Modulation of trophoblast function by tumor necrosis factor-alpha: a role in pregnancy establishment and maintenance?

Trophoblast differentiation is a critical process for successful implantation and establishment of the human placenta. The aim of this study was to characterize the effect of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) on the expression of markers of trophoblast function and differentiation.

Human cytotrophoblasts were stimulated with 1 and 10 ng/mL recombinant TNF-alpha or IL-6. Cell viability was determined and conditioned culture media was analyzed by gelatin zymography to assess protease secretion and by enzyme-linked immunosorbent assays to measure production of beta-human chorionic gonadotropin and oncofetal fibronectin.

TNF-alpha increased secretion of urokinase-type plasminogen activator up to 3-fold of basal unstimulated production. Stimulation of cytotrophoblasts with this cytokine also inhibited beta-human chorionic gonadotropin secretion up to 75%. TNF-alpha did not modify the secretion of matrix metalloproteinase-9 and oncofetal fibronectin. IL-6 had no effect on these trophoblast differentiation markers.

These results show that TNF-alpha stimulated cytotrophoblasts modulate the expression of differentiation markers, down-regulating the autocrine signals that promote syncytialization, and increasing their invasive capacity through up-regulation of proteases. We suggest that this regulatory mechanism of trophoblast function could play an important role during trophoblast implantation, in pregnancy failure and in the normal and pathologic rupture of fetal membranes.