Oncostatin-M (OSM), a hematopoietic
cytokine, and
vascular endothelial growth factor (
VEGF), a quintessential angiogenic signal, are coexpressed in development,
cancer and
inflammation. Here, we report that OSM treatment of human
astroglioma cell lines increases
VEGF levels by approximately threefold.
Interleukin-1beta (IL-1beta), in combination with OSM, induces up to sevenfold higher
VEGF expression, without significantly inducing
VEGF on its own. Specifically examining the OSM contribution to
VEGF expression,
neutralizing antibodies to OSM receptor subunits gp130 and OSMRbeta, but not LIFRbeta, inhibited OSM induction of
VEGF, indicating that the OSM-specific receptor OSMRbeta/gp130 transduces the OSM signal for
VEGF synthesis. OSM induction of
VEGF promoter activity maps to the (-1171, -786) region of the
VEGF promoter, which contains a STAT-3-binding site. STAT-3 is indeed essential for this response, since overexpression of a dominant-negative STAT-3 blocks OSM induction of
VEGF promoter activity, as well as endogenous
VEGF expression. Finally, we demonstrate that OSM is expressed in
glioblastoma multiforme tumor biopsies, a particularly malignant form of
brain tumor. This novel mechanism of
VEGF regulation in
astroglioma cells may be active in pathophysiological states where both OSM and IL-1beta are present.