Normoxic Induction of the Hypoxic-Inducible Factor-1(alpha) by Interleukin-1(beta) Involves the Extracellular Signal-Regulated Kinase 1/2 Pathway in Normal Human Cytotrophoblast Cells

During early pregnancy, an environment of relative low oxygen tension is essential for normal embryonic and placental vasculature. In low-oxygen conditions, the hypoxic-inducible factor-1 (HIF-1), composed of (alpha)and (beta) subunits, controls the expression of a number of genes such as vascular endothelial growth factor (VEGF), a key angiogenic factor. The recent studies in some tumor cells have found that the labile component, HIF-1(alpha), is not only activated by hypoxia but also by peptides such as interleukin-1 (IL-1) in normoxia. In this article, we demonstrated that exposure of normal human cytotrophoblast cells to IL-1(beta) stimulated the expression of HIF1(alpha) protein. Meanwhile, IL-1(beta) also induced the secretion of VEGF in normal human cytotrophoblast cells. Our data indicated that IL-1(beta) induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Moreover, treatment of cells with PD98059, an inhibitor of ERK1/2 signaling, inhibited the stimulation of HIF-1(alpha) protein expression and VEGF secretion by IL-1(beta). These data indicate that, in normal human cytotrophoblast cells, IL-1(beta) induces HIF- 1(alpha)-mediated VEGF secretion and that IL-1(beta)-stimulated ERK1/2 activation may be involved in this process.