Oncostatin M Causes Vegf Release from Human Airway Smooth Muscle: Synergy with Il-1β

Vascular endothelial growth factor (VEGF), a potent angiogenesis factor, likely contributes to airway remodeling in asthma. We sought to examine the effects and mechanism of action of IL-6 family cytokines on VEGF release from human airway smooth muscle (HASM) cells. Oncostatin M (OSM), but not other IL-6 family cytokines, increased VEGF release and IL-1β enhanced OSM-induced VEGF release. OSM increased VEGF mRNA expression and VEGF promoter activity, whereas IL-1β had no effect. IL-1β did not augment the effects of OSM on VEGF promoter activity, but did augment OSM induced VEGF mRNA expression and mRNA stability. The STAT-3 inhibitor, piceatannol, decreased both OSM induced VEGF release and the synergy between OSM and IL-1β, without affecting responses to IL-1β alone. Piceatannol also inhibited OSM-induced VEGF mRNA expression. (Deleted sentence indicating role of COX-2). In contrast, inhibitors of the mitogen activated protein kinase pathway had no effect on OSM or OSM plus IL-1β induced VEGF release. OSM increased IL-1R1 mRNA expression, as measured by real time-PCR, and piceatannol attenuated this response. Consistent with the increase in IL-1R1 expression, OSM markedly augmented IL-1β induced VEGF, MCP1, and IL-6 release. In summary, our data indicate that OSM causes VEGF expression in HASM cells by a transcriptional mechanism involving STAT-3. IL-1β also synergizes with OSM to increase VEGF release, likely as a result of effects of IL-1β on VEGF mRNA stability as well as effects of OSM on IL-1R1 expression. This is the first description of a role for OSM on IL-1R1 expression in any cell type. OSM may contribute to airway remodeling observed in chronic airways disease.