HYPOXIA STIMULATES CYTOKINE PRODUCTION BY VILLOUS EXPLANTS FROM THE HUMAN PLACENTA

It has been hypothesized that inadequate placentation in the hypertens ive disorder of pregnancy known as preeclampsia creates foci of placen tal ischemia/hypoxia leading to the elaboration of factors that compro mise systemic endothelial function to produce disease sequelae. As tum or necrosis factor-alpha (TNF alpha) and interleukin-1 (IL-I) are infl ammatory cytokines capable of eliciting endothelial cell dysfunction. Re investigated whether the production of these inflammatory cytokines by cultured villous explants from the human placenta was affected by incubation in reduced oxygen (2% O-2). The term placenta produced TNF alpha, IL-6, and low levels of IL-1 alpha and IL-1 beta under standard tissue culture conditions. Hypoxia significantly increased TNF alpha, IL-1 alpha, and IL-1 beta production by 2-, 6-, and 23-fold, respecti vely, but did not affect IL-6 production. Further, cytokines were immu nolocalized to the syncytiotrophoblast layer as well as to some villou s core cells. Hypoxic regulation of placental TNF alpha and IL-1 beta production also appeared to differ based on gestational age. Finally, treatment with either cobalt chloride or an iron chelator mimicked the hypoxic response, suggesting that stimulation of placental cytokine p roduction may involve a heme-containing, O-2-sensing protein. These re sults suggest that placental hypoxia can lead to the elaboration of in flammatory cytokines, which may contribute to the pathophysiology of p reeclampsia.