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Emiko Senba - One of the best experts on this subject based on the ideXlab platform.
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deficiency of Oncostatin M Receptor β osMrβ exacerbates high fat diet induced obesity and related Metabolic disorders in Mice
Journal of Biological Chemistry, 2014Co-Authors: Tadasuke Komori, Emiko Senba, Atsushi Miyajima, Minoru Tanaka, Yoshihiro MorikawaAbstract:Oncostatin M (OSM) belongs to the IL-6 faMily of cytokines and has diverse biological effects, including the Modulation of inflaMMatory responses. In the present study we analyzed the roles of OSM signaling in obesity and related Metabolic disorders. Under a high-fat diet condition, OSM Receptor β subunit-deficient (OSMRβ−/−) Mice exhibited increases in body weight and food intake coMpared with those observed in WT Mice. In addition, adipose tissue inflaMMation, insulin resistance, and hepatic steatosis were More severe in OSMRβ−/− Mice than in wild-type (WT) Mice. These Metabolic phenotypes did not iMprove when OSMRβ−/− Mice were pair-fed with WT Mice, suggesting that the effects of OSM signaling on these phenotypes are independent of the increases in the body weight and food intake. In the liver of OSMRβ−/− Mice, the insulin-induced phosphorylation of p70 S6 kinase reMained intact, whereas insulin-induced FOXO1 phosphorylation was iMpaired. In addition, OSMRβ−/− Mice displayed a higher expression of genes related to de novo lipogenesis in the liver than WT Mice. FurtherMore, treatMent of genetically obese ob/ob Mice with OSM iMproved insulin resistance, adipose tissue inflaMMation, and hepatic steatosis. Intraportal adMinistration of OSM into ob/ob Mice activated STAT3 and increased the expression of long-chain acyl-CoA synthetase (ACSL) 3 and ACSL5 with decreased expression of fatty acid synthase in the liver, suggesting that OSM directly induces lipolysis and suppresses lipogenesis in the liver of obese Mice. These findings suggest that defects in OSM signaling proMote the deterioration of high-fat diet-induced obesity and related Metabolic disorders.
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lack of Oncostatin M Receptor β leads to adipose tissue inflaMMation and insulin resistance by switching Macrophage phenotype
Journal of Biological Chemistry, 2013Co-Authors: Tadasuke Komori, Emiko Senba, Atsushi Miyajima, Minoru Tanaka, Yoshihiro MorikawaAbstract:Oncostatin M (OSM), a MeMber of the IL-6 faMily of cytokines, plays iMportant roles in a variety of biological functions, including inflaMMatory responses. However, the roles of OSM in Metabolic diseases are unknown. We herein analyzed the Metabolic paraMeters of OSM Receptor β subunit-deficient (OSMRβ−/−) Mice under norMal diet conditions. At 32 weeks of age, OSMRβ−/− Mice exhibited Mature-onset obesity, severer hepatic steatosis, and insulin resistance. Surprisingly, insulin resistance without obesity was observed in OSMRβ−/− Mice at 16 weeks of age, suggesting that insulin resistance precedes obesity in OSMRβ−/− Mice. Both OSM and OSMRβ were expressed strongly in the adipose tissue and little in soMe other Metabolic organs, including the liver and skeletal Muscle. In addition, OSMRβ is Mainly expressed in the adipose tissue Macrophages (ATMs) but not in adipocytes. In OSMRβ−/− Mice, the ATMs were polarized to M1 phenotypes with the augMentation of adipose tissue inflaMMation. TreatMent of OSMRβ−/− Mice with an anti-inflaMMatory agent, sodiuM salicylate, iMproved insulin resistance. In addition, the stiMulation of a Macrophage cell line, RAW264.7, and peritoneal exudate Macrophages with OSM resulted in the increased expression of M2 Markers, IL-10, arginase-1, and CD206. FurtherMore, treatMent of C57BL/6J Mice with OSM increased insulin sensitivity and polarized the phenotypes of ATMs to M2. Thus, OSM suppresses the developMent of insulin resistance at least in part through the polarization of the Macrophage phenotypes to M2, and OSMRβ−/− Mice provide a unique Mouse Model of Metabolic diseases.
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coMplete overlap of interleukin 31 Receptor a and Oncostatin M Receptor β in the adult dorsal root ganglia with distinct developMental expression patterns
Neuroscience, 2006Co-Authors: Takayoshi Bando, Tadasuke Komori, Yoshihiro Morikawa, Emiko SenbaAbstract:Abstract Interleukin-31 Receptor A (IL-31RA) is a newly identified type I cytokine Receptor, that is related to gp130, the coMMon Receptor of the interleukin (IL) -6 faMily cytokines. Recent studies have shown that IL-31RA forMs a functional Receptor coMplex for IL-31 together with the β subunit of Oncostatin M Receptor (OSMRβ). However, little is known about the target cells of IL-31 because it reMains unclear which types of cells express IL-31RA. In our previous reports, we deMonstrated that OSMRβ is expressed in a subset of sMall-sized nociceptive neurons of adult dorsal root ganglia (DRGs). In the present study, we investigated the IL-31RA expression in the adult and developing DRGs. FroM a northern blot analysis and in situ hybridization histocheMistry, IL-31RA MRNA was found to be expressed in the adult DRGs. According to reverse-transcriptase polyMerase chain reaction, IL-31RA MRNA was detected in the DRGs and trigeMinal ganglia, while no expression of IL-31RA MRNA was observed in the CNS. Double iMMunofluorescence staining revealed IL-31RA to be expressed in a subset of sMall-sized neurons, all of which colocalized with OSMRβ. In addition, the expression of IL-31 RA was detected in afferent fibers in the spinal cord and the derMis of the skin. We also found that the developMental expression pattern of IL-31RA was different froM that of OSMRβ; IL31RA-positive neurons in DRGs first appeared at postnatal day (PN) 10 and reached the adult level at PN14, whereas OSMRβ-positive neurons were observed at PN0 for the first tiMe. We previously deMonstrated OSMRβ-expressing neurons to decrease, however, they were not found to disappear in Oncostatin M (OSM) -deficient Mice. These findings suggest that IL-31 and OSM May thus have redundant functions in the developMent of OSMRβ-expressing neurons.
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up regulated phosphorylation of signal transducer and activator of transcription 3 and cyclic aMp responsive eleMent binding protein by peripheral inflaMMation in priMary afferent neurons possibly through Oncostatin M Receptor
Neuroscience, 2005Co-Authors: Shinobu Tamura, Yoshihiro Morikawa, Emiko SenbaAbstract:Abstract Oncostatin M (OSM), a MeMber of interleukin-6 faMily cytokines, contributes to the developMent of nociceptive sensory neurons. However, little is known about the role of OSM in dorsal root ganglia (DRGs) of adult Mice after peripheral inflaMMation. In the present study, we showed that OSM MRNA was highly expressed in the inflaMed skin during acute inflaMMation induced by coMplete Freund’s adjuvant (CFA), while the expression of Oncostatin M Receptor (OSMR) did not change in the ipsilateral DRG. Although peripheral inflaMMation induced significant increases in the nuMber of neurons with phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated p38 Mitogen-activated protein kinase (p-p38) in ipsilateral DRGs, OSMR-positive neurons exhibited neither p-ERK nor p-p38. In addition, we found significant increases in the nuMber of neurons with phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and phosphorylated cAMP-responsive eleMent binding protein (p-CREB) in the ipsilateral DRGs. Interestingly, OSMR-positive neurons with p-STAT3 and p-CREB were significantly increased after peripheral inflaMMation. Thus, our results suggest that acute inflaMMation induce the phosphorylations of several signal Molecules, including ERK, p38, cAMP-responsive eleMent binding protein, and STAT3. AMong theM, the up-regulation of p-STAT3 and p-CREB May be induced possibly through OSMR.
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localization of Oncostatin M Receptor β in adult and developing cns
Neuroscience, 2003Co-Authors: Shinobu Tamura, Yoshihiro Morikawa, Emiko SenbaAbstract:Oncostatin M (OSM) is a MeMber of the interleukin-6 cytokine faMily, which is involved in definitive heMatopoiesis, the developMent of liver, and local inflaMMation. However, little is known about the role of OSM in the Murine CNS. Using Northern blot analysis, we exaMined the regional distribution of OSM Receptor β (OSMRβ) MRNA in the adult CNS. OSMRβ MRNA was observed predoMinantly in the olfactory bulb, and with low levels in the other regions. In situ hybridization shows that OSMRβ gene expression was found in astrocytes of olfactory bulb, epithelial cells of choroid plexus, and Meningeal cells in pia Mater. In addition, we investigated the gene expression of OSMRβ in the developing CNS at different tiMe points. Its gene expression was first observed in large neurons of the hypoglossal nucleus at 14.5 days postcoituM, which was sustained until neonatal Mice. OSMRβ MRNA and protein were Mainly localized in the ventral subnucleus of the developing hypoglossal nucleus. Our results suggest that OSM contributes to the developMent of specific subpopulations of both neurons and astrocytes in the Murine CNS.
Yoshihiro Morikawa - 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, 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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deficiency of Oncostatin M Receptor β osMrβ exacerbates high fat diet induced obesity and related Metabolic disorders in Mice
Journal of Biological Chemistry, 2014Co-Authors: Tadasuke Komori, Emiko Senba, Atsushi Miyajima, Minoru Tanaka, Yoshihiro MorikawaAbstract:Oncostatin M (OSM) belongs to the IL-6 faMily of cytokines and has diverse biological effects, including the Modulation of inflaMMatory responses. In the present study we analyzed the roles of OSM signaling in obesity and related Metabolic disorders. Under a high-fat diet condition, OSM Receptor β subunit-deficient (OSMRβ−/−) Mice exhibited increases in body weight and food intake coMpared with those observed in WT Mice. In addition, adipose tissue inflaMMation, insulin resistance, and hepatic steatosis were More severe in OSMRβ−/− Mice than in wild-type (WT) Mice. These Metabolic phenotypes did not iMprove when OSMRβ−/− Mice were pair-fed with WT Mice, suggesting that the effects of OSM signaling on these phenotypes are independent of the increases in the body weight and food intake. In the liver of OSMRβ−/− Mice, the insulin-induced phosphorylation of p70 S6 kinase reMained intact, whereas insulin-induced FOXO1 phosphorylation was iMpaired. In addition, OSMRβ−/− Mice displayed a higher expression of genes related to de novo lipogenesis in the liver than WT Mice. FurtherMore, treatMent of genetically obese ob/ob Mice with OSM iMproved insulin resistance, adipose tissue inflaMMation, and hepatic steatosis. Intraportal adMinistration of OSM into ob/ob Mice activated STAT3 and increased the expression of long-chain acyl-CoA synthetase (ACSL) 3 and ACSL5 with decreased expression of fatty acid synthase in the liver, suggesting that OSM directly induces lipolysis and suppresses lipogenesis in the liver of obese Mice. These findings suggest that defects in OSM signaling proMote the deterioration of high-fat diet-induced obesity and related Metabolic disorders.
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lack of Oncostatin M Receptor β leads to adipose tissue inflaMMation and insulin resistance by switching Macrophage phenotype
Journal of Biological Chemistry, 2013Co-Authors: Tadasuke Komori, Emiko Senba, Atsushi Miyajima, Minoru Tanaka, Yoshihiro MorikawaAbstract:Oncostatin M (OSM), a MeMber of the IL-6 faMily of cytokines, plays iMportant roles in a variety of biological functions, including inflaMMatory responses. However, the roles of OSM in Metabolic diseases are unknown. We herein analyzed the Metabolic paraMeters of OSM Receptor β subunit-deficient (OSMRβ−/−) Mice under norMal diet conditions. At 32 weeks of age, OSMRβ−/− Mice exhibited Mature-onset obesity, severer hepatic steatosis, and insulin resistance. Surprisingly, insulin resistance without obesity was observed in OSMRβ−/− Mice at 16 weeks of age, suggesting that insulin resistance precedes obesity in OSMRβ−/− Mice. Both OSM and OSMRβ were expressed strongly in the adipose tissue and little in soMe other Metabolic organs, including the liver and skeletal Muscle. In addition, OSMRβ is Mainly expressed in the adipose tissue Macrophages (ATMs) but not in adipocytes. In OSMRβ−/− Mice, the ATMs were polarized to M1 phenotypes with the augMentation of adipose tissue inflaMMation. TreatMent of OSMRβ−/− Mice with an anti-inflaMMatory agent, sodiuM salicylate, iMproved insulin resistance. In addition, the stiMulation of a Macrophage cell line, RAW264.7, and peritoneal exudate Macrophages with OSM resulted in the increased expression of M2 Markers, IL-10, arginase-1, and CD206. FurtherMore, treatMent of C57BL/6J Mice with OSM increased insulin sensitivity and polarized the phenotypes of ATMs to M2. Thus, OSM suppresses the developMent of insulin resistance at least in part through the polarization of the Macrophage phenotypes to M2, and OSMRβ−/− Mice provide a unique Mouse Model of Metabolic diseases.
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coMplete overlap of interleukin 31 Receptor a and Oncostatin M Receptor β in the adult dorsal root ganglia with distinct developMental expression patterns
Neuroscience, 2006Co-Authors: Takayoshi Bando, Tadasuke Komori, Yoshihiro Morikawa, Emiko SenbaAbstract:Abstract Interleukin-31 Receptor A (IL-31RA) is a newly identified type I cytokine Receptor, that is related to gp130, the coMMon Receptor of the interleukin (IL) -6 faMily cytokines. Recent studies have shown that IL-31RA forMs a functional Receptor coMplex for IL-31 together with the β subunit of Oncostatin M Receptor (OSMRβ). However, little is known about the target cells of IL-31 because it reMains unclear which types of cells express IL-31RA. In our previous reports, we deMonstrated that OSMRβ is expressed in a subset of sMall-sized nociceptive neurons of adult dorsal root ganglia (DRGs). In the present study, we investigated the IL-31RA expression in the adult and developing DRGs. FroM a northern blot analysis and in situ hybridization histocheMistry, IL-31RA MRNA was found to be expressed in the adult DRGs. According to reverse-transcriptase polyMerase chain reaction, IL-31RA MRNA was detected in the DRGs and trigeMinal ganglia, while no expression of IL-31RA MRNA was observed in the CNS. Double iMMunofluorescence staining revealed IL-31RA to be expressed in a subset of sMall-sized neurons, all of which colocalized with OSMRβ. In addition, the expression of IL-31 RA was detected in afferent fibers in the spinal cord and the derMis of the skin. We also found that the developMental expression pattern of IL-31RA was different froM that of OSMRβ; IL31RA-positive neurons in DRGs first appeared at postnatal day (PN) 10 and reached the adult level at PN14, whereas OSMRβ-positive neurons were observed at PN0 for the first tiMe. We previously deMonstrated OSMRβ-expressing neurons to decrease, however, they were not found to disappear in Oncostatin M (OSM) -deficient Mice. These findings suggest that IL-31 and OSM May thus have redundant functions in the developMent of OSMRβ-expressing neurons.
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up regulated phosphorylation of signal transducer and activator of transcription 3 and cyclic aMp responsive eleMent binding protein by peripheral inflaMMation in priMary afferent neurons possibly through Oncostatin M Receptor
Neuroscience, 2005Co-Authors: Shinobu Tamura, Yoshihiro Morikawa, Emiko SenbaAbstract:Abstract Oncostatin M (OSM), a MeMber of interleukin-6 faMily cytokines, contributes to the developMent of nociceptive sensory neurons. However, little is known about the role of OSM in dorsal root ganglia (DRGs) of adult Mice after peripheral inflaMMation. In the present study, we showed that OSM MRNA was highly expressed in the inflaMed skin during acute inflaMMation induced by coMplete Freund’s adjuvant (CFA), while the expression of Oncostatin M Receptor (OSMR) did not change in the ipsilateral DRG. Although peripheral inflaMMation induced significant increases in the nuMber of neurons with phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated p38 Mitogen-activated protein kinase (p-p38) in ipsilateral DRGs, OSMR-positive neurons exhibited neither p-ERK nor p-p38. In addition, we found significant increases in the nuMber of neurons with phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and phosphorylated cAMP-responsive eleMent binding protein (p-CREB) in the ipsilateral DRGs. Interestingly, OSMR-positive neurons with p-STAT3 and p-CREB were significantly increased after peripheral inflaMMation. Thus, our results suggest that acute inflaMMation induce the phosphorylations of several signal Molecules, including ERK, p38, cAMP-responsive eleMent binding protein, and STAT3. AMong theM, the up-regulation of p-STAT3 and p-CREB May be induced possibly through OSMR.
Heike M Hermanns - One of the best experts on this subject based on the ideXlab platform.
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characterization of the rat Oncostatin M Receptor coMplex which reseMbles the huMan but differs froM the Murine cytokine Receptor
PLOS ONE, 2012Co-Authors: Johannes Drechsler, Joachim Grotzinger, Heike M HermannsAbstract:Evaluation of a pathophysiological role of the interleukin-6-type cytokine Oncostatin M (OSM) for huMan diseases has been coMplicated by the fact that Mouse Models of diseases targeting either OSM or the OSM Receptor (OSMR) coMplex cannot fully reflect the huMan situation. This is due to earlier findings that huMan OSM utilizes two Receptor coMplexes, glycoprotein 130 (gp130)/leukeMia inhibitory factor Receptor (LIFR) (type I) and gp130/OSMR (type II), both with wide expression profiles. Murine OSM on the other hand only binds to the gp130/OSMR (type II) Receptor coMplex with high affinity. Here, we characterize the Receptor usage for rat OSM. Using different experiMental approaches (knock-down of the OSMR expression by RNA interference, blocking of the LIFR by LIF-05, an antagonistic LIF variant and stably transfected Ba/F3 cells) we can clearly show that rat OSM surprisingly utilizes both, the type I and type II Receptor coMplex, therefore MiMicking the huMan situation. FurtherMore, it displays cross-species activities and stiMulates cells of huMan as well as Murine origin. Its signaling capacities closely MiMic those of huMan OSM in cell types of different origin in the way that strong activation of the Jak/STAT, the MAP kinase as well as the PI3K/Akt pathways can be observed. Therefore, rat disease Models would allow evaluation of the relevance of OSM for huMan biology.
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Box 2 region of the Oncostatin M Receptor deterMines specificity for recruitMent of Janus kinases and STAT5 activation.
The Journal of biological chemistry, 2008Co-Authors: Christoph Hintzen, Simone Radtke, Peter C. Heinrich, Christina Evers, Barbara E. Lippok, Rudolf Volkmer, Heike M HermannsAbstract:Abstract HuMan and Murine Oncostatin M (OSM) induce their bioactivities through a heterodiMeric Receptor coMplex consisting of gp130 and the OSM Receptor (OSMR), which initiates a signaling pathway involving Janus kinases (JAKs) and transcription factors of the signal transducers and activators of transcription (STAT) faMily. In contrast to the signal transducing Receptor subunit gp130, the OSMR allows strong activation of STAT5B. The underlying Molecular MechanisM, however, reMained unclear. Here we deMonstrate that the huMan and Murine OSM Receptors use distinct MechanisMs for STAT5B activation. The huMan Receptor contains a STAT5B recruiting tyrosine Motif (Tyr837/Tyr839) C-terMinal to the box 1/2 region, which is absent in the Mouse Receptor. In contrast, the Murine Receptor initiates STAT5 activation directly via the Receptor bound Janus kinases. Intriguingly, the Murine Receptor preferentially recruits JAK2, whereas the huMan Receptor seeMs to have a higher affinity for JAK1. We identify a single aMino acid (Phe820) in the huMan Receptor that is responsible for this preference. Exchange by the Murine counterpart (Cys815) allows recruitMent of JAK2 by the huMan Receptor and consequently activation of STAT5B independently of Receptor tyrosine Motifs. STAT5B interacts directly with JAK2 only in response to activation of the Murine OSMR or the Mutated huMan OSMR. Additionally, we show that OSM-induced STAT1 phosphorylation occurs independently of Receptor tyrosine Motifs and is Mediated directly by Janus kinases, whereas the two C-terMinally located tyrosine residues Tyr917/Tyr945 of the OSMR are crucial for STAT3 activation.
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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.
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non redundant signal transduction of interleukin 6 type cytokines the adapter protein shc is specifically recruited to rhe Oncostatin M Receptor
Journal of Biological Chemistry, 2000Co-Authors: Heike M Hermanns, Simone Radtke, Peter C. Heinrich, Fred Schaper, Iris BehrmannAbstract:The coMMon use of the cytokine Receptor gp130 has served as an explanation for the extreMely redundant biological activities exerted by interleukin (IL)-6-type cytokines. Indeed, hardly any differences in signal transduction initiated by these cytokines are known. In the present study, we deMonstrate that Oncostatin M (OSM), but not IL-6 or leukeMia inhibitory factor, induces tyrosine phosphorylation of the Shc isoforMs p52 and p66 and their association with Grb2. ConcoMitantly, OSM turns out to be a stronger activator of ERK1/2 MAPKs. Shc is recruited to the OSM Receptor (OSMR), but not to gp130. Binding involves Tyr861 of the OSMR, located within a consensus binding sequence for the Shc PTB doMain. Moreover, Tyr861 is essential for activation of ERK1/2 and for full activation of the α2-Macroglobulin proMoter, but not for an exclusively STAT-responsive proMoter. This study therefore provides evidence for qualitative differential signaling MechanisMs exerted by IL-6-type cytokines.
Iris Behrmann - One of the best experts on this subject based on the ideXlab platform.
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three dileucine like Motifs within the interbox1 2 region of the huMan Oncostatin M Receptor prevent efficient surface expression in the absence of an associated janus kinase
Journal of Biological Chemistry, 2006Co-Authors: Simone Radtke, Hildegard Schmitzvan De Leur, Peter C. Heinrich, Angela Jorissen, Iris BehrmannAbstract:The Oncostatin M Receptor (OSMR) is part of Receptor coMplexes for Oncostatin M and interleukin-31. Signaling events are triggered by Jaks (Janus kinases) that constitutively bind to MeMbrane-proxiMal Receptor regions. Besides their established role in signaling, Jaks are involved in the regulation of the surface expression of several cytokine Receptors. Here, we analyzed the structural requireMents within the huMan OSMR that underlie its liMited surface expression in the absence of associated Jaks. We identified three dileucine-like Motifs within the Jak-binding region of the OSMR that control Receptor surface and overall expression. A Receptor Mutant in which all three Motifs were Mutated to alanine displayed Markedly increased surface expression. Although the surface half-life of this Mutant was increased coMpared with that of the wild-type Receptor, no difference in the internalization rate was detectable, iMplying that these Receptors differ in their post-endocytic fate. The protein stability of the wild-type Receptor was Markedly lower than that of Mutant Receptors, but could be strongly increased in the presence of the lysosoMal inhibitor chloroquine. Our data are consistent with the dileucine Motifs being involved in destabilization of Receptors devoid of associated Jaks as part of a quality control ensuring signaling coMpetence of OSMRs.
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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.
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non redundant signal transduction of interleukin 6 type cytokines the adapter protein shc is specifically recruited to rhe Oncostatin M Receptor
Journal of Biological Chemistry, 2000Co-Authors: Heike M Hermanns, Simone Radtke, Peter C. Heinrich, Fred Schaper, Iris BehrmannAbstract:The coMMon use of the cytokine Receptor gp130 has served as an explanation for the extreMely redundant biological activities exerted by interleukin (IL)-6-type cytokines. Indeed, hardly any differences in signal transduction initiated by these cytokines are known. In the present study, we deMonstrate that Oncostatin M (OSM), but not IL-6 or leukeMia inhibitory factor, induces tyrosine phosphorylation of the Shc isoforMs p52 and p66 and their association with Grb2. ConcoMitantly, OSM turns out to be a stronger activator of ERK1/2 MAPKs. Shc is recruited to the OSM Receptor (OSMR), but not to gp130. Binding involves Tyr861 of the OSMR, located within a consensus binding sequence for the Shc PTB doMain. Moreover, Tyr861 is essential for activation of ERK1/2 and for full activation of the α2-Macroglobulin proMoter, but not for an exclusively STAT-responsive proMoter. This study therefore provides evidence for qualitative differential signaling MechanisMs exerted by IL-6-type cytokines.
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Contributions of LeukeMia Inhibitory Factor Receptor and Oncostatin M Receptor to Signal Transduction in HeterodiMeric CoMplexes with Glycoprotein 130
Journal of immunology (Baltimore Md. : 1950), 1999Co-Authors: Heike M Hermanns, Claude Haan, Hildegard Schmitzvan De Leur, Simone Radtke, Peter C. Heinrich, Jan Tavernier, Iris BehrmannAbstract:LeukeMia inhibitory factor (LIF), cardiotrophin-1, ciliary neurotrophic factor, and Oncostatin M (OSM) lead to heterodiMerization of LIF Receptor (LIFR) or the OSM-specific Receptor (OSMR) with glycoprotein (gp) 130, the coMMon Receptor subunit for IL-6-type cytokines. Thereby intracellular signaling via Janus kinases (Jaks) and STAT transcription factors is initiated. We investigated the contributions of LIFR and OSMR to signal transduction in the context of heterodiMers with gp130. ChiMeric Receptors based on the extracellular parts of the IL-5R α- and β-chains were generated, allowing the induced heterodiMerization of two different cytoplasMic tails. Our studies deMonstrate that upon heterodiMerization with the gp130 cytoplasMic region, the cytoplasMic parts of both LIFR and OSMR were critical for activation of an acute phase protein proMoter in HepG2 hepatoMa cells. The MeMbrane-proxiMal region of LIFR or OSMR was crucial for the ability of such Receptor coMplexes to induce DNA binding of STAT1 and STAT3 in COS-7 cells. MeMbrane-distal regions of LIFR and OSMR contributed to STAT activation even in the absence of gp130 STAT recruitMent sites. We further show that the Janus kinases Jak1 and Jak2 constitutively associated with Receptor constructs containing the cytoplasMic part of LIFR, OSMR, or gp130, respectively. HoModiMers of the LIFR or OSMR cytoplasMic regions did not elicit responses in COS-7 cells but did in HepG2 cells and in MCF-7 breast carcinoMa cells. Thus, in spite of extensive functional siMilarities, differential signaling abilities of gp130, LIFR, and OSMR May becoMe evident in a cell-type-specific Manner.
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Box 2 region of the Oncostatin M Receptor deterMines specificity for recruitMent of Janus kinases and STAT5 activation.
The Journal of biological chemistry, 2008Co-Authors: Christoph Hintzen, Simone Radtke, Peter C. Heinrich, Christina Evers, Barbara E. Lippok, Rudolf Volkmer, Heike M HermannsAbstract:Abstract HuMan and Murine Oncostatin M (OSM) induce their bioactivities through a heterodiMeric Receptor coMplex consisting of gp130 and the OSM Receptor (OSMR), which initiates a signaling pathway involving Janus kinases (JAKs) and transcription factors of the signal transducers and activators of transcription (STAT) faMily. In contrast to the signal transducing Receptor subunit gp130, the OSMR allows strong activation of STAT5B. The underlying Molecular MechanisM, however, reMained unclear. Here we deMonstrate that the huMan and Murine OSM Receptors use distinct MechanisMs for STAT5B activation. The huMan Receptor contains a STAT5B recruiting tyrosine Motif (Tyr837/Tyr839) C-terMinal to the box 1/2 region, which is absent in the Mouse Receptor. In contrast, the Murine Receptor initiates STAT5 activation directly via the Receptor bound Janus kinases. Intriguingly, the Murine Receptor preferentially recruits JAK2, whereas the huMan Receptor seeMs to have a higher affinity for JAK1. We identify a single aMino acid (Phe820) in the huMan Receptor that is responsible for this preference. Exchange by the Murine counterpart (Cys815) allows recruitMent of JAK2 by the huMan Receptor and consequently activation of STAT5B independently of Receptor tyrosine Motifs. STAT5B interacts directly with JAK2 only in response to activation of the Murine OSMR or the Mutated huMan OSMR. Additionally, we show that OSM-induced STAT1 phosphorylation occurs independently of Receptor tyrosine Motifs and is Mediated directly by Janus kinases, whereas the two C-terMinally located tyrosine residues Tyr917/Tyr945 of the OSMR are crucial for STAT3 activation.
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enhanced expression levels of il 31 correlate with il 4 and il 13 in atopic and allergic contact derMatitis
The Journal of Allergy and Clinical Immunology, 2006Co-Authors: Mark M Neis, Peter C. Heinrich, Bettina Peters, Alexandra Dreuw, Joerg Wenzel, Thomas Bieber, Cornelia Mauch, Thomas Krieg, Sven Stanzel, Hans F MerkAbstract:Background IL-31 is produced by activated T lyMphocytes, preferentially by T H 2 cells. Transgenic Mice overexpressing IL-31 have a phenotype reseMbling allergic derMatitis in huMan subjects. Objective We sought to evaluate the potential iMportance of IL-31 in the pathogenesis of huMan T cell–Mediated skin diseases. Methods We analyzed total RNA taken froM 149 skin biopsy speciMens froM patients with atopic derMatitis (AD), allergic contact derMatitis (ACD), or psoriasis in coMparison with speciMens taken froM patients with healthy skin (n = 13) by using quantitative real-tiMe PCR for the expression of T H 1/T H 2 cytokines. Results We found statistically increased MRNA levels of IL-31 in biopsy speciMens taken froM patients with AD, irrespective of the severity of the disease and seruM IgE levels. Moreover, IL-31 MRNA levels were strongly increased in Many biopsy speciMens taken froM patients with ACD. However, no increased transcription of IL-31 could be detected in biopsy speciMens taken froM psoriatic plaques. A coMparison of MRNA levels of IL-31 with T H 1 or T H 2 cytokines deMonstrates a correlation of the expression of IL-31 with IL-4 and IL-13 but not with IFN-γ. No significant increase of IL-31 Receptor MRNA could be detected in any disease, whereas the second Receptor subunit of IL-31, the Oncostatin M Receptor, seeMs to be enhanced transcribed in patients with psoriasis. Conclusion IL-31 expression is not only increased in patients with AD but also in those with ACD, 2 pruritic skin disorders. In both types of eczeMa, expression of IL-31 is associated with the expression of the T H 2 cytokines IL-4 and IL-13. Clinical iMplications IL-31 Might contribute not only to the developMent of AD but also to ACD-provoked skin inflaMMation.
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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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three dileucine like Motifs within the interbox1 2 region of the huMan Oncostatin M Receptor prevent efficient surface expression in the absence of an associated janus kinase
Journal of Biological Chemistry, 2006Co-Authors: Simone Radtke, Hildegard Schmitzvan De Leur, Peter C. Heinrich, Angela Jorissen, Iris BehrmannAbstract:The Oncostatin M Receptor (OSMR) is part of Receptor coMplexes for Oncostatin M and interleukin-31. Signaling events are triggered by Jaks (Janus kinases) that constitutively bind to MeMbrane-proxiMal Receptor regions. Besides their established role in signaling, Jaks are involved in the regulation of the surface expression of several cytokine Receptors. Here, we analyzed the structural requireMents within the huMan OSMR that underlie its liMited surface expression in the absence of associated Jaks. We identified three dileucine-like Motifs within the Jak-binding region of the OSMR that control Receptor surface and overall expression. A Receptor Mutant in which all three Motifs were Mutated to alanine displayed Markedly increased surface expression. Although the surface half-life of this Mutant was increased coMpared with that of the wild-type Receptor, no difference in the internalization rate was detectable, iMplying that these Receptors differ in their post-endocytic fate. The protein stability of the wild-type Receptor was Markedly lower than that of Mutant Receptors, but could be strongly increased in the presence of the lysosoMal inhibitor chloroquine. Our data are consistent with the dileucine Motifs being involved in destabilization of Receptors devoid of associated Jaks as part of a quality control ensuring signaling coMpetence of OSMRs.
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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.
