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Heike M Hermanns - One of the best experts on this subject based on the ideXlab platform.
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Oncostatin M and interleukin 31 cytokines receptors signal transduction and physiology
Cytokine & Growth Factor Reviews, 2015Co-Authors: Heike M HermannsAbstract:Oncostatin M (OSM) and interleukin-31 (IL-31) are two cytokines belonging to the IL-6 faMily which share a coMMon signaling receptor subunit, the OSM receptor beta (OSMRβ). Both of theM are released by Monocytes/Macrophages, dendritic cells and T lyMphocytes in inflaMMatory situations and upon binding to their respective receptor coMplexes they signal Mainly via the JAK/STAT pathway. Besides sharing Many biocheMical properties, both display divergent physiological functions. This review suMMarizes aspects of cytokine transcription and biosynthesis, cytokine-receptor interactions, cross-species activities, signal transduction and physiology delineated froM recent findings in genetic Mouse Models for both cytokines, OSM and IL-31.
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Oncostatin M receptor Mediated signal transduction is negatively regulated by socs3 through a receptor tyrosine independent MechanisM
Journal of Biological Chemistry, 2006Co-Authors: Claudia Stross, Simone Radtke, Peter C. Heinrich, Thomas Clahsen, Christa Gerlach, Rudolf Volkmerengert, Fred Schaper, Heike M HermannsAbstract:Down-regulation of interleukin (IL)-6-type cytokine signaling has been shown to occur, aMong other MechanisMs, via induction of the feedback inhibitor SOCS3 (suppressor of cytokine signaling 3). Binding of SOCS3 to the phosphorylated Tyr759 in the cytoplasMic region of gp130, the coMMon signal transducing receptor chain of all IL-6-type cytokines, is necessary for inhibition of Janus kinase-Mediated signaling. In the present study, we analyzed the effect of SOCS3 on signal transduction by the proinflaMMatory cytokine Oncostatin M (OSM), which signals through a receptor coMplex of gp130 and the OSM receptor (OSMR). OSM leads to a Much stronger and prolonged induction of SOCS3 in HepG2 hepatoMa cells and Murine eMbryonal fibroblasts (MEF) coMpared with IL-6. A negative effect of SOCS3 on OSM signaling was confirMed using MEF cells lacking SOCS3. We can show that the OSMR-Mediated signaling is inhibited by SOCS3 to a siMilar extent as previously described for gp130. However, the inhibition occurs independent of tyrosine Motifs within the OSMR. Instead, SOCS3 interacts directly with JAK1 in a stiMulation-dependent Manner, a MechanisM so far only known for SOCS1.
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novel role of janus kinase 1 in the regulation of Oncostatin M receptor surface expression
Journal of Biological Chemistry, 2002Co-Authors: Simone Radtke, Heike M Hermanns, Hugues Gascan, Claude Haan, Hildegard Schmitzvan De Leur, Peter C. Heinrich, Iris BehrmannAbstract:Abstract The Oncostatin M receptor (OSMR) is part of a heterodiMeric receptor coMplex that Mediates signal transduction of the pleiotropic cytokine OSM via a signaling pathway involving Janus kinases (Jaks) and transcription factors of the signal transducers and activators of transcription (STAT) faMily. Upon heterologous expression of the OSMR in several cell lines, we observed that its surface expression was significantly enhanced by coexpression of the Janus kinases Jak1, Jak2, and Tyk2 but not Jak3. ChiMeric receptors consisting of the extracellular region of the interleukin-5 receptor β chain and the transMeMbrane and intracellular part of the OSMR were siMilarly up-regulated on the plasMa MeMbrane when Jak1 was coexpressed. The overall expression level of these constructs did not change significantly, but Jak1 coexpression increased the aMount of endoglycosidase H-resistant, fully processed OSMR chiMeras. Using Mutated receptor and Jak1 constructs, we were able to deMonstrate that association of Jak1 with the MeMbrane proxiMal region of the receptor, but not its kinase activity, is necessary for this effect. Moreover, deletion of the OSMR box1/2 region also resulted in an iMproved surface expression indicating that this region May contain a signal preventing efficient receptor surface expression in the absence of associated Jaks. Finally we deMonstrate that in Jak1-deficient cells, the endogenous OSMR is significantly down-regulated, an effect that can be reversed by transient expression of Jak1 in these cells.
Srinath C Sampath - One of the best experts on this subject based on the ideXlab platform.
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induction of Muscle steM cell quiescence by the secreted niche factor Oncostatin M
Nature Communications, 2018Co-Authors: Andrew T. V. Ho, Stephane Y Corbel, Srinath C Sampath, Joshua D MillstoneAbstract:The balance between steM cell quiescence and proliferation in skeletal Muscle is tightly controlled, but perturbed in a variety of disease states. Despite progress in identifying activators of steM cell proliferation, the niche factor(s) responsible for quiescence induction reMain unclear. Here we report an in vivo iMaging-based screen which identifies Oncostatin M (OSM), a MeMber of the interleukin-6 faMily of cytokines, as a potent inducer of Muscle steM cell (MuSC, satellite cell) quiescence. OSM is produced by Muscle fibers, induces reversible MuSC cell cycle exit, and Maintains steM cell regenerative capacity as judged by serial transplantation. Conditional OSM receptor deletion in satellite cells leads to steM cell depletion and iMpaired regeneration following injury. These results identify Oncostatin M as a secreted niche factor responsible for quiescence induction, and for the first tiMe establish a direct connection between induction of quiescence, steMness, and transplantation potential in solid organ steM cells.
Atsushi Miyajima - One of the best experts on this subject based on the ideXlab platform.
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Essential roles of Oncostatin M receptor β signaling in renal crystal forMation in Mice
Scientific Reports, 2020Co-Authors: Shimpei Yamashita, Atsushi Miyajima, Tadasuke Komori, Yasuo Kohjimoto, Isao Hara, Yoshihiro MorikawaAbstract:Oncostatin M (OSM), a MeMber of the IL-6 faMily of cytokines, has iMportant roles in renal diseases. The relationship between OSM and kidney stone disease, however, reMains unclear. To investigate the roles of OSM in the developMent of kidney stone disease, we generated a Mouse Model of renal crystal forMation using OSM receptor β (OSMRβ)-deficient Mice (OSMRβ^−/− Mice). There were fewer renal crystal deposits in OSMRβ^−/− Mice than in wild-type (WT) Mice. Crystal-binding Molecules (osteopontin, annexin A1, and annexin A2), inflaMMatory cytokines (TNF-α and IL-1β), and fibrosis Markers (TGF-β, collagen 1a2, and α-sMooth Muscle actin) were also decreased in the kidneys of OSMRβ^−/− Mice coMpared with those in WT Mice. IMMunofluorescence staining showed that OSMRβ was expressed in renal tubular epithelial cells (RTECs) and renal fibroblasts in the Model of renal crystal forMation. In the cultured RTECs and renal fibroblasts, OSM directly induced the expression of crystal-binding Molecules and fibrosis Markers. Expressions of inflaMMatory cytokines were increased by stiMulation with OSM in cultured renal fibroblasts. OSM May proMote the forMation of renal crystal deposits by directly acting on RTECs and renal fibroblasts to produce crystal-binding Molecules and inflaMMatory cytokines.
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Oncostatin M Maintains the heMatopoietic MicroenvironMent in the bone Marrow by Modulating adipogenesis and osteogenesis
PLOS ONE, 2014Co-Authors: Fumi Sato, Yuichiro Miyaoka, Atsushi Miyajima, Minoru TanakaAbstract:The bone Marrow (BM) is an essential organ for heMatopoiesis in adult, in which proliferation and differentiation of heMatopoietic steM/progenitor cells (HSPC) is orchestrated by various stroMal cells. Alterations of BM heMatopoietic environMent lead to various heMatopoietic disorders as exeMplified by the linking of fatty Marrow with increased adipogenesis to aneMia or pancytopenia. Therefore, the coMposition of MesenchyMal stroMal cell (MSC)-derived cells in the BM could be crucial for proper heMatopoiesis, but the MechanisMs underlying the MSC differentiation for heMatopoiesis reMain poorly understood. In this study, we show that Oncostatin M (OSM) knock out Mice exhibited pancytopenia advancing fatty Marrow with age. OSM strongly inhibited adipogenesis froM BM MSC in vitro, whereas it enhanced their osteogenesis but suppressed the terMinal differentiation. Intriguingly, OSM allowed the MSC-derived cells to support the ex vivo expansion of HSPC effectively as feeder cells. FurtherMore, the adMinistration of OSM in lethally irradiated wild-type Mice blocked fatty Marrow and enhanced the recovery of HSPC nuMber in the BM and peripheral blood cells after engraftMent of HSPC. Collectively, OSM plays Multiple critical roles in the Maintenance and developMent of the heMatopoietic MicroenvironMent in the BM at a steady state as well as after injury.
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Oncostatin M gene therapy attenuates liver daMage induced by diMethylnitrosaMine in rats
American Journal of Pathology, 2007Co-Authors: Tetsuhiro Hamada, Minoru Tanaka, Ayuko Sato, Tadamichi Hirano, Takashi Yamamoto, Gakuhei Son, Masayuki Onodera, Ikuko Torii, Takashi Nishigami, Atsushi MiyajimaAbstract:To assess the usefulness of Oncostatin M (osM) gene therapy in liver regeneration, we exaMined whether the introduction of OSM cDNA enhances the regeneration of livers daMaged by diMethylnitrosaMine (DMN) in rats. Repeated injection of OSM cDNA enclosed in heMagglutinating virus of Japan envelope into the spleen resulted in the exclusive expression of OSM protein in Kupffer cells of the liver, which was accoMpanied by increases in body weight, liver weight, and seruM albuMin levels and the reduction of seruM liver injury paraMeters (bilirubin, aspartate aMinotransferase, and alanine aMinotransferase) and a seruM fibrosis paraMeter (hyaluronic acid). Histological exaMination showed that osM gene therapy reduced centrilobular necrosis and inflaMMatory cell infiltration and augMented hepatocyte proliferation. The apoptosis of hepatocytes and fibrosis were suppressed by osM gene therapy. TiMe-course studies on osM gene therapy before or after DMN treatMent showed that this therapy was effective not only in enhancing regeneration of hepatocytes daMaged by DMN but in preventing hepatic cytotoxicity caused by subsequent treatMent with DMN. These results indicate that OSM is a key Mediator for proliferation and anti-apoptosis of hepatocytes and suggest that osM gene therapy is useful, as preventive and curative Means, for the treatMent of patients with liver daMage.
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Oncostatin M inhibits adipogenesis through the ras erk and stat5 signaling pathways
Journal of Biological Chemistry, 2006Co-Authors: Yuichiro Miyaoka, Minoru Tanaka, Takahiro Naiki, Atsushi MiyajimaAbstract:Adipocytes play a key role in energy hoMeostasis and several cytokines have been shown to regulate adipogenesis. While the interleukin (IL)-6 faMily of cytokines was previously reported to be involved in adipogenesis, roles of this faMily in adipogenesis and their MechanisMs of action are not fully understood. Here we show that aMong the IL-6 faMily, Oncostatin M (OSM) Most strongly inhibits adipogenesis of 3T3-L1 cells and Mouse eMbryonic fibroblasts (MEFs). We also deMonstrate that OSM inhibits adipogenesis through the Ras/extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) 5 signaling pathways. In addition, OSM inhibits the early phase of the differentiation without affecting cell proliferation throughout adipogenesis including Mitotic clonal expansion. CCAAT/enhancer-binding protein (C/EBP) α, C/EBPβ, and peroxisoMe proliferator-activated receptor (PPAR) γ are known to be required for adipogenesis. Expression of C/EBPα and PPARγ was alMost coMpletely abrogated by OSM. In contrast, neither the MRNA nor protein level of C/EBPβ was affected by OSM. Forced expression of C/EBPβ induced differentiation in the presence of troglitazone, and OSM inhibited this C/EBPβ-induced differentiation. Taken together, our results indicate that OSM inhibits the onset of terMinal differentiation of adipocytes through the Ras/ERK and STAT5 signaling pathways by possibly regulating C/EBPβ activity.
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hepatocyte proliferation and tissue reModeling is iMpaired after liver injury in Oncostatin M receptor knockout Mice
Hepatology, 2004Co-Authors: Koji Nakamura, Minoru Tanaka, Hidenori Nonaka, Hiroki Saito, Atsushi MiyajimaAbstract:Oncostatin M (OSM) is a MeMber of the IL-6 faMily of cytokines. Mice deficient in the OSM receptor (OSMR-/-) showed iMpaired liver regeneration with persistent parenchyMal necrosis after carbon tetrachloride (CCl4) exposure. The recovery of liver Mass froM partial hepatectoMy was also significantly delayed in OSMR-/- Mice. In contrast to wildtype Mice, CCl4 adMinistration only Marginally induced expression of tissue inhibitor of Metalloproteinase (TIMP)-1 and TIMP-2 genes in OSMR-/- Mice, correlating with the increased gelatinase activity of Matrix Metalloproteinase (MMP)-9 and Matrix degradation in injured livers. The activation of STAT3 and expression of iMMediate early genes and cyclins were decreased in OSMR-/- liver, indicating that OSM signaling is required for hepatocyte proliferation and tissue reModeling during liver regeneration. We also found that CCl4 adMinistration in IL-6-/- Mice failed to induce OSM expression and that OSM adMinistration in IL-6-/- Mice after CCl4 injection induced the expression of cyclin D1 and proliferating cell nuclear antigen, suggesting that OSM is a key Mediator of IL-6 in liver regeneration. Consistent with these results, adMinistration of OSM aMeliorated liver injury in wildtype Mice by preventing hepatocyte apoptosis as well as tissue destruction. In conclusion, OSM and its signaling pathway May provide a useful therapeutic target for liver regeneration. (HEPATOLOGY 2004;39:635–644.)
Heinz Baumann - One of the best experts on this subject based on the ideXlab platform.
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interleukin 31 and Oncostatin M Mediate distinct signaling reactions and response patterns in lung epithelial cells
Journal of Biological Chemistry, 2007Co-Authors: Souvik Chattopadhyay, Stefan Rosejohn, Erin Tracy, Ping Liang, Olivier Robledo, Heinz BaumannAbstract:Lung epithelial cells are priMary targets of Oncostatin M (OSM) and, to a lower degree, of interleukin (IL)-6 and IL-31, all MeMbers of the IL-6 cytokine faMily. The OSM receptor (OSMR) signals through activation of STAT and Mitogen-activated protein kinase pathways to induce genes encoding differentiated cell functions, reduce cell-cell interaction, and suppress cell proliferation. IL-31 functions through the heteroMeric IL-31 receptor, which shares with OSMR the OSMRbeta subunit, but does not engage gp130, the coMMon subunit of all other IL-6 cytokine receptors. Because the response of epithelial cells to IL-31 is unknown, the action of IL-31 was characterized in the huMan alveolar epithelial cell line A549 in which the expression of the ligand-binding IL-31Ralpha subunit was increased. IL-31 initiated signaling that differed froM other IL-6 cytokines by the particularly strong recruitMent of the STAT3, ERK, JNK, and Akt pathways. IL-31 was highly effective in suppressing proliferation by altering expression of cell cycle proteins, including up-regulation of p27(Kip1) and down-regulation of cyclin B1, CDC2, CDK6, MCM4, and retinoblastoMa. A single STAT3 recruitMent site (Tyr-721) in the cytoplasMic doMain of IL-31Ralpha exerts a doMinant function in the entire receptor coMplex and is critical for gene induction, Morphological changes, and growth inhibition. The data suggest that inflaMMatory and iMMune reactions involving activated T-cells regulate functions of epithelial cells by IL-6 cytokines through receptor-defined signaling reactions.
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Oncostatin M regulates the synthesis and turnover of gp130 leukeMia inhibitory factor receptor α and Oncostatin M receptor β by distinct MechanisMs
Journal of Biological Chemistry, 2001Co-Authors: Frederic Blanchard, Yanping Wang, Erin Kinzie, Laurence Duplomb, Anne Godard, Heinz BaumannAbstract:Abstract The cytokine receptor subunits gp130, leukeMia inhibitory factor receptor α (LIFRα), and Oncostatin M receptor β (OSMRβ) transduce OSM signals that regulate gene expression and cell proliferation. After ligand binding and activation of the Janus protein-tyrosine kinase/STAT and Mitogen-activated protein kinase signal transduction pathways, negative feedback processes are recruited. These processes attenuate receptor action by suppression of cytokine signaling and by down-regulation of receptor protein expression. This study deMonstrates that in huMan fibroblasts or epithelial cells, OSM first decreases the level of gp130, LIFRα, and OSMRβ by ligand-induced receptor degradation and then increases the level of the receptors by enhanced synthesis. The transcriptional induction of gp130 gene by OSM involves STAT3. Various cell lines expressing receptor subunits to the different interleukin-6 class cytokines revealed that only LIFRα degradation is proMoted by activated ERK and that degradation of gp130, OSMRβ, and a fraction of LIFRα involves MechanisMs that are separate froM signal transduction. These MechanisMs include ligand-Mediated diMerization, internalization, and endosoMal/lysosoMal degradation. ProteosoMal degradation appears to involve a fraction of receptor subunit proteins that are ubiquitinated independently of ligand binding.
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reconstitution of the response to leukeMia inhibitory factor Oncostatin M and ciliary neurotrophic factor in hepatoMa cells
Journal of Biological Chemistry, 1993Co-Authors: Heinz Baumann, S F Ziegler, Bruce Mosley, K K Morella, Sanja Pajovic, D P GearingAbstract:Abstract Ciliary neurotrophic factor (CNTF) has been described as a neuro-active cytokine that shares functional siMilarities with the leukeMia inhibitory factor (LIF). We deMonstrate here that, like LIF, CNTF stiMulates expression of acute phase plasMa proteins in rat H-35 hepatoMa cells. Transfection of the LIF receptor into Hep3B hepatoMa cells reconstituted LIF and Oncostatin M regulation of acute phase plasMa protein genes. Co-expression of the LIF receptor and the CNTF receptor, but not expression of either subunit alone, generated CNTF responsiveness in Hep3B cells, suggesting cooperativity of these receptor subunits. Evidence is presented for direct interaction of the LIF receptor with the intracellular signal transduction Machinery.
Cheryl L Jorcyk - One of the best experts on this subject based on the ideXlab platform.
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Oncostatin M proMotes MaMMary tuMor Metastasis to bone and osteolytic bone degradation
Genes & Cancer, 2012Co-Authors: Celeste Bolin, Ken Tawara, Caleb Sutherland, Jeff Redshaw, Patrick S Aranda, Jim Moselhy, Robin L Anderson, Cheryl L JorcykAbstract:Oncostatin M (OSM) is an interleukin-6 (IL-6) faMily cytokine that has been iMplicated in a nuMber of biological processes including inflaMMation, heMatopoiesis, iMMune responses, developMent, and bone hoMeostasis. Recent evidence suggests that OSM May proMote breast tuMor invasion and Metastasis. We investigated the role of OSM in the forMation of bone Metastases in vivo using the 4T1.2 Mouse MaMMary tuMor Model in which OSM expression was knocked down using shRNA (4T1.2-OSM). 4T1.2-OSM cells were injected orthotopically into Balb/c Mice, resulting in a greater than 97% decrease in spontaneous Metastasis to bone coMpared to control cells. Intratibial injection of these saMe 4T1.2-OSM cells also draMatically reduced the osteolytic destruction of trabecular bone voluMe coMpared to control cells. FurtherMore, in a tuMor resection Model, Mice bearing 4T1.2-OSM tuMors showed an increase in survival by a Median of 10 days. To investigate the specific cellular MechanisMs iMportant for OSM-induced osteolytic Metastasis to bone, an in vitro Model was developed using the RAW 264.7 preosteoclast cell line co-cultured with 4T1.2 Mouse MaMMary tuMor cells. TreatMent of co-cultures with OSM resulted in a 3-fold induction of osteoclastogenesis using the TRAP assay. We identified several tuMor cell–induced factors including vascular endothelial growth factor, IL-6, and a previously uncharacterized OSM-regulated bone Metastasis factor, aMphiregulin (AREG), which increased osteoclast differentiation by 4.5-fold. In addition, pretreatMent of co-cultures with an anti-AREG neutralizing antibody coMpletely reversed OSM-induced osteoclastogenesis. Our results suggest that one MechanisM for OSM-induced osteoclast differentiation is via an AREG autocrine loop, resulting in decreased osteoprotegerin secretion by the 4T1.2 cells. These data provide evidence that OSM Might be an iMportant therapeutic target for the prevention of breast cancer Metastasis to bone.
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breast cancer cells stiMulate neutrophils to produce Oncostatin M potential iMplications for tuMor progression
Cancer Research, 2005Co-Authors: Marisa M Queen, Randall E Ryan, Ryan G Holzer, Cynthia R Kellerpeck, Cheryl L JorcykAbstract:TuMor-associated and tuMor-infiltrating neutrophils (TAN) and Macrophages (TAM) can account for as Much as 50% of the total tuMor Mass in invasive breast carcinoMas. It is thought that tuMors secrete factors that elicit a wound-repair response froM TAMs and TANs and that this response inadvertently stiMulates tuMor progression. Oncostatin M is a pleiotropic cytokine belonging to the interleukin-6 faMily that is expressed by several cell types including activated huMan T lyMphocytes, Macrophages, and neutrophils. Whereas Oncostatin M can inhibit the proliferation of breast cancer cells in vitro, recent studies suggest that Oncostatin M May proMote tuMor progression by enhancing angiogenesis and Metastasis. In addition, neutrophils can be stiMulated to synthesize and rapidly release large quantities of Oncostatin M. In this article, we show that huMan neutrophils secrete Oncostatin M when cocultured with MDA-MB-231 and T47D huMan breast cancer cells. Neutrophils isolated froM whole blood or breast cancer cells alone express little Oncostatin M by iMMunocytocheMistry and ELISA, but neutrophils express and release high levels of Oncostatin M when they are cocultured with breast cancer cells. In addition, we show that granulocyte-Macrophage colony-stiMulating factor produced by breast cancer cells and cell-cell contact are both necessary for the release of Oncostatin M froM neutrophils. IMportantly, neutrophil-derived Oncostatin M induces vascular endothelial growth factor froM breast cancer cells in coculture and increases breast cancer cell detachMent and invasive capacity, suggesting that neutrophils and Oncostatin M May proMote tuMor progression in vivo.
