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1 Physiology Program, Harvard School of Public Health, Boston, MA, USA; Laboratory of Respiration Physiology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
2 Physiology Program, Harvard School of Public Health, Boston, MA, USA
3 Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphhia, PA, USA
* To whom correspondence should be addressed. E-mail: sshore{at}hsph.harvard.edu.
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
enhanced OSM-induced VEGF release. OSM increased VEGF mRNA expression and VEGF promoter activity, whereas IL-1 had no effect. IL-1 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-1, without affecting responses to IL-1 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-1 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-1 induced VEGF, MCP-1, 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-1 also synergizes with OSM to increase VEGF release, likely as a result of effects of IL-1 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.
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