Role Of Oncostatin M Research Articles

Abstract 6984: Investigating the function of the OSM-OSMR axis in pancreatic ductal adenocarcinoma (PDAC)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, characterized by a low survival rate and a significant global mortality impact. The interaction between PDAC and the immune system is complex and plays a crucial role in the progression of the disease. PDAC creates an immunosuppressive tumor microenvironment, which hampers the ability of immune cells to effectively infiltrate the tumor and mount an anti-cancer immune response. Additionally, there is an imbalance of cytokines, with an overabundance of immunosuppressive factors and a deficiency in pro-inflammatory cytokines. This hostile immunological landscape contributes to the aggressive nature of PDAC and hinders the success of immunotherapies and adjuvant treatments. One cytokine of particular interest is oncostatin M (OSM), a member of the interleukin-6 (IL-6) family. OSM has been implicated in the regulation of cancer and has been associated with poor overall survival in pancreatic cancer and other malignancies. Similar to other cytokines, OSM is secreted by immune cells and acts as a regulator of the inflammatory microenvironment surrounding the tumor. The levels of OSM in this milieu can potentially influence cancer development and regulation through multiple mechanisms. Despite the growing understanding of cytokines in cancer, research on the role of OSM in PDAC is still limited and requires further investigation to identify potential therapeutic targets. Therefore, there is a critical need to delve deeper into the functions of OSM and its receptor, oncostatin M receptor (OSMR), in the initiation and progression of pancreatic cancer. As such, our goal is to examine the functions of OSM and its receptor (OSMR) in initiating and advancing pancreatic cancer to better comprehend the role of the OSM-OSMR axis in PDAC, both in vivo and in vitro. Citation Format: Yuan Sui, Tony Hunter. Investigating the function of the OSM-OSMR axis in pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6984.

Exercise-induced crosstalk between immune cells and adipocytes in humans: Role of oncostatin-M

The discovery of exercise-regulated circulatory factors has fueled interest in organ crosstalk, especially between skeletal muscle and adipose tissue, and the role in mediating beneficial effects of exercise. We studied the adipose tissue transcriptome in men and women with normal glucose tolerance or type 2 diabetes following an acute exercise bout, revealing substantial exercise- and time-dependent changes, with sustained increase in inflammatory genes in type 2 diabetes. We identify oncostatin-M as one of the most upregulated adipose-tissue-secreted factors post-exercise. In cultured human adipocytes, oncostatin-M enhances MAPK signaling and regulates lipolysis. Oncostatin-M expression arises predominantly from adipose tissue immune cell fractions, while the corresponding receptors are expressed in adipocytes. Oncostatin-M expression increases in cultured human Thp1 macrophages following exercise-like stimuli. Our results suggest that immune cells, via secreted factors such as oncostatin-M, mediate a crosstalk between skeletal muscle and adipose tissue during exercise to regulate adipocyte metabolism and adaptation.

Oncostatin M and Nivolumab Affect the Cytotoxic T-Cell Proportions and the Susceptibility to TRAIL-Induced Death in Non-Leukocyte Cell Subpopulations in Soft Tissue Sarcomas

Introduction: Soft tissue sarcomas (STSs) are malignant tumors arising from mesenchymal tissues. Patients with advanced and metastatic STSs have low overall survival rates and relatively limited treatment options. Oncostatin M (OSM) is a pleiotropic cytokine that was shown to carry both pro- and anti-tumorigenic properties in various cancer types. However, the role of OSM in STSs has not yet been elucidated. Moreover, the potential additive effects of combining OSM and anti-PD-1 therapy have not been carried out so far. Methods: The aim of this study was to determine the effects of in vitro OSM administration on liposarcoma, leiomyosarcoma, and myxofibrosarcoma immune cells isolated from peripheral blood and tumor tissues and the potential cooperative nature of OSM and nivolumab in treating these STSs. We designed a cohort study to explore novel histology-driven therapies in our target STSs. The immune cells were isolated from the peripheral blood and tumors of patients with STS, and the proportions and phenotypes of immune cells were evaluated with flow cytometry after cultivation with therapeutic monoclonal antibodies. Results: The proportion of peripheral CD45+ cells was not affected by OSM but was significantly increased by nivolumab, whereas both treatments had an effect on CD8+ T cells. In tumor tissues, CD8+ T cell and CD45‒ TRAIL+ cell cultures were boosted by nivolumab and significantly enriched by OSM. Our data suggest that OSM may play a role in the treatment of leiomyosarcoma, myxofibrosarcoma, and liposarcoma. Conclusion: In conclusion, the biological efficacy of OSM is reflected in the tumor microenvironment rather than in the peripheral blood of the patients in our cohort, and nivolumab could potentiate its mechanism of action in selected cases. Nevertheless, more histotype-tailored studies are needed to fully understand the functions of OSM in STSs.

Oncostatin M, Serpins, and Oxidative Stress in Extracellular Matrix Remodeling and Arteriovenous Fistula Maturation.

End-stage renal disease is a crippling diagnosis that generally requires dialysis to prolong life. To facilitate filtration of patient's blood in dialysis, surgical formation of an arteriovenous fistula (AVF) is commonly performed. Maturation of the AVF is required to allow for successful dialysis. However, AVFs commonly fail to mature, leading to the fistula closure, the necessity for another fistula site, and markedly increased morbidity and mortality. The current literature concerning molecular mechanisms associated with AVF maturation failure supports the role of inflammatory mediators involving immune cells and inflammatory cytokines. However, the role of oncostatin M (OSM), an inflammatory cytokine, and its downstream targets are not well investigated. Through inflammation, oxidative stress, and hypoxic conditions, the vascular tissue surrounding the AVF undergoes fibrosis, stenosis, and wall thickening, leading to complete occlusion and nonfunctional. In this report, first we critically review the existing literature on the role of OSM in the most common causes of early AVF failure - vascular inflammation, thrombosis, and stenosis. We next consider the potential of using OSM as a therapeutic target, and finally discuss therapeutic agents targeting inflammatory mediators involved in OSM signaling to potentiate successful maturation of the AVF.

Oncostatin M triggers brain inflammation by compromising blood-brain barrier integrity.

Oncostatin M (OSM) is an IL-6 family member which exerts neuroprotective and remyelination-promoting effects after damage to the central nervous system (CNS). However, the role of OSM in neuro-inflammation is poorly understood. Here, we investigated OSM's role in pathological events important for the neuro-inflammatory disorder multiple sclerosis (MS). We show that OSM receptor (OSMRβ) expression is increased on circulating lymphocytes of MS patients, indicating their elevated responsiveness to OSM signalling. In addition, OSM production by activated myeloid cells and astrocytes is increased in MS brain lesions. In experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, OSMRβ-deficient mice exhibit milder clinical symptoms, accompanied by diminished T helper 17 (Th17) cell infiltration into the CNS and reduced BBB leakage. In vitro, OSM reduces BBB integrity by downregulating the junctional molecules claudin-5 and VE-cadherin, while promoting secretion of the Th17-attracting chemokine CCL20 by inflamed BBB-endothelial cells and reactive astrocytes. Using flow cytometric fluorescence resonance energy transfer (FRET) quantification, we found that OSM-induced endothelial CCL20 promotes activation of lymphocyte function-associated antigen 1 (LFA-1) on Th17 cells. Moreover, CCL20 enhances Th17 cell adhesion to OSM-treated inflamed endothelial cells, which is at least in part ICAM-1 mediated. Together, these data identify an OSM-CCL20 axis, in which OSM contributes significantly to BBB impairment during neuro-inflammation by inducing permeability while recruiting Th17 cells via enhanced endothelial CCL20 secretion and integrin activation. Therefore, care should be taken when considering OSM as a therapeutic agent for treatment of neuro-inflammatory diseases such as MS.

Oncostatin M induces C2C12 myotube atrophy by modulating muscle differentiation and degradation

Oncostatin M (OSM) is a cytokine of the interleukin-6 family and plays a role in various disorders such as cancer and inflammatory diseases, which are often accompanied by skeletal muscle atrophy, or sarcopenia. However, the role of OSM in the regulation of skeletal muscle mass remains to be identified. In this study, we investigated the effect of OSM on C2C12 myotube formation in vitro. C2C12 myoblasts were induced to differentiate into myotubes for 3 days and then treated with OSM for 24 or 48 h. The diameter of differentiated C2C12 myotubes were reduced by 18.7% and 23.3% compared to control cells after treatment with OSM for 24 and 48 h, respectively. The expression levels of MyoD and myogenin were decreased, while those of atrogin-1, CCAAT/enhancer binding protein δ, and OSM receptor were increased in C2C12 myotubes treated with OSM for 24 h compared to control cells. Furthermore, the inhibitory effect of OSM on myotube formation was significantly attenuated by pretreatment with an inhibitor of signal transducer and activator of transcription (STAT) 3 or by knockdown of Stat3. Finally, the OSM-induced changes in the expression levels of MyoD, myogenin, and atrogin-1 were reversed by pretreatment with an inhibitor of STAT3 or by Stat3 knockdown in C2C12 myotubes. In conclusion, OSM induces C2C12 myotube atrophy by inhibiting myogenic differentiation and activating muscle degradation in a STAT3-dependent manner.

2481-PUB: Oncostatin M Is Involved in Skeletal Muscle Atrophy via the STAT3 Pathway

Recent clinical evidences indicate that sarcopenia is closely related to obesity, type 2 diabetes and atherosclerosis, and mortality risk as well. It has been demonstrated that oncostatin M (OSM), a member of the interleukin-6 family of cytokines, is produced in the adipose tissue and that it promotes adipose tissue inflammation and insulin resistance in obesity. However, the role of OSM in the regulation of skeletal muscle mass remains unknown. In this study, we investigated the effect of OSM on myotube formation of differentiated C2C12 cells in vitro. After C2C12 myoblasts were differentiated into myotubes by a differentiation medium for 72 hours, C2C12 myotubes were treated with OSM for 12 to 48 hours. The diameters of differentiated C2C12 myotubes were reduced by 18.7% and 23.3% compared to the control cells by the treatment with OSM for 24 and 48 hours, respectively. The mRNA expression levels of OSM receptor, atrogin-1, myostatin, and C/EBPδ were significantly increased by 24 hour-treatment with OSM compared to the control cells; while those of myogenin and MyoD were decreased. Moreover, the protein expression of atrogin-1 was increased, myogenin protein level was decreased. Furthermore, OSM phosphorylated STAT3 in differentiated myotubes at 12 and 24 hours. Finally, the inhibitory effect of OSM on the diameter of myotubes was significantly attenuated by the pretreatment with STAT3 inhibitor (C188-9) or by STAT3 knockdown. These in vitro data indicate that OSM contributes to the atrophy of C2C12 myotubes not only by promoting muscle degradation, but also by inhibiting myogenesis via the STAT3 pathway. This study suggests that OSM may regulate skeletal muscle mass in metabolic disorders such as type 2 diabetes. Disclosure Y. Miki: None. T. Morioka: Research Support; Self; Eli Lilly and Company, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Sanofi K.K., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Roche Diagnostics K.K., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Other Relationship; Self; Ono Pharmaceutical Co., Ltd. A. Shioi: None. T. Sakura: None. Y. Kakutani: None. K. Fujimoto: None. H. Uedono: None. K. Mori: Speaker's Bureau; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd. T. Shoji: Research Support; Self; Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd. Speaker's Bureau; Self; Kissei Pharmaceutical Co., Ltd., Kowa, Kyowa Hakko Kirin Co., Ltd. M. Emoto: Research Support; Self; Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical CO., Ltd., Takeda Pharmaceutical Company Limited. M. Inaba: None.

Oncostatin M exerts a protective effect against excessive scarring by counteracting the inductive effect of TGF\u03b21 on fibrosis markers

Wound healing is a complex physiological process that repairs a skin lesion and produces fibrous tissue. In some cases, this process can lead to hypertrophic scars (HS) or keloid scars (KS), for which the pathophysiology remains poorly understood. Previous studies have reported the presence of oncostatin M (OSM) during the wound healing process; however, the role of OSM in pathological scarring remains to be precisely elucidated. This study aims to analyse the presence and involvement of OSM in the pathological scarring process. It was conducted with 18 patients, including 9 patients with hypertrophic scarring and 9 patients with keloid scarring. Histological tissue analysis of HS and KS showed minor differences in the organization of the extracellular matrix, the inflammatory infiltrate and the keratinocyte phenotype. Transcriptomic analysis showed increased expression levels of fibronectin, collagen I, TGFβ1, β-defensin-2 and S100A7 in both pathological samples. OSM expression levels were greater in HS than in KS and control skin. In vitro, OSM inhibited TGFβ1-induced secretion of components of the extracellular matrix by normal and pathological fibroblasts. Overall, we suggest that OSM is involved in pathological wound healing processes by inhibiting the evolution of HS towards KS by controlling the fibrotic effect of TGFβ1.

Oncostatin M: Potential Implications for Malignancy and Metabolism.

The gp130 cytokine, oncostatin M (OSM), serves several physiological and pathological functions. At the molecular level, OSM can directly or indirectly participate in tumorigenesis and insulin resistance development. Although OSM was initially found to be anti-proliferative in tumors, numerous tumorigenic roles for OSM have been reported in a variety of cancers. In metabolic diseases, OSM signaling may be required for homeostasis in both the liver and the adipose tissue, since abrogation of OSM signaling causes obesity, hepatic steatosis, and insulin resistance. This review aims to: 1) examine the current literature regarding the role of OSM in the development of cancers and insulin resistance; and 2) propose a possible link between cancerassociated OSM and the development of the insulin resistance observed with cancer cachexia. In light of the potential links between cancer-associated OSM and cachexia-related insulin resistance, additional research is needed, especially given the possible link between these disease states. When considering OSM as a pharmaceutical target, its tumorigenic effects and role in tissue homeostasis must be carefully considered.

Induction of STAT3-Dependent CXCL5 Expression and Neutrophil Recruitment by Oncostatin-M during Pneumonia.

Acute bacterial pneumonia is a significant public health concern worldwide. Understanding the signals coordinating lung innate immunity may foster the development of therapeutics that limit tissue damage and promote host defense. We have previously shown that lung messenger RNA expression of the IL-6 family cytokine oncostatin-M (OSM) is significantly elevated in response to bacterial stimuli. However, its physiological significance during pneumonia is unknown. Here we demonstrate that OSM is rapidly increased in the airspaces of mice after pulmonary infection with Escherichia coli. Neutralization of OSM caused a substantial decrease in airspace neutrophils and macrophages. OSM blockade also caused a marked reduction in lung chemokine (C-X-C motif) ligand (CXCL) 5 expression, whereas other closely related neutrophil chemokines, CXCL1 and CXCL2, were unaffected. Intratracheal administration of recombinant OSM was sufficient to recapitulate the effect on CXCL5 induction, associated with robust activation of the signal transducer and activator of transcription 3 (STAT3) transcription factor. Cell sorting revealed that OSM effects were specific to lung epithelial cells, including a positive feedback loop in which OSM may facilitate expression of its own receptor. Finally, in vitro studies demonstrated that STAT3 was required for maximal OSM-induced CXCL5 expression. These studies demonstrate a novel role for OSM during pneumonia as an important signal to epithelial cells for chemokine induction mediating neutrophil recruitment.

Oncostatin-M Differentially Regulates Mesenchymal and Proneural Signature Genes in Gliomas via STAT3 Signaling

Glioblastoma (GBM), the most malignant of the brain tumors is classified on the basis of molecular signature genes using TCGA data into four subtypes- classical, mesenchymal, proneural and neural. The mesenchymal phenotype is associated with greater aggressiveness and low survival in contrast to GBMs enriched with proneural genes. The proinflammatory cytokines secreted in the microenvironment of gliomas play a key role in tumor progression. The study focused on the role of Oncostatin-M (OSM), an IL-6 family cytokine in inducing mesenchymal properties in GBM. Analysis of TCGA and REMBRANDT data revealed that expression of OSMR but not IL-6R or LIFR is upregulated in GBM and has negative correlation with survival. Amongst the GBM subtypes, OSMR level was in the order of mesenchymal > classical > neural > proneural. TCGA data and RT-PCR analysis in primary cultures of low and high grade gliomas showed a positive correlation between OSMR and mesenchymal signature genes-YKL40/CHI3L1, fibronectin and vimentin and a negative correlation with proneural signature genes-DLL3, Olig2 and BCAN. OSM enhanced transcript and protein level of fibronectin and YKL-40 and reduced the expression of Olig2 and DLL3 in GBM cells. OSM-regulated mesenchymal phenotype was associated with enhanced MMP-9 activity, increased cell migration and invasion. Importantly, OSM induced mesenchymal markers and reduced proneural genes even in primary cultures of grade-III glioma cells. We conclude that OSM-mediated signaling contributes to aggressive nature associated with mesenchymal features via STAT3 signaling in glioma cells. The data suggest that OSMR can be explored as potential target for therapeutic intervention.

Lack of Oncostatin M Receptor β Leads to Adipose Tissue Inflammation and Insulin Resistance by Switching Macrophage Phenotype

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.

Opposing roles of STAT-1 and STAT-3 in regulating vascular endothelial growth factor expression in vascular smooth muscle cells

Increased microvessel density in atherosclerotic plaques plays a major role in promoting plaque destabilization resulting in increased risk of stroke and myocardial infarction. Previously we have shown that expression of the inflammatory cytokine, Oncostatin-M (OSM), in human atherosclerotic plaques correlated with increased microvessel density, indicating a role for OSM in promoting plaque angiogenesis. The purpose of this study was to determine the mechanism by which OSM regulates Vascular Endothelial Growth Factor (VEGF) expression in human coronary artery smooth muscle cells. Using shRNA and overexpression studies, we have shown that the transcription factor, STAT-1 inhibited VEGF expression, while STAT-3 promoted the expression of VEGF. We further show that the mechanism by which STAT-1 and STAT-3 regulates VEGF expression is through modulation of Hypoxia Inducible Factor-1α (HIF-1α). STAT-1 suppresses HIF-1α expression, whereas STAT-3 positively regulates HIF-1α expression. These results provide evidence that activated STAT-1 and STAT-3 regulate VEGF expression indirectly, by modulating HIF-1α activity.

Abstract B57: Oncostatin M promotes progression of Pten-deficient prostate cancer

Abstract Chronic inflammation has been proposed to play a crucial role in several cancers including gastric, pancreatic, colon and lung, with recent evidence suggesting involvement in prostate cancer. While both interleukin 6 (IL6) and the related cytokine oncostatin M (OSM) have been implicated in prostate cancer, there have been few studies using in vivo models. To address this issue, we employed a dissociated prostate tissue recombination system using epithelium derived from conditional Pten knockout mice. Loss of Pten is common in prostate cancer and generates an intermediate murine prostatic intraepithelial neoplasia (mPIN) lesion in our system, providing an ideal means to assess functional synergy. We hypothesize that increased expression of these cytokines in the prostate microenvironment will promote malignant progression of intermediate prostate cancer lesions. Paracrine expression of IL6 did not transform naïve prostate epithelium nor did it exhibit functional synergy with Pten null epithelium in our system. Grafts expressing OSM alone did not transform naïve tissue, though in contrast, presented dramatic functional synergy with loss of Pten in prostate epithelium. Loss of Pten combined with OSM exhibited progression to poorly differentiated adenocarcinoma with features of epithelial-to-mesenchymal transition (EMT). Transformed tissues displayed loss of cytokeratin expression with down-regulation and mis-localization of e-cadherin. These tumors exhibit activation of several pathways downstream of OSM signaling including STAT3 and Erk1/2 as seen by immunohistochemical analysis. Further, we interrogated the role of OSM in promoting hormone refractory prostate cancer by castrating host animals following tumor establishment. Loss of Pten alone failed to progress beyond mPIN lesions and eventually regressed at 6 months post castration. In dramatic contrast, grafts expressing the OSM ligand exhibited initial regression with castration resistant growth following a latency period, recapitulating events commonly observed in human disease. Our evidence suggests that in the context of Pten loss, IL6 does not appear to promote prostate malignancy in the murine system. Conversely, we have identified that OSM synergizes with loss of Pten to promote aggressive prostate malignancy. Paracrine expression of OSM results in activation of several pathways, providing a means to interrogate hierarchy within signaling modules in the context of prostate cancer progression. Our study further indicates that OSM could play a role in promoting castration resistance, allowing investigation of potential points for therapeutic intervention. Citation Format: Daniel A. Smith, Yang Zong, Atsushi Kiba, Owen N. Witte. Oncostatin M promotes progression of Pten-deficient prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B57.

Oncostatin M induces dendritic cell maturation and Th1 polarization

Oncostatin M (OSM) is a pleiotropic cytokine and a member of the gp130/IL-6 cytokine family that has been found to be involved in both pro- and anti-inflammatory responses in cell-mediated immunity. Maturation of dendritic cells (DCs) is crucial for initiation of primary immune responses and is regulated by several stimuli. In this study, the role of OSM in the phenotypic and functional maturation of DCs was evaluated in vitro. Stimulation with OSM upregulated the expression of CD80, CD86, MHC class I and MHC class II and reduced the endocytic capacity of immature DCs. Moreover, OSM induced the allogeneic immunostimulatory capacity of DCs by stimulating the production of the Th1-promoting cytokine IL-12. OSM also increased the production of IFN-γ by T cells in mixed-lymphocyte reactions, which would be expected to contribute to the Th1 polarization of the immune response. The expression of surface markers and cytokine production in DCs was mediated by both the MAPK and NF-κB pathways. Taken together, these results indicate that OSM may play a role in innate immunity and in acquired immunity by enhancing DCs maturation and promoting Th1 immune responses.

Oncostatin M differentially regulates CXC chemokines in mouse cardiac fibroblasts

Ischemia-reperfusion injury in the heart is characterized by marked infiltration of neutrophils in the myocardial interstitial space. Studies in human, canine, and murine models have revealed oncostatin M (OSM) expression in infiltrating leukocytes. In an effort to assess possible roles of OSM in the myocardium, we used cardiac fibroblasts (mCFs) isolated from adult mouse heart to determine whether recombinant murine OSM regulates the synthesis and release of MIP2/CXCL2, KC/CXCL1, and LIX/CXCL5, which are three potent neutrophil chemoattractants in the mouse. Our results demonstrate that mCFs express OSM receptors and that, within the IL-6 cytokine family, OSM uniquely induces significant release of KC and LIX in mCFs. In addition, although OSM activates the JAK-signal transducers and activators of transcription and MAPK pathways, we demonstrate that the OSM-mediated CXC chemokine release in mCFs is also dependent on the activation of the phosphatidylinositol 3-kinase pathway.

Immunocytochemical detection and reverse transcription polymerase chain reaction expression of oncostatin M (OSM) and its receptor (OSM-Rβ) in human fetal and adult ovaries

To investigate the immunocytochemical expression and presence of mRNA transcripts of oncostatin M (OSM) and its exclusive receptor (OSM-Rbeta) in ovaries from human adults and fetuses. Immunocytochemical and reverse transcription polymerase chain reaction (RT-PCR) study. Major tertiary care and referral academic centers. Ten women and girls undergoing laparoscopic ovarian biopsy and 30 women undergoing second-trimester and third-trimester pregnancy terminations. None. Microscopic morphometric analysis, immunocytochemistry for OSM and OSM-Rbeta, and RT-PCR analyses. There was strong to moderate immunocytochemical staining for OSM in both oocytes and granulosa cells of follicles from primordial stages onwards in ovaries from both fetuses and adults/adolescents. OSM-Rbeta was detected mainly in the oocytes. Transcripts of OSM and OSM-Rbeta RNA were detected by RT-PCR analyses. The expression of OSM and its receptor in ovarian tissue from fetuses and women suggests a possible role of OSM in growth initiation of human primordial follicles.

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

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.

Immunohistochemical analysis of the IL-6 family of cytokines and their receptors in benign, hyperplasic, and malignant human prostate.

Interleukin-6 (IL-6) and its receptor have been implicated in prostate cancer progression. Because other members of the IL-6 family such as leukaemia inhibitory factor (LIF) and oncostatin M (OSM) share gp130, the signal transduction subunit of their receptors, interpretation of the data without considering the expression of these cytokines and their specific receptor subunits could be misleading. The immunohistochemical pattern of the IL-6 family and their receptor subunits in normal prostate, benign prostatic hyperplasia (BPH), and prostatic carcinoma (PC) was investigated. In normal prostates, gp130 and OSMRalpha were detected exclusively in the stroma and LIFRbeta was very scarce. While IL-6 was scarcely immunolocalized to the basal cells of the epithelium, OSM was detected in the stroma and LIF in both the epithelium and the stroma. This suggests an autocrine role for this family of cytokines in the stroma of normal prostates. In BPH, gp130 and OSMRalpha were detected both in the epithelium and in the stroma, whereas LIFRbeta was localized only to the epithelium. IL-6 localized preferentially to the epithelium, OSM to the stroma, and LIF to both compartments. Therefore, in addition to the autocrine role in the stroma, IL-6 and OSM may play a paracrine role from the stroma to the epithelium in BPH. In PC, gp130 and OSMRalpha were detected both in the epithelium and in the stroma, increasing with rising Gleason grade, whereas LIFRbeta was localized exclusively to the epithelium of low Gleason grade carcinomas. IL-6, LIF, and OSM localized in all cell types, with immunostaining increasing with Gleason grade. These data suggest an autocrine role for these cytokines in the epithelial cells of PC. The distinct pattern of expression of LIFRbeta exclusively in low Gleason grade carcinomas makes LIFRbeta a candidate for malignancy diagnosis. The role of OSM mainly in high Gleason grade carcinomas makes OSM a putative target for prostate cancer therapy.

Localization of oncostatin M receptor β in adult and developing CNS

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.