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

Oncostatin M (OSM) is a member of the interleukin-6 (IL-6) cytokine family and known to be induced in the nervous system as a result of cell stress. OSM is expressed in most human brain tumors, but the effects on tumor cells are unclear. The cytokine is known to activate the JAK/STAT signaling pathway by binding to its receptors gp130/OSMbeta or gp130/LIFRbeta and thereby initiating activation or suppression of a number of STAT target genes. The objective of the study was to identify OSM-regulated genes that could help in understanding the function of OSM in glioma cells. The glioma cell line, U1242MG was stimulated by OSM and the gene expression patterns were analyzed by microarray. In total, nineteen differentially expressed genes were selected due to high intensity, level of up/down-regulation and biological functions. The differentially expressed genes were verified using quantitative PCR. Additional validation of the confirmed OSM-induced proteins was performed in human astrocytoma tissues by immunohistochemistry. Among the up-regulated genes were CHI3L1, PLAU, MT2A and EPAS1. These genes are known to be involved in cell matrix remodeling, migration, proliferation control and angiogenesis. The results suggest that OSM induces genes that might contribute to the development and progression of astrocytomas.
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PMID:Oncostatin M-induced genes in human astrocytomas. 1798 72

Oncostatin M (OSM) is a member of the interleukin-6 (IL-6) family of cytokines, and binds to the OSM receptor (OSMR) to inhibit cancer growth. Four forms of OSMR have been identified: leukemia inhibitory factor receptor (LIFR), OSMR beta, short-form OSMR (OSMRs) and soluble OSMR (sOSMR). In this study, we examined the type and expression of OSMR in lung adenocarcinomas (LADCs). Expression of OSMR was determined by reverse transcription-polymerase chain reaction (RT-PCR), immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy (CIM). Our results showed that, among the four forms of OSMR, OSMRs was mainly expressed in LADC, and expression level of OSMRs correlated with patient survival. CIM revealed that OSMRs was localized on the cell membrane of LADC cell lines in vitro. OSMRs acts as a decoy receptor by reducing the inhibitory effect of OSM on cell growth. Decrease in OSMRs expression by siRNA increased cell sensitivity to OSM, and ectopic expression of OSMRs reduced cell sensitivity to OSM. These results suggest that expression of OSMRs, which operates as a decoy receptor for OSM, is correlated with disease progression and adverse prognosis in patients with LADC.
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PMID:Expression of short-form oncostatin M receptor as a decoy receptor in lung adenocarcinomas. 1849 53

Oncostatin M (OSM), a member of the interleukin-6 family, is produced by monocytes and macrophages in the peripheral blood and microglia in the brain. The present study aimed to elucidate a regulatory role of OSM in the functions of blood-brain barrier (BBB) comprised of rat brain capillary endothelial cells (RBECs). OSM decreased the transendothelial electrical resistance of RBEC monolayers in a concentration- and time-dependent manner. Immunocytochemical observations of ZO-1 and claudin-5 in OSM-treated RBECs showed a zipper-like and/or zigzag shape along the junctions between cells, in contrast with the smooth and linear shape in vehicle-treated cultures. When RBECs were pre-treated with anti-OSM antibody, OSM failed to evoke these changes. The cellular constituents producing OSM in the brain and peripheral blood could be implicated in the functional and structural impairment of the BBB.
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PMID:Oncostatin M induces functional and structural impairment of blood-brain barriers comprised of rat brain capillary endothelial cells. 1860 69

Obesity can be considered as a low grade inflammatory disease, characterized by increased plasma levels of proinflammatory cytokines such as tumoral necrosis factor-a (TNF-a), and acute phase reactant proteins like C-reactive protein. In this context, some cytokines of the interleukin-6 (IL-6) family have been involved in the inflammatory processes associated to obesity. In addition to IL-6, the IL-6 cytokine family includes IL-11, ciliary neurotrophic factor (cntf), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), leukemia inhibitory factor (LIF) y Oncostatin M (OsM). These proteins are also known as gp130 cytokines because all of them exert their action via the glycoprotein 130 (gp130) as a common transducer protein within their functional receptor complexes. However, their role in obesity and related disorders is controversial; thus, whereas some studies have described the involvement of gp130 cytokines in the development of obesity and its related cluster of pathophysiologic conditions like insulin-resistance, fatty liver and cardiovascular diseases, other trials have proposed the gp130 receptor ligands as therapeutic targets in the treatment of obesity and its related disorders. In fact, CNTF treatment has demonstrated to be effective in the reduction of body weight, by promoting the inhibition of food intake and the activation of the energy expenditure, together with an improvement of insulin sensitivity. This review analyzes the potential therapeutic role of some of the gp130 ligands in obesity and related diseases.
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PMID:[Obesity, inflammation and insulin resistance: role of gp 130 receptor ligands]. 1895 60

Oncostatin M (OSM) and leukemia inhibitory factor (LIF) belong to the interleukin-6 family of cytokines. The authors' previous in vitro work demonstrated that in mouse cells mouse OSM (mOSM) signals through a heterodimeric receptor complex incorporating the mOSM-specific receptor mOSMRbeta while human OSM (hOSM) and bovine OSM (bOSM) use the mouse LIF receptor mLIFRbeta rather than mOSMRbeta. These in vitro data suggest that prior studies in mouse systems with hOSM or bOSM (the usual molecules used in early studies) reflect LIF rather than OSM biology. The current work assessed whether or not this divergence in actions among these three OSMs also occurs in vivo in mouse models. Adult female (C57BL/6J x DBA/2J) F(1) mice were engineered to stably overexpress mOSM, hOSM, or bOSM by retrovirus-mediated gene transfer (n = 10 or more per group). After 4 weeks, molecular and hematologic profiles and anatomic phenotypes in multiple organs were assessed by standard techniques. Animals overexpressing either hOSM or bOSM had an identical phenotype resembling that associated with LIF activation, including significant hematologic abnormalities (anemia, neutrophilia, lymphopenia, eosinopenia, and thrombocytosis); weight loss; profound enlargement (lymph node, spleen) and/or structural reorganization (lymph node, spleen, thymus) of lymphoid organs; and severe osteosclerosis. In contrast, mice overexpressing mOSM did not develop hematologic changes, weight loss, or osteosclerosis and exhibited more modest and anatomically distinct restructuring of lymphoid organs. These data indicate that activities imputed to OSM and the mOSMRbeta signaling pathway using in vitro and in vivo mouse experimental systems are unique to mOSM.
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PMID:Mice overexpressing murine oncostatin M (OSM) exhibit changes in hematopoietic and other organs that are distinct from those of mice overexpressing human OSM or bovine OSM. 1911 26

Oncostatin M (OSM), a member of the interleukin-6 family, possesses various functions, including hepatocyte differentiation and suppression of melanoma cell growth. Here, we report anti-hepatitis C virus (HCV) activity of OSM as a new function of this cytokine. OSM possessed marked anti-HCV activity (50% effective concentration: 0.71 ng/ml) in an HCV RNA replication cell culture system. The most striking finding is that OSM exhibited synergistic inhibitory activity on interferon (IFN)-alpha even at a low concentration with weak anti-HCV activity, such as 25 pg/ml. OSM is a candidate anti-HCV reagent and may improve the current IFN therapy for patients with chronic hepatitis C.
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PMID:Oncostatin M synergistically inhibits HCV RNA replication in combination with interferon-alpha. 1933 62

Elevated levels of Oncostatin M (OSM), an interleukin-6 family cytokine, have been observed in multiple sclerosis (MS), HIV-associated neurocognitive disorder (HAND), and glioblastoma (GBM); however, its effects within the CNS are not well understood. OSM regulates gene expression primarily by activating the JAK/STAT, NF-kappaB, and/or MAPK pathways, in a cell-type specific manner. In our studies, OSM induces the production of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) from microglia in an NF-kappaB-dependent manner. This expression also partially requires the intermediate production of TNF-alpha and subsequent NF-kappaB activation via TNF-R1. We also demonstrate that OSM-induced TNF-alpha production from microglia is neurotoxic. The IL-12 family member, IL-27, suppresses OSM-mediated TNF-alpha and iNOS expression at the transcriptional level by inhibiting activation of the NF-kappaB pathway, and rescues the neurotoxicity induced by OSM-stimulated microglia. These studies are the first to demonstrate the proinflammatory effects of OSM in microglia, and also identify IL-27 as a novel inhibitor of inflammatory processes in these cells.
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PMID:IL-27 inhibits OSM-mediated TNF-alpha and iNOS gene expression in microglia. 2046 50

Oncostatin M (OSM) is a cytokine of the interleukin-6 family and plays important roles during inflammation. However, its roles in myoblast differentiation and muscle regeneration remain unexplored. We show here that OSM potently inhibited myoblast differentiation mainly by activating the JAK1/STAT1/STAT3 pathway. OSM downregulated myocyte enhancer-binding factor 2A (MEF2A), upregulated the expression of Id1 and Id2, and inhibited the transcriptional activity of MyoD and MEF2. In addition, OSM also enhanced the expression of STAT3 and OSM receptor, which constituted a positive feedback loop to further amplify OSM-induced signaling. Moreover, we found that STAT1 physically associated with MEF2 and repressed its transcriptional activity, which could account for the OSM-mediated repression of MEF2. Although undetectable in normal muscles in vivo, OSM was rapidly induced on muscle injury and then promptly downregulated just before the majority of myoblasts differentiate. Prolonged expression of OSM in muscles compromised the regeneration process without affecting myoblast proliferation, suggesting that OSM functions to prevent proliferating myoblasts from premature differentiation during the early phase of muscle regeneration.
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PMID:Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration. 2095 96

Oncostatin M (OSM) is a member of the interleukin-6 cytokine family and regulates eg. gene activation, cell survival, proliferation and differentiation. OSM binds to a receptor complex consisting of the ubiquitously expressed signal transducer gp130 and the ligand binding OSM receptor subunit, which is expressed on a specific subset of primary afferent neurons. In the present study, the effect of OSM on heat nociception was investigated in nociceptor-specific gp130 knock-out (SNS-gp130-/-) and gp130 floxed (gp130fl/fl) mice.Subcutaneous injection of pathophysiologically relevant concentrations of OSM into the hind-paw of C57BL6J wild type mice significantly reduced paw withdrawal latencies to heat stimulation. In contrast to gp130fl/fl mice, OSM did not induce heat hypersensitivity in vivo in SNS-gp130-/- mice. OSM applied at the receptive fields of sensory neurons in in vitro skin-nerve preparations showed that OSM significantly increased the discharge rate during a standard ramp-shaped heat stimulus. The capsaicin- and heat-sensitive ion channel TRPV1, expressed on a subpopulation of nociceptive neurons, has been shown to play an important role in inflammation-induced heat hypersensitivity. Stimulation of cultured dorsal root ganglion neurons with OSM resulted in potentiation of capsaicin induced ionic currents. In line with these recordings, mice with a null mutation of the TRPV1 gene did not show any signs of OSM-induced heat hypersensitivity in vivo.The present data suggest that OSM induces thermal hypersensitivity by directly sensitizing nociceptors via OSMR-gp130 receptor mediated potentiation of TRPV1.
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PMID:Oncostatin M induces heat hypersensitivity by gp130-dependent sensitization of TRPV1 in sensory neurons. 2219 63

Oncostatin M (OSM) and leukemia inhibitory factor are pleiotropic cytokines that belong to the interleukin-6 (IL-6) family. These cytokines play a crucial role in diverse biological events like inflammation, neuroprotection, hematopoiesis, metabolism, and development. The family is grouped together based on structural similarities and their ability to activate the transmembrane receptor glycoprotein 130 (gp130). The common structure among these cytokines defines the spacing and the orientation of binding sites for cell surface receptors. OSM is unique in this family as it can signal using heterodimers of gp130 with either leukemia inhibitory factor receptor (LIFR) (type I) or oncostatin M receptor (OSMR) (type II). We have identified a unique helical loop on OSM between its B and C helices that is not found on other IL-6 family cytokines. This loop is located near the "FXXK" motif in active site III, which is essential for OSM's binding to both LIFR and OSMR. In this study, we show that the BC loop does not play a role in OSM's unique ability to bind OSMR. Shortening of the loop enhanced OSM's interaction with OSMR and LIFR as shown by kinetic and equilibrium binding analysis, suggesting the loop may hinder receptor interactions. As a consequence of improved binding, these structurally modified OSMs exhibited enhanced biological activity, including suppressed proliferation of A375 melanoma cells.
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PMID:A unique loop structure in oncostatin M determines binding affinity toward oncostatin M receptor and leukemia inhibitory factor receptor. 2282 97


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