Placental cytokines and the pathogenesis of preeclampsia

K P Conrad, D F Benyo
American Journal of Reproductive Immunology: AJRI 1997, 37 (3): 240-9
The authors explore the hypothesis that tumor necrosis factor-alpha (TNF-alpha) and possibly other inflammatory cytokines are overproduced by the placenta in response to local ischemia/hypoxia contributing to increased plasma levels, and subsequent endothelial activation and dysfunction in the pregnancy disorder, preeclampsia. It is widely held that inadequate trophoblast invasion and physiologic remodeling of spiral arteries initiate placental ischemia/hypoxia in preeclampsia. Furthermore, focal areas of placental hypoxia have been implicated in the production of "toxic" factor(s) by the placenta, which circulate and cause maternal disease. Placental trophoblast cells and fetoplacental macrophages normally produce TNF-alpha and interleukin-1 (IL-1), which are capable of producing endothelial cell activation and dysfunction. Hypoxia has recently been reported to increase TNF-alpha and IL-1 production by term villous explants from the human placenta. Placental cells also express erythropoietin (EPO), which is the prototype molecule for transcriptional regulation by hypoxia in mammals. Interestingly, TNF-alpha and IL-1 have DNA sequence homologous or nearly homologous to the hypoxia-responsive enhancer element of the EPO gene, thus providing a potential, but as of yet, untested molecular link between placental hypoxia and stimulation of cytokine production. Inflammatory cytokines 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 evaluate the hypothesis that placental cytokines contribute to the pathogenesis of preeclampsia. Of note, the etiology of the disease presumably related to deficient trophoblast invasion is beyond the scope of this work.

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