IL-33 Mediates Lung Inflammation by the IL-6-Type Cytokine Oncostatin M.

The interleukin-1 family member IL-33 participates in both innate and adaptive T helper-2 immune cell responses in models of lung disease. The IL-6-type cytokine Oncostatin M (OSM) elevates lung inflammation, Th2-skewed cytokines, alternatively activated (M2) macrophages, and eosinophils in C57Bl/6 mice in vivo. Since OSM induces IL-33 expression, we here test the IL-33 function in OSM-mediated lung inflammation using IL-33-/- mice. Adenoviral OSM (AdOSM) markedly induced IL-33 mRNA and protein levels in wild-type animals while IL-33 was undetectable in IL-33-/- animals. AdOSM treatment showed recruitment of neutrophils, eosinophils, and elevated inflammatory chemokines (KC, eotaxin-1, MIP1a, and MIP1b), Th2 cytokines (IL-4/IL-5), and arginase-1 (M2 macrophage marker) whereas these responses were markedly diminished in IL-33-/- mice. AdOSM-induced IL-33 was unaffected by IL-6-/- deficiency. AdOSM also induced IL-33R+ ILC2 cells in the lung, while IL-6 (AdIL-6) overexpression did not. Flow-sorted ILC2 responded in vitro to IL-33 (but not OSM or IL-6 stimulation). Matrix remodelling genes col3A1, MMP-13, and TIMP-1 were also decreased in IL-33-/- mice. In vitro, IL-33 upregulated expression of OSM in the RAW264.7 macrophage cell line and in bone marrow-derived macrophages. Taken together, IL-33 is a critical mediator of OSM-driven, Th2-skewed, and M2-like responses in mouse lung inflammation and contributes in part through activation of ILC2 cells.

A Role for Oncostatin M in the Impairment of Glucose Homeostasis in Obesity.

CONTEXT: Oncostatin M (OSM) plays a key role in inflammation, but its regulation and function during obesity is not fully understood. OBJECTIVE: The aim of this study was to evaluate the relationship of OSM with the inflammatory state that leads to impaired glucose homeostasis in obesity. We also assessed whether OSM immunoneutralization could revert metabolic disturbances caused by a high-fat diet (HFD) in mice. DESIGN: 28 patients with severe obesity were included and stratified into two groups: (1) glucose levels <100 mg/dL and (2) glucose levels >100 mg/dL. White adipose tissue was obtained to examine OSM gene expression. Human adipocytes were used to evaluate the effect of OSM in the inflammatory response, and HFD-fed C57BL/6J mice were injected with anti-OSM antibody to evaluate its effects. RESULTS: OSM expression was elevated in subcutaneous and visceral fat from patients with obesity and hyperglycemia, and correlated with Glut4 mRNA levels, serum insulin, homeostatic model assessment of insulin resistance, and inflammatory markers. OSM inhibited adipogenesis and induced inflammation in human adipocytes. Finally, OSM receptor knockout mice had increased Glut4 mRNA levels in adipose tissue, and OSM immunoneutralization resulted in a reduction of glucose levels and Ccl2 expression in adipose tissue from HFD-fed mice. CONCLUSIONS: OSM contributes to the inflammatory state during obesity and may be involved in the development of insulin resistance.

Oncostatin-M-Reactive Pericytes Aggravate Blood-Brain Barrier Dysfunction by Activating JAK/STAT3 Signaling In Vitro.

Oncostatin M (OSM) is a cytokine of the interleukin (IL)-6 family members. It induces blood-brain barrier (BBB) dysfunction by activating Janus-activated kinase (JAK) and signal transducer and activator of transcription (STAT) 3 pathways in brain endothelial cells. Brain pericytes located around microvessels are one of the BBB constituents. Pericytes work as a boundary surface between the blood circulation and brain parenchyma, and their functions are altered under pathophysiological conditions, leading to BBB dysregulation. However, it remains unknown whether pericytes are associated with OSM-induced BBB dysfunction. We demonstrated that pericyte exposure to OSM (100 ng/mL) elevated phosphorylation of STAT3, a main OSM signaling pathway, and that pericytes expressed OSM receptors (OSMRs) including OSMRß and glycoprotein 130. These results suggest that pericytes are able to respond to OSM. To determine the effects of OSM-reactive pericytes on BBB functions, rat brain endothelial cell (RBEC) monolayers were cultured with OSM-treated pericytes. The presence of pericytes exposed to 100 ng/mL of OSM for 48 h aggravated both the elevated permeability to sodium fluorescein and the lowered transendothelial electrical resistance which were induced by OSM in RBECs. This OSM-reactive pericyte-induced aggravation of lowered RBEC barrier function was reversed by ruxolitinib, a JAK inhibitor. These findings suggest that activated JAK/STAT3 signaling in pericytes contributes to OSM-produced BBB breakdown. Thus, OSM-reactive pericytes may have to be considered a characteristic machinery in the formation and progression of BBB breakdown under pathological conditions associated with increased OSM levels.

Induction of muscle stem cell quiescence by the secreted niche factor Oncostatin M.

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.

Oncostatin M in the development of metabolic syndrome and its potential as a novel therapeutic target.

Oncostatin M (OSM), a member of the IL-6 family of cytokines, plays an important role in various biologic actions, including cell growth, neuronal development, and inflammatory responses. Recently, we demonstrated the unique relationship between OSM and metabolic syndrome in mice. Mice lacking OSM receptor ß subunit (OSMRß-/- mice) exhibited late-onset obesity. Before the onset of obesity, adipose tissue inflammation and insulin resistance were observed in OSMRß-/- mice. In addition, high-fat diet-induced metabolic disorders, including obesity, adipose tissue inflammation, insulin resistance, and hepatic steatosis, were aggravated in OSMRß-/- mice compared to those in wild-type mice. Consistent with these findings, OSM treatment dramatically improved these metabolic disorders in the mouse model of metabolic syndrome. Interestingly, OSM directly changed the phenotypes of adipose tissue macrophages toward anti-inflammatory M2 type. Furthermore, fatty acid content in the hepatocytes was decreased by OSM through expression regulation of several key enzymes of hepatic lipid metabolism. These findings suggest that OSM is a novel therapeutic target for metabolic syndrome.

[Neutrophils regulate the process of angiogenesis].

Neutrophils are one of the most abundant leukocytes present in the human blood circulation system, which could provide continuous immune surveillance. Recent studies have shown that neutrophils are closely related to angiogenesis. Neutrophils could release various cytokines, which regulate the angiogenic process by affecting the growth and migration of endothelial cells directly or indirectly. In the present review, the regulatory effects of neutrophils on angiogenic process and mechanisms are analyzed and summarized, which would provide clues for the treatment of related diseases using neutrophils as the targets in the future.

Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling.

Increasing evidence supports the idea that cancer cell plasticity promotes metastasis and tumor recurrence, resulting in patient mortality. While it is clear that the tumor microenvironment (TME) contributes to cancer cell plasticity, the specific TME factors most actively controlling plasticity remain largely unknown. Here, we performed a screen to identify TME cytokines and growth factors that promote epithelial-mesenchymal plasticity, and acquisition of cancer stem cell (CSC) properties. Of 28 TME cytokines and growth factors tested, we identified Oncostatin M (OSM) as the most potent inducer of mesenchymal/CSC properties. OSM-induced plasticity was Signal Transducer and Activator of Transcription 3 (STAT3)-dependent, and also required a novel intersection with transforming growth factor-ß (TGF-ß)/SMAD signaling. OSM/STAT3 activation promoted SMAD3 nuclear accumulation, DNA binding and induced SMAD3-dependent transcriptional activity. Suppression of TGF-ß receptor activity or ablation of SMAD3 or SMAD4, but not SMAD2, strongly suppressed OSM/STAT3-mediated plasticity. Moreover, removal of OSM or inhibition of STAT3 or SMAD3 resulted in a marked reversion to a non-invasive, epithelial phenotype. We propose that targeted blockade of the STAT3/SMAD3 axis in tumor cells may represent a novel therapeutic approach to prevent the plasticity required for metastatic progression and tumor recurrence.

Oncostatin M Suppresses Activation of IL-17/Th17 via SOCS3 Regulation in CD4+ T Cells.

Oncostatin M (OSM) is a pleiotropic cytokine and a member of the IL-6 family. It has both proinflammatory and anti-inflammatory functions and is involved in the activation of STAT3 and STAT5. Rheumatoid arthritis is an autoimmune disease that causes chronic and excessive inflammation. Rheumatoid arthritis can lead to induction of Th17 cells, which express IL-17. The aim of this study was to measure the effects of OSM on the proliferation of regulatory T cells and Th17 cells from mice. IL-2 immune complex suppressed the development of collagen-induced arthritis in mice and altered the regulatory T/Th17 cell balance by increasing OSM expression. OSM mitigated the proliferation of Th17 cells and decreased the expression of IL-17 and IL-21. It promoted the activation of suppressor of cytokine signaling 3 (SOCS3), STAT3, and STAT5. Inhibition of SOCS3, STAT3, and STAT5 lessened the OSM-induced reduction in proliferation of Th17 cells. These observations suggest that OSM can inhibit Th17 differentiation by reciprocally controlling SOCS3, STAT3, and STAT5.

Oncostatin M-induced cardiomyocyte dedifferentiation regulates the progression of diabetic cardiomyopathy through B-Raf/Mek/Erk signaling pathway.

It has been reported that oncostatin M (OSM) could initiate cardiomyocyte dedifferentiation both in vivo and in vitro. OSM-induced cardiomyocyte dedifferentiation might be a new target for the treatment of diabetic cardiomyopathy (DCM). This study was designed to determine the role of OSM in cardiomyocyte dedifferentiation and the progression of DCM. A mouse DCM model was established to evaluate the effects of OSM in vivo. Echocardiography was applied to determine cardiac function. Sirius red staining was used to detect fibrosis area. Transmission electron microscopy was used to evaluate mitochondria impairment. Real-time polymerase chain reaction and western blot analysis were performed to detect relative mRNA expressions and cardiomyocyte dedifferentiation-related protein expressions, respectively. OSM treatment induced similar impaired cardiac function and cardiac ultrastructure impairment to those detected in DCM mice. The expressions of dedifferentiation markers of cardiomyocyte (Runx1, and α-SM-actin) were up-regulated in the OSM-treated mice compared with those in the control group. To further demonstrate the important role of OSM, OSM receptor knockout (Oß(ko)) mice were used. In Oß(ko) mice, cardiomyocytes dedifferentiation markers of c-kit, Runx1, and atrial natriuretic peptide were down-regulated, with attenuated DCM injury and abrogated OSM/B-Raf/Mek/Erk signaling pathway. In conclusion, OSM-induced cardiomyocyte dedifferentiation plays a crucial role in the progression of DCM. The mechanism of OSM-induced cardiomyocyte dedifferentiation is associated with B-Raf/Mek/Erk signaling pathway through the OSM receptor Oß.

Integrated genome-wide analysis of genomic changes and gene regulation in human adrenocortical tissue samples.

To gain insight into the pathogenesis of adrenocortical carcinoma (ACC) and whether there is progression from normal-to-adenoma-to-carcinoma, we performed genome-wide gene expression, gene methylation, microRNA expression and comparative genomic hybridization (CGH) analysis in human adrenocortical tissue (normal, adrenocortical adenomas and ACC) samples. A pairwise comparison of normal, adrenocortical adenomas and ACC gene expression profiles with more than four-fold expression differences and an adjusted P-value < 0.05 revealed no major differences in normal versus adrenocortical adenoma whereas there are 808 and 1085, respectively, dysregulated genes between ACC versus adrenocortical adenoma and ACC versus normal. The majority of the dysregulated genes in ACC were downregulated. By integrating the CGH, gene methylation and expression profiles of potential miRNAs with the gene expression of dysregulated genes, we found that there are higher alterations in ACC versus normal compared to ACC versus adrenocortical adenoma. Importantly, we identified several novel molecular pathways that are associated with dysregulated genes and further experimentally validated that oncostatin m signaling induces caspase 3 dependent apoptosis and suppresses cell proliferation. Finally, we propose that there is higher number of genomic changes from normal-to-adenoma-to-carcinoma and identified oncostatin m signaling as a plausible druggable pathway for therapeutics.

Role of cytokines and chemokines in itch.

Cytokines classically are secreted "messenger" proteins that modulate cellular function of immune cells. Chemokines attract immune cells to the site where they exert various functions in inflammation, autoimmunity or cancer. Increasing evidence is emerging that cytokines or chemokines can act as "neuro-modulators" by activating high-affinity receptors on peripheral or central neurons, microglia cells or Schwann cells. Very recently, cytokines have been shown to act as pruritogens in rodents and humans, while a role of chemokines in itch has thus far been only demonstrated in mice. Upon stimulation, cytokines are released by skin or immune cells and form a "bridge of communication" between the immune and nervous system. For some cytokines such as IL-31 and TSLP, the evidence for this role is strong in rodents. For cytokines such as IL-4, there is some convincing evidence, while for cytokines such as oncostatin M, IL-2, IL-6, IL-8 and IL-13, direct evidence is currently limited. Current clinical trials support the idea that cytokines and chemokines and their receptors or signalling pathways are promising targets for the future therapy of certain subtypes of itch.

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.

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.

Novel function of Oncostatin M as a potent tumour-promoting agent in lung.

Oncostatin M is a leukocyte product that has been reported to have anti-proliferative effects directly on melanoma and other cancer cell lines in vitro. However, its function(s) in cancers in vivo appears complex and its roles in cancer growth in lungs are unknown. Here, we show that OSM promotes marked growth of tumour cells in mouse lungs. Local pulmonary administration of adenovirus vector expressing mouse OSM (AdOSM) induced >13-fold increase in lung tumour burden of ectopically delivered B16-F10 melanoma cells in C57BL/6 mice. AdOSM caused increases in tumour size (14 days post-challenge), whereas control vector (Addel70) did not. AdOSM had no such action in C57BL/6 mice deficient in the OSM receptor beta chain (OSMRß-/-), indicating that these effects required OSMRß expression on non-tumour cells in the recipient mice. AdOSM induced elevated levels of chemokines and inflammatory cells in the bronchoalveolar lavage (BAL) fluid, elevated arginase-1 mRNA levels (60-fold), and increased arginase-1+immunostaining macrophage numbers in lungs. Adherent BAL cells collected from AdOSM-treated mice expressed elevated arginase-1 activity. In contrast to AdOSM-induced effects, pulmonary over-expression of IL-1ß (AdIL-1ß) induced neutrophil accumulation and iNOS mRNA, but did not modulate tumour burden. AdOSM also increased lung tumour load (>50-fold) upon ectopic administration of Lewis lung carcinoma (LLC) cells in vivo. However, in vitro, neither recombinant OSM nor AdOSM infection stimulated B16-F10 or LLC cell growth directly. We conclude that pulmonary over-expression of OSM promotes tumour growth, and does so through altering the local lung environment with accumulation of M2 macrophages.

Characterization of the CD40L/Oncostatin M/Oncostatin M receptor axis as an antiviral and immunostimulatory system disrupted in chronic HCV infection.

BACKGROUND & AIMS: Oncostatin M (OSM) is an inflammatory cytokine which interacts with a heterodimeric receptor formed by gp130 and either OSMRß or LIFR. Here we have analysed OSM and its receptors in livers with chronic hepatitis C (CHC) and studied the factors that regulate this system. METHODS: OSM, OSM receptors and OSM-target molecules were studied by immunohistochemistry and/or qPCR analysis in livers from CHC patients and controls. We determined the production of OSM by CD40L-stimulated antigen presenting cells (APC) and its biological effects on HuH7 cells containing HCV replicon (HuH7 Core-3'). RESULTS: OSM was upregulated in livers with CHC and its production was mapped to CD11c+ cells. OSM levels correlated directly with inflammatory activity and CD40L expression. In vitro studies showed that OSM is released by APC upon interaction with activated CD4+ T cells in a CD40L-dependent manner. Culture of HuH7 Core-3' cells with supernatant from CD40L-stimulated APC repressed HCV replication and induced IL-7 and IL-15Rα. These effects were dampened by antibodies blocking OSM or gp130 and by silencing OSMRß. In CHC livers OSMRß and LIFR were significantly downregulated and their values correlated with those of OSM-induced molecules. Experiments in HuH7 cells showed that impaired STAT3 signaling and exposure to TGFß1, two findings in CHC, are factors involved in repressing OSMRß and LIFR, respectively. CONCLUSIONS: OSM is a cytokine possessing vigorous antiviral and immunostimulatory properties which is released by APC upon interaction with CD40L present on activated CD4+ T cells. In livers with CHC, OSM is overexpressed but its biological activity appears to be hampered because of downregulation of its receptor subunits.

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.

Monocytes induce STAT3 activation in human mesenchymal stem cells to promote osteoblast formation.

A major therapeutic challenge is how to replace bone once it is lost. Bone loss is a characteristic of chronic inflammatory and degenerative diseases such as rheumatoid arthritis and osteoporosis. Cells and cytokines of the immune system are known to regulate bone turnover by controlling the differentiation and activity of osteoclasts, the bone resorbing cells. However, less is known about the regulation of osteoblasts (OB), the bone forming cells. This study aimed to investigate whether immune cells also regulate OB differentiation. Using in vitro cell cultures of human bone marrow-derived mesenchymal stem cells (MSC), it was shown that monocytes/macrophages potently induced MSC differentiation into OBs. This was evident by increased alkaline phosphatase (ALP) after 7 days and the formation of mineralised bone nodules at 21 days. This monocyte-induced osteogenic effect was mediated by cell contact with MSCs leading to the production of soluble factor(s) by the monocytes. As a consequence of these interactions we observed a rapid activation of STAT3 in the MSCs. Gene profiling of STAT3 constitutively active (STAT3C) infected MSCs using Illumina whole human genome arrays showed that Runx2 and ALP were up-regulated whilst DKK1 was down-regulated in response to STAT3 signalling. STAT3C also led to the up-regulation of the oncostatin M (OSM) and LIF receptors. In the co-cultures, OSM that was produced by monocytes activated STAT3 in MSCs, and neutralising antibodies to OSM reduced ALP by 50%. These data indicate that OSM, in conjunction with other mediators, can drive MSC differentiation into OB. This study establishes a role for monocyte/macrophages as critical regulators of osteogenic differentiation via OSM production and the induction of STAT3 signalling in MSCs. Inducing the local activation of STAT3 in bone cells may be a valuable tool to increase bone formation in osteoporosis and arthritis, and in localised bone remodelling during fracture repair.

c-MYC functions as a molecular switch to alter the response of human mammary epithelial cells to oncostatin M.

Cytokines play an important role in creating an inflammatory microenvironment, which is now considered a hallmark of cancer. Although tumor cells can exploit cytokine signaling to promote growth, invasion, and metastasis, the response of normal and premalignant epithelial cells to cytokines present in a developing tumor microenvironment remains unclear. Oncostatin M (OSM), an IL-6 family cytokine responsible for STAT3 activation, has been implicated in cancer development, progression, invasion, and metastasis. Paradoxically, OSM can also suppress the growth of normal cells and certain tumor-derived cell lines. Using isogenic human mammary epithelial cells (HMEC) at different stages of neoplastic transformation, we found that OSM signaling suppressed c-MYC expression and engaged a p16- and p53-independent growth arrest that required STAT3 activity. Inhibition of STAT3 activation by expressing a dominant-negative STAT3 protein or a STAT3-shRNA prevented the OSM-mediated arrest. In addition, expression of c-MYC from a constitutive promoter also abrogated the STAT3-mediated arrest, and strikingly, cooperated with OSM to promote anchorage-independent growth (AIG), a property associated with malignant transformation. Cooperative transformation by c-MYC and OSM required PI3K and AKT signaling, showing the importance of multiple signaling pathways downstream of the OSM receptor in defining the cellular response to cytokines. These findings identify c-MYC as an important molecular switch that alters the cellular response to OSM-mediated signaling from tumor suppressive to tumor promoting.

Oncostatin M promotes proliferation of ovarian cancer cells through signal transducer and activator of transcription 3.

Oncostatin M (OSM), a pleiotropic cytokine, has been shown to have distinctive effects in different tissues. In ovarian carcinoma, it is commonly co-expressed together with its receptors but its precise role and the underlying molecular mechanism governing its activity remains unclear. The aim of the present study was to investigate the function of the recombinant human OSM (rH-OSM) in human ovarian cancer. The study demonstrated that rH-OSM promotes the proliferation of SKOV3 ovarian cancer cells. Western blot analysis showed that phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), phosphorylated-extracellular signal-regulated protein kinase 1/2 (p-ERK1/2) and p-p38 protein levels increased in the cell lines treated with rH-OSM. Proliferation in SKOV3 cells induced by rH-OSM was suppressed by inhibitors of p-p38 or p-ERK1/2. Western blot analysis showed that p-STAT3 protein levels decreased in SKOV3 cells treated with inhibitors of p-p38 prior to treatment with rH-OSM. Also, p-STAT3 levels did not increase in cells treated with inhibitors of ERK1/2 prior to treatment with rH-OSM. Cell proliferation was moderately increased, and p-ERK1/2 and p-p38 protein expression were similarly affected in STAT3-RNAi knocked-down SKOV3 cells treated with rH-OSM compared to the control group. The data demonstrate that the growth-promoting activity of rH-OSM may be mediated through different signaling pathways. ERK1/2 and p38 proteins regulate STAT3 expression in SKOV3 cells, while STAT3 may be pivotal to the proliferation of SKOV3 cells in vitro.