in myonuclei and/or nuclei of muscle precursor cells (mpcs) and in mononuclear cells located in extracellular spaces between myofibers after muscle contusion, but IL-6R mRNA was expressed only in mononuclear cells. At Day 7 post contusion, signals for gp130, LIFR, and IL-6R mRNAs were not detected in newly formed myotubes, whereas the CNTFR mRNA level was upregulated in myotubes. These findings suggest that the upregulation of receptor subunits in distinct cell populations plays an important role in the effective regeneration of both myofibers and motor neurons. (J Histochem Cytochem 48:1203-1213, 2000)
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PMID:Gene expression of receptors for IL-6, LIF, and CNTF in regenerating skeletal muscles. 1095 Aug 77

Interleukin-6 (IL-6) is a neurotrophic cytokine, however, its direct effect on nerve regeneration has not been well characterized. We therefore examined the effect of IL-6 on neurite regeneration using the rat dorsal root ganglion. IL-6 significantly enhanced neurite regeneration from transected nerve terminals. We also examined the mRNA expression of IL-6 family cytokines and their receptors during the regeneration. The mRNA expressions of IL-6, IL-6 receptor, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) receptor alpha, and LIF receptor beta showed no significant differences by the addition of IL-6. In contrast, IL-6 enhanced the mRNA expression of gp130 and CNTF. In addition, CNTF significantly increased neurite regeneration when added exogenously. Our data suggest that IL-6 enhanced regeneration via up-regulating CNTF expression.
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PMID:IL-6 up-regulates CNTF mRNA expression and enhances neurite regeneration. 1130 50

The mRNA levels of neuropoietic cytokines, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and interleukin-6 (IL-6), and their receptor components (CNTFR alpha, LIFR beta, IL-6R alpha, and gp130) were examined in seventy-six patients with various peripheral neuropathies to determine the extent of expression of these cytokines and receptors, and their relationship to nerve fiber pathology and cell infiltration in the diseased nerves. The CNTF mRNA levels were significantly decreased in the diseased nerves and were correlated to residual myelinated fiber population. In contrast, the mRNA levels of LIF, IL-6 and the ligand-binding receptor components (CNTFR alpha, LIFR beta and IL-6R alpha) were elevated to variable extent in the diseased nerves. The CNTFR alpha, LIFR beta, and IL-6R alpha mRNA levels showed a weak positive correlation with the extent of demyelinating pathology and their levels were related to each other. Moreover, the CNTF and LIF mRNA levels were inversely proportional to the extent of macrophage invasion, whereas the CNTFR alpha and IL-6R alpha mRNA expressions were correlated to the increase in macrophage infiltration. The neuropoietic cytokine family and its receptor expressions in the diseased human nerves are regulated by an underlying pathology-related process rather than type of diseases, and could play a role in peripheral nerve regeneration and repair.
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PMID:Expression of mRNAs for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and their receptors (CNTFR alpha, LIFR beta, IL-6R alpha, and gp130) in human peripheral neuropathies. 1135 82

The cytokines that signal through the common receptor subunit gp130, including ciliary neurotrophic factor (CNTF), interleukin-6, leukemia inhibitory factor (LIF) and oncostatin M, have pleiotropic functions in CNS development. Given the restricted expression domain of the CNTF receptor alpha (CNTFR) in the developing forebrain germinal zone and adult forebrain periventricular area, we have examined the putative role of CNTFR/LIFR/gp130-mediated signaling in regulating forebrain neural stem cell fate in vivo and in vitro. Analysis of LIFR-deficient mice revealed that a decreased level of LIFR expression results in a reduction in the number of adult neural stem cells. In adult LIFR heterozygote (+/-) mice, the number of neural stem cells and their progeny in the forebrain subependyma and TH-immunoreactive neurons in the olfactory bulb were significantly reduced. Intraventricular infusion of CNTF into the adult mouse forebrain, in the absence or presence of epidermal growth factor (EGF), enhanced self-renewal of neural stem cells in vivo. Analyses of EGF-responsive neural stem cells proliferating in vitro found that CNTF inhibits lineage restriction of neural stem cells to glial progenitors, which in turn results in enhanced expansion of stem cell number. These results suggest that CNTFR/LIFR/gp130-mediated signaling supports the maintenance of forebrain neural stem cells, likely by suppressing restriction to a glial progenitor cell fate.
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PMID:The ciliary neurotrophic factor/leukemia inhibitory factor/gp130 receptor complex operates in the maintenance of mammalian forebrain neural stem cells. 1156 54


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