PLACENTAL CYTOKINES AND THE PATHOGENESIS OF PREECLAMPSIA

The authors explore the hypothesis that tumor necrosis factor-alpha (T NF-alpha) and possibly other inflammatory cytokines are overproduced b y the placenta in response to local ischemia/hypoxia contributing to i ncreased plasma levels, and subsequent endothelial activation and dysf unction in the pregnancy disorder, preeclampsia. It is widely held tha t inadequate trophoblast invasion and physiologic remodeling of spiral arteries initiate placental ischemia/hypoxia in preeclampsia. Further more, focal areas of placental hypoxia have been implicated in the pro duction of ''toxic'' factor(s) by the placenta, which circulate and ca use maternal disease. Placental trophoblast cells and fetoplacental ma crophages normally produce TNF-alpha and interleukin-l (IL-1), which a re capable of producing endothelial cell activation and dysfunction. H ypoxia has recently been reported to increase TNF-alpha and IL-1 produ ction by term villous explants from the human placenta. Placental cell s also express erythropoietin (EPO), which is the prototype molecule f or transcriptional regulation by hypoxia in mammals. Interestingly, TN F-alpha and IL-1 have DNA sequences homologous or nearly homologous to the hypoxia-responsive enhancer element of the EPO gene, thus providi ng a potential, but as of yet, untested molecular link between placent al hypoxia and stimulation of cytokine production. Inflammatory cytoki nes overproduced by the placenta in response to hypoxia may then lead to increased plasma levels and endothelial activation and dysfunction in preeclampsia. The purpose of this short review is to critically eva luate the hypothesis that placental cytokines contribute to the pathog enesis of preeclampsia. Of note, the etiology of the disease presumabl y related to deficient trophoblast invasion is beyond the scope of thi s work.