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Reproductive Endocrinology |
Magee-Womens Research Institute and the Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: Kirk P. Conrad, M.D., Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, Pennsylvania 15213.
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-
(TNF) 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, IL-6, and low
levels of IL-1 and IL-1ß under standard tissue culture conditions.
Hypoxia significantly increased TNF, IL-1, and IL-1ß 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 and IL-1ß 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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