Oncostatin M: Risks and Benefits of a Novel Therapeutic Target for Atherosclerosis.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of death worldwide. It is predicted that approximately 23.6 million people will die from CVDs annually by 2030. Therefore, there is a great need for an effective therapeutic approach to combat this disease. The European Cardiovascular Target Discovery (CarTarDis) consortium identified Oncostatin M (OSM) as a potential therapeutic target for atherosclerosis. The benefits of modulating OSM - an interleukin (IL)-6 family cytokine - have since been studied for multiple indications. However, as decades of high attrition rates have stressed, the success of a drug target is determined by the fine balance between benefits and the risk of adverse events. Safety issues should therefore not be overlooked. OBJECTIVE: In this review, a risk/benefit analysis is performed on OSM inhibition in the context of atherosclerosis treatment. First, OSM signaling characteristics and its role in atherosclerosis are described. Next, an overview of in vitro, in vivo, and clinical findings relating to both the benefits and risks of modulating OSM in major organ systems is provided. Based on OSM's biological function and expression profile as well as drug intervention studies, safety concerns of inhibiting this target have been identified, assessed, and ranked for the target population. CONCLUSION: While OSM may be of therapeutic value in atherosclerosis, drug development should also focus on de-risking the herein identified major safety concerns: tissue remodeling, angiogenesis, bleeding, anemia, and NMDA- and glutamate-induced neurotoxicity. Close monitoring and/or exclusion of patients with various comorbidities may be required for optimal therapeutic benefit.

Serum oncostatin M predicts mucosal healing in patients with inflammatory bowel diseases treated with anti-TNF, but not vedolizumab.

BACKGROUND: Oncostatin M was recently highlighted as a promising biomarker for therapeutic effectiveness in inflammatory bowel diseases (IBD), with particular regard for infliximab. The primary aim was to evaluate the ability of serum oncostatin M to predict endoscopic response to different drugs in IBD. METHODS: We selected two different cohorts of patients with IBD, treated with anti-TNF (infliximab and adalimumab) or with vedolizumab. Therapeutic response was evaluated at week 54 in terms of mucosal healing. Serum oncostatin M and C-reactive protein were measured at baseline; fecal calprotectin was measured at baseline and after 14 weeks of treatment. We evaluated the association of these biomarkers with mucosal healing at week 54. RESULTS: Among 66 patients treated with anti-TNFs and 68 treated with vedolizumab, 35 and 31 attained mucosal healing, respectively. Mucosal healing at 54 weeks was significantly associated with low oncostatin M levels at baseline in the anti-TNF cohort; the diagnostic accuracy of oncostatin M at baseline in predicting mucosal healing was 0.91 (95% CI 0.84 to 0.99) in the anti-TNF cohort and 0.56 (95% CI 0.43 to 0.70, P < 0.001) in the vedolizumab cohort. Mucosal healing was also associated with low fecal calprotectin levels at week 14 in both cohorts. CONCLUSION: Our study suggests that serum oncostatin M is a drug-specific biomarker, since it could be used to predict therapeutic effectiveness to anti-TNFs but not to vedolizumab. Moreover, these results emphasize the utility of serum oncostatin M measurement in patients treated with anti-TNF.

Association between Oncostatin M Expression and Inflammatory Phenotype in Experimental Arthritis Models and Osteoarthritis Patients.

Pro-inflammatory cytokines are considered to play a major role in osteoarthritis (OA), yet so far, the specific cytokines involved in the pathology of OA have not been identified. Oncostatin M (OSM) is a cytokine from the interleukin 6 (IL-6) family that has been shown to be elevated in synovial fluid of most rheumatoid arthritis (RA) patients, but only in a limited subset of OA patients. Little is known about OSM in the different joint tissues during OA and how its expression correlates with hallmarks of disease. Here, we mapped OSM expression in the joint tissues of two rat models of arthritis: an acute inflammatory model and an instability-induced osteoarthritic model. OSM expression was correlated with hallmarks of OA, namely cartilage damage, synovitis, and osteophyte formation. Reanalysis of an existing dataset on cytokine profiling of OA synovial fluid was performed to assess pattern differences between patients positive and negative for OSM. In the inflammatory model, OSM expression correlated with synovitis and osteophyte formation but not with cartilage damage. On the contrary, in the instability model of OA, an increase in synovitis, cartilage damage, and osteophyte formation was observed without changes in OSM expression. In line with these findings, synovial fluid of OA patients with detectable OSM contained higher levels of other inflammatory cytokines, namely interferon gamma (IFN-γ), IL-1α and tumor necrosis factor alpha (TNF-α), likely indicating a more inflammatory state. Taken together these data indicate OSM might play a prominent role in inflammatory phenotypes of OA.

Oncostatin M: A mysterious cytokine in cancers.

Oncostatin M (OSM), as a member of the Interleukin-6 family cytokines, plays a significant role in inflammation, autoimmunity, and cancers. It is mainly secreted by T lymphocytes, neutrophils, and macrophages and was initially introduced as anti-cancer agent. However, in some cases, it promotes cancer progression. Overexpression of OSM and OSM receptor has been detected in various cancers including colon cancer, breast cancer, pancreatic cancer, myeloma, brain tumors, chronic lymphocytic leukemia, and hepatoblastoma. STAT3 is the main downstream signaling molecule of OSM, which operates the leading role in modifications of cancer cells and enhancing cell growth, invasion, survival, and all other hallmarks of cancer cells. However, due to the presence of multiple signaling pathways, it can act contradictory in some cancers. In this review, we will discuss the emerging roles of OSM in cancer and elucidate its function in tumor control or progression and finally discuss therapeutic approaches designed to manipulate this cytokine in cancer.

Oncostatin M Plays a Critical Role in Survival after Acute Intestinal Ischemia: Reperfusion Injury.

Background: Acute intestinal ischemia-reperfusion injury (AIIRI) is a devastating clinical condition relevant to multiple diseases processes, including sepsis, trauma, transplantation, and burns. An AIIRI is a contributor to the development of multiple organ dysfunction syndrome (MODS). Oncostatin M (OSM)/oncostatin M receptor (OSMR) signaling is an unrecognized and novel candidate pathway for the mediation of MODS. In this study, we hypothesized that OSM mediates the injury mechanism of AIIRI leading to MODS. Methods: Wild-type (WT) and OSMR-knockout (OSMR-/-) C57BL/6 mice underwent AIIRI using a well-established model of selective occlusion of the superior mesenteric artery (SMA). Serum cytokine concentrations were measured using a multiplex detection system. Further tissue analysis was conducted with polymerase chain reaction, enzyme-linked immunosorbent assay, Western blots, and histologic review. Results: Survival was significantly higher in WT than in OSMR-/- groups at 30 minutes of ischemia with 2 hours of reperfusion (100% versus 42.9%; P = 0.015). No significant differences in the degree of local intestinal injury was seen in the two groups. In contrast, the degree of lung injury, as evidenced by myeloperixodase activity, was lower in OSMR-/- animals in the early AIIRI groups. There was a greater degree of renal dysfunction in OSMR-/- mice. Oncostatin M mediated interleukin (IL)-10 upregulation, with WT animals having significantly lower IL-10 concentrations (52.04 ± 23.06 pg/mL versus 324.37 ± 140.35 pg/mL; P = 0.046). Conclusion: Oncostatin M signalling is essential during acute intestinal ischemia-reperfusion injury. An OSMR deficiency results in decreased early lung injury but increased renal dysfunction. There was a significantly increased mortality rate after AIIRI in mice with OSMR deficiency. Augmentation of OSM may be a novel immunomodulatory strategy for AIIRI.

Oncostatin M-induced upregulation of SDF-1 improves Bone marrow stromal cell migration in a rat middle cerebral artery occlusion stroke model.

Bone marrow-derived mesenchymal stem cells (BMSCs) exhibit potential regenerative effects on the injured brain. However, these effects are constrained by their limited ability to migrate to the injured site. Oncostatin M (OSM) has been shown to affect the proliferation and migration of mesenchymal stem cells. Therefore, in the present study, we explored whether OSM improves BMSC migration and secretion of growth factors and cytokines in a rat middle cerebral artery occlusion (MCAO) stroke model. The effect of OSM on the proliferation and apoptosis of rat BMSCs was first assessed in vitro, and the gene and secretion levels of factors related to cell nutrition and migration, such as SDF-1 and VEGF, were detected. To further explore underlying pathways triggered by OSM, BMSCs were treated with OSM in the presence or absence of inhibitors of the STAT3 and ERK pathways. Effects of OSM on SDF-1 expression in astrocytes and BMSC migration were also evaluated. In the rat MCAO model, OSM secretion levels were detected in the brain for up to 72 h after model establishment. Ventricle injection of OSM alone or OSM combined with caudal vein graft of BMSCs was then performed in MCAO stroke rats. After 72 h, production of SDF-1 and grafted BMSCs was detected in the lesion areas of the brain, and the nerve function score was evaluated. We found that the production of OSM continually increased in the brains of MCAO rats from 12 h to 72 h. OSM significantly upregulated SDF-1 in BMSCs via the STAT3 and ERK pathways and significantly promoted the expression of VEGF and MMP-2. OSM also promoted the secretion of SDF-1 in astrocytes through the STAT3 and ERK pathways to in turn enhance BMSC migration. Combination treatment with OSM and BMSCs in MCAO rats increased the migration efficiency of BMSCs in the brain, which significantly improved neurofunctional recovery while reducing the expression of inflammatory mediators and promoting the secretion of nutrition factors. Overall, these results show that OSM is highly expressed in the brains of MCAO stroke rats and can upregulate SDF-1 to promote BMSC migration. Thus, combination treatment with OSM and BMSCs improves the graft efficiency of BMSCs and neurofunctional recovery.

Oncostatin M: Potential Implications for Malignancy and Metabolism.

BACKGROUND: 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. CONCLUSION: 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.

The barrier hypothesis and Oncostatin M: Restoration of epithelial barrier function as a novel therapeutic strategy for the treatment of type 2 inflammatory disease.

Mucosal epithelium maintains tissue homeostasis through many processes, including epithelial barrier function, which separates the environment from the tissue. The barrier hypothesis of type 2 inflammatory disease postulates that epithelial and epidermal barrier dysfunction, which cause inappropriate exposure to the environment, can result in allergic sensitization and development of type 2 inflammatory disease. The restoration of barrier dysfunction once it's lost, or the prevention of barrier dysfunction, have the potential to be exciting new therapeutic strategies for the treatment of type 2 inflammatory disease. Neutrophil-derived Oncostatin M has been shown to be a potent disrupter of epithelial barrier function through the induction of epithelial-mesenchymal transition (EMT). This review will discuss these events and outline several points along this axis at which therapeutic intervention could be beneficial for the treatment of type 2 inflammatory diseases.

Influence of different body positions in vital capacity in patients on postoperative upper abdominal / Influência de diferentes posições corporais na capacidade vital em pacientes no pós-operatório abdominal superior / Influencia de diferentes posiciones corporales en la capacidad vital en pacientes en el postoperatorio abdominal superior

RATIONALE: The changes in body position can cause changes in lung function, and it is necessary to understand them, especially in the postoperative upper abdominal surgery, since these patients are susceptible to postoperative pulmonary complications. OBJECTIVE: To assess the vital capacity in the supine position (head at 0° and 45°), sitting and standing positions in patients in the postoperative upper abdominal surgery. METHODS: A cross-sectional study conducted between August 2008 and January 2009 in a hospital in Salvador/BA. The instrument used to measure vital capacity was analogic spirometer, the choice of the sequence of positions followed a random order obtained from the draw of the four positions. Secondary data were collected from the medical records of each patient. RESULTS: The sample consisted of 30 subjects with a mean age of 45.2 ± 11.2 years, BMI 20.2 ± 1.0 kg/m2. The position on orthostasis showed higher values of vital capacity regarding standing (mean change: 0.15 ± 0.03 L; p = 0.001), the supine to 45 (average difference: 0.32 ± 0.04 L; p = 0.001) and 0° (0.50 ± 0.05 L; p = 0.001). There was a positive trend between the values of forced vital capacity supine to upright posture (1.68 ± 0.47; 1.86 ± 0.48; 2.02 ± 0.48 and 2.18 ± 0.52 L; respectively). CONCLUSION: Body position affects the values of vital capacity in patients in the postoperative upper abdominal surgery, increasing in postures where the chest is vertical. .

JUSTIFICATIVA: As alterações no posicionamento corporal podem ocasionar mudanças na função respiratória e é necessário compreendê-las, principalmente no pós-operatório abdominal superior, já que os pacientes estão suscetíveis a complicações pulmonares pós-operatórias. OBJETIVO: Verificar a capacidade vital nas posições de decúbito dorsal (cabeceira a 0° e 45°), sentado e em ortostase em pacientes no pós-operatório de cirurgia abdominal superior. MÉTODOS: Estudo transversal, feito entre agosto de 2008 e janeiro de 2009, em um hospital na cidade de Salvador (BA). O instrumento usado para mensuração da capacidade vital (CV) foi o ventilômetro analógico e a escolha da sequência das posições seguiu uma ordem aleatória obtida a partir de sorteio das quatro posições. Os dados secundários foram colhidos nos prontuários de cada paciente. RESULTADOS: A amostra foi composta por 30 indivíduos com idade média de 45,2 ± 11,2 anos e IMC 20,2 ± 1,0 kg/m2. A posição em ortostase apresentou valores maiores da CV em relação à sedestração (média das diferenças: 0,15 ± 0,03 litros; p = 0,001), ao decúbito dorsal a 45° (média das diferenças: 0,32 ± 0,04 litros; p = 0,001) e 0° (0,50 ± 0,05 litros; p = 0,001). Houve um aumento positivo entre os valores de CVF do decúbito dorsal para a postura ortostática (1,68 ± 0,47; 1,86 ± 0,48; 2,02 ± 0,48 e 2,18 ± 0,52 litros; respectivamente). CONCLUSÃO: A posição do corpo afeta os valores da CV em pacientes no pós-operatório de cirurgia abdominal superior, com aumento nas posturas em que o tórax encontra-se verticalizado. .

JUSTIFICACIÓN: Las alteraciones en el posicionamiento corporal pueden ocasionar cambios en la función respiratoria y es necesario comprenderlas, principalmente en el postoperatorio abdominal superior, ya que los pacientes son susceptibles a complicaciones pulmonares postoperatorias. OBJETIVO: Verificar la capacidad vital en las posiciones de decúbito dorsal (cabeza a 0° y 45°), sentado y en ortostasis en pacientes en el postoperatorio de cirugía abdominal superior. MÉTODOS: Estudio transversal realizado entre agosto de 2008 y enero de 2009, en un hospital en la ciudad de Salvador (BA). El instrumento usado para la medición de la capacidad vital (CV) fue el espirómetro analógico y la elección de la secuencia de las posiciones siguió un orden aleatorio que se obtuvo a partir de un sorteo de las 4 posiciones. Los datos secundarios fueron extraídos de las historias clínicas de cada paciente. RESULTADOS: La muestra se compuso de 30 individuos con edades medias de 45,2 ± 11,2 años e IMC de 20,2 ± 1 kg/m2. La posición en ortostasis presentó valores mayores de CV con relación a la posición sedente (media de las diferencias: 0,15 ± 0,03 L; p = 0,001), al decúbito dorsal a 45° (media de las diferencias: 0,32 ± 0,04 L; p = 0,001) y a 0° (0,50 ± 0,05 L; p = 0,001). Hubo un aumento positivo entre los valores de CV forzada del decúbito dorsal para la postura ortostática (1,68 ± 0,47; 1,86 ± 0,48; 2,02 ± 0,48 y 2,18 ± 0,52 L, respectivamente). CONCLUSIÓN: La posición del cuerpo afecta los valores de la CV en pacientes durante el postoperatorio de cirugía abdominal superior, con aumento en las posturas en las que el tórax está verticalizado. .

Oncostatin M is a potential agent for the treatment of obesity and related metabolic disorders: a study in mice.

AIMS/HYPOTHESIS: Obesity and insulin resistance are closely associated with adipose tissue dysfunction caused by the abnormal recruitment of inflammatory cells, including macrophages. Oncostatin M (OSM), a member of the IL-6 family of cytokines, plays important roles in a variety of biological functions including the regulation of inflammatory responses. In previous reports, we have demonstrated that mice deficient in the OSM receptor ß subunit show obesity, adipose tissue inflammation, insulin resistance and hepatic steatosis, all of which are exacerbated by feeding the mice a high-fat diet. These results prompted us to test the therapeutic effects of OSM on obesity-induced metabolic disorders using mouse models of obesity. METHODS: In diet-induced obese and ob/ob mice, metabolic variables were assessed physiologically, histologically and biochemically after the intraperitoneal injection of recombinant mouse OSM twice a day for 1 week. RESULTS: Treatment with OSM improved obesity, adipose tissue inflammation, insulin resistance and hepatic steatosis in both mouse models. Although OSM reduced food intake, such therapeutic effects of OSM were observed even under pair-feeding conditions. Functionally, OSM directly changed the phenotype of adipose tissue macrophages from M1 type (inflammatory) to M2 type (anti-inflammatory). In the liver, OSM suppressed the expression of genes related to fatty acid synthesis and increased the expression of genes related to fatty acid oxidation. Furthermore, OSM decreased lipid absorption and increased the expression of active glucagon-like peptide-1 in the intestine. CONCLUSIONS/INTERPRETATION: We showed that OSM is a novel candidate to act as a powerful therapeutic agent for the treatment of obesity-induced metabolic disorders.

Oncostatin M reduces lesion size and promotes functional recovery and neurite outgrowth after spinal cord injury.

The family of interleukin (IL)-6 like cytokines plays an important role in the neuroinflammatory response to injury by regulating both neural as well as immune responses. Here, we show that expression of the IL-6 family member oncostatin M (OSM) and its receptor is upregulated after spinal cord injury (SCI). To reveal the relevance of increased OSM signaling in the pathophysiology of SCI, OSM was applied locally after spinal cord hemisection in mice. OSM treatment significantly improved locomotor recovery after mild and severe SCI. Improved recovery in OSM-treated mice was associated with a reduced lesion size. OSM significantly diminished astrogliosis and immune cell infiltration. Thus, OSM limits secondary damage after CNS trauma. In vitro viability assays demonstrated that OSM protects primary neurons in culture from cell death, suggesting that the underlying mechanism involves direct neuroprotective effects of OSM. Furthermore, OSM dose-dependently promoted neurite outgrowth in cultured neurons, indicating that the cytokine plays an additional role in CNS repair. Indeed, our in vivo experiments demonstrate that OSM treatment increases plasticity of serotonergic fibers after SCI. Together, our data show that OSM is produced at the lesion site, where it protects the CNS from further damage and promotes recovery.

Experimental studies on the inhibition of adenovirus-ING4-OSM therapy on nasopharyngeal carcinoma proliferation in vitro and in vivo.

In the present study, the effects of the co-transfer of the tumor growth inhibitor 4 gene (ING4) together with the Oncostatin M (OSM) were investigated on tumor regression and subsequent tumor recurrence. We constructed a recombinant adenovirus carrying ING4 and OSM, which could induce high-level expression of these three genes in NPC CNE-1 cells. Ad-ING4, Ad-OSM and Ad-ING4-OSM infection all inhibited the growth of CNE-1 cells in vitro, while the Ad-ING4-OSM exerted the strongest inhibitory effect. In CNE-1 xenograft tumor models mice, an intratumoral injection of Ad-ING4, Ad-OSM and Ad-ING4-OSM resulted in a reduced tumor burden, compared to normal saline controls. Therefore, we suggested that the introduction of adenovirus-mediated ING4 and OSM genes could synergistically decrease the recurrence or metastases and develop a control of NPC tumors, which advocate a promising therapeutic future in NPC treatment.

A computer simulation approach to assessing therapeutic intervention points for the prevention of cytokine-induced cartilage breakdown.

OBJECTIVE: To use a novel computational approach to examine the molecular pathways involved in cartilage breakdown and to use computer simulation to test possible interventions for reducing collagen release. METHODS: We constructed a computational model of the relevant molecular pathways using the Systems Biology Markup Language, a computer-readable format of a biochemical network. The model was constructed using our experimental data showing that interleukin-1 (IL-1) and oncostatin M (OSM) act synergistically to up-regulate collagenase protein levels and activity and initiate cartilage collagen breakdown. Simulations were performed using the COPASI software package. RESULTS: The model predicted that simulated inhibition of JNK or p38 MAPK, and overexpression of tissue inhibitor of metalloproteinases 3 (TIMP-3) led to a reduction in collagen release. Overexpression of TIMP-1 was much less effective than that of TIMP-3 and led to a delay, rather than a reduction, in collagen release. Simulated interventions of receptor antagonists and inhibition of JAK-1, the first kinase in the OSM pathway, were ineffective. So, importantly, the model predicts that it is more effective to intervene at targets that are downstream, such as the JNK pathway, rather than those that are close to the cytokine signal. In vitro experiments confirmed the effectiveness of JNK inhibition. CONCLUSION: Our study shows the value of computer modeling as a tool for examining possible interventions by which to reduce cartilage collagen breakdown. The model predicts that interventions that either prevent transcription or inhibit the activity of collagenases are promising strategies and should be investigated further in an experimental setting.

Prostaglandin E2 induces oncostatin M expression in human chronic wound macrophages through Axl receptor tyrosine kinase pathway.

Monocytes and macrophages (m) are plastic cells whose functions are governed by microenvironmental cues. Wound fluid bathing the wound tissue reflects the wound microenvironment. Current literature on wound inflammation is primarily based on the study of blood monocyte-derived macrophages, cells that have never been exposed to the wound microenvironment. We sought to compare pair-matched monocyte-derived macrophages with m isolated from chronic wounds of patients. Oncostatin M (OSM) was differentially overexpressed in pair-matched wound m. Both PGE2 and its metabolite 13,14-dihydro-15-keto-PGE2 (PGE-M) were abundant in wound fluid and induced OSM in wound-site m. Consistently, induction of OSM mRNA was observed in m isolated from PGE2-enriched polyvinyl alcohol sponges implanted in murine wounds. Treatment of human THP-1 cell-derived m with PGE2 or PGE-M caused dose-dependent induction of OSM. Characterization of the signal transduction pathways demonstrated the involvement of EP4 receptor and cAMP signaling. In human m, PGE2 phosphorylated Axl, a receptor tyrosine kinase (RTK). Axl phosphorylation was also induced by a cAMP analogue demonstrating interplay between the cAMP and RTK pathways. PGE2-dependent Axl phosphorylation led to AP-1 transactivation, which is directly implicated in inducible expression of OSM. Treatment of human m or mice excisional wounds with recombinant OSM resulted in an anti-inflammatory response as manifested by attenuated expression of endotoxin-induced TNF-α and IL-1ß. OSM treatment also improved wound closure during the early inflammatory phase of healing. In summary, this work recognizes PGE2 in the wound fluid as a potent inducer of m OSM, a cytokine with an anti-inflammatory role in cutaneous wound healing.

Relationship between responsiveness of cancer cells to Oncostatin M and/or IL-6 and survival of stage III melanoma patients treated with tumour-infiltrating lymphocytes.

Immunotherapy by adoptive transfer of autologous tumour-infiltrating lymphocytes (TIL) shows promising clinical results for stage III (lymph nodes metastasis) melanoma patients, but some of them remain unresponsive. Here we analysed retrospectively the impact of resistance of melanoma cells to anti-proliferative cytokines on the clinical outcome of 24 TIL-treated metastatic melanoma patients. Patient relapse-free survival correlated significantly with Oncostatin M (OSM) and/or IL-6 sensitivity of melanoma cells, but not with interferon (IFN) gamma or tumour necrosis factor (TNF) alpha sensitivity. However, OSM/IL-6 sensitivity did not correlate with other known prognostic factors. Moreover, OSM and IL-6 were produced by TIL just before their injection to patients. In immunodeficient mice, OSM reduced human melanoma xenograft tumour growth, this effect being directly through inhibition of tumour cell proliferation rather than induction of apoptosis or necrosis. Thus, OSM/IL-6 resistance of melanoma cells appears to be a new escape mechanism to TIL treatment that could be added to the existing prognostic factors for early stage melanoma patients. This mechanism of action could be also relevant in other immunotherapy protocols, and could lead to better prognosis and anti-cancer treatments.

Oncostatin M gene therapy attenuates liver damage induced by dimethylnitrosamine in rats.

To assess the usefulness of oncostatin M (osm) gene therapy in liver regeneration, we examined whether the introduction of OSM cDNA enhances the regeneration of livers damaged by dimethylnitrosamine (DMN) in rats. Repeated injection of OSM cDNA enclosed in hemagglutinating virus of Japan envelope into the spleen resulted in the exclusive expression of OSM protein in Kupffer cells of the liver, which was accompanied by increases in body weight, liver weight, and serum albumin levels and the reduction of serum liver injury parameters (bilirubin, aspartate aminotransferase, and alanine aminotransferase) and a serum fibrosis parameter (hyaluronic acid). Histological examination showed that osm gene therapy reduced centrilobular necrosis and inflammatory cell infiltration and augmented hepatocyte proliferation. The apoptosis of hepatocytes and fibrosis were suppressed by osm gene therapy. Time-course studies on osm gene therapy before or after DMN treatment showed that this therapy was effective not only in enhancing regeneration of hepatocytes damaged by DMN but in preventing hepatic cytotoxicity caused by subsequent treatment with DMN. These results indicate that OSM is a key mediator for proliferation and anti-apoptosis of hepatocytes and suggest that osm gene therapy is useful, as preventive and curative means, for the treatment of patients with liver damage.

Oncostatin M is a neuroprotective cytokine that inhibits excitotoxic injury in vitro and in vivo.

Oncostatin M (OsM) is a member of the interleukin (IL)-6 family of cytokines and is well known for its role in inflammation, cell proliferation, and hematopoiesis. OsM, together with its glycoprotein 130 containing receptor complex, is expressed and regulated in most cells of the central nervous system (CNS), yet the function of OsM within this compartment is poorly understood. Here we have investigated the effect of OsM using in vitro and in vivo models of excitotoxic injury. Using primary cultures of mouse cortical neurons, OsM was shown to reduce N-methyl-D-aspartate (NMDA) -induced neuronal death by 50% when added simultaneously with NMDA while pretreatment of neurons with OsM fully prevented NMDA toxicity indicating a profound protective effect of this cytokine. OsM was also shown to inhibit NMDA-mediated increase in levels of free intracellular calcium and to selectively reduce neuronal expression of the NR2C subunit of the NMDA receptor. Finally, using an in vivo model of excitotoxic injury, OsM significantly reduced the NMDA-induced lesion volume when coinjected with NMDA into the mouse striatum. Taken together, these results identify OsM as a powerful neuroprotective cytokine and provide a rational foundation to explore the therapeutic potential for OsM in diseases of the CNS.