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-1 beta enhanced OSM- induced VEGF release. OSM increased VEGF mRNA expression and VEGF promoter activity, whereas IL-1 beta had no effect. IL-1 beta did not augment the effects of OSM on VEGF promoter activity but did augment OSM- induced VEGF mRNA expression and mRNA stability. The STAT3 inhibitor piceatannol decreased both OSM- induced VEGF release and synergy between OSM and IL-1 beta, without affecting responses to IL-1 beta alone. Piceatannol also inhibited OSM- induced VEGF mRNA expression. In contrast, inhibitors of MAPK pathway had no effect on OSM or OSM plus IL-1 beta-induced VEGF release. OSM increased type 1 IL-1 receptor (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-1 beta-induced VEGF, MCP-1, and IL-6 release. In summary, our data indicate OSM causes VEGF expression in HASM cells by a transcriptional mechanism involving STAT3. IL-1 beta also synergizes with OSM to increase VEGF release, likely as a result of effects of IL-1 beta 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 airway disease.