Elevated levels of TNF-alpha and IL-6 may contribute to the putative endothelial dysfunction of preeclampsia.
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.
It has been hypothesized that inadequate placentation in the hypertensive disorder of pregnancy known as preeclampsia creates foci of placental ischemia/hypoxia leading to the elaboration of factors that compromise systemic endothelial function to produce disease sequelae. As tumor necrosis factor-alpha (TNF alpha) and interleukin-1 (IL-1) are inflammatory cytokines capable of eliciting endothelial cell dysfunction, we investigated whether the production of these inflammatory cytokines by cultured villous explants from the human placenta was affected by incubation in reduced oxygen (2% O2). The term placenta produced TNF alpha, IL-6, and low levels of IL-1alpha and IL-1beta under standard tissue culture conditions. Hypoxia significantly increased TNF alpha, IL-1alpha, and IL-1beta production by 2-, 6-, and 23-fold, respectively, but did not affect IL-6 production. Further, cytokines were immunolocalized to the syncytiotrophoblast layer as well as to some villous core cells. Hypoxic regulation of placental TNF alpha and IL-1beta 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 production may involve a heme-containing, O2-sensing protein. These results suggest that placental hypoxia can lead to the elaboration of inflammatory cytokines, which may contribute to the pathophysiology of preeclampsia.
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