Induction of progesterone receptor A form attenuates the induction of cytosolic phospholipase A2α expression by cortisol in human amnion fibroblasts

Abstract

Cytosolic phospholipase A 2a (cPLA 2a , now known as PLA2G4A) is the enzyme catalyzing the formation of the rate-limiting substrate, arachidonic acid, for prostaglandin (PG) synthesis. The increasing expression of PLA2G4A toward term gestation in human amnion fibroblasts is believed to be the crucial event in parturition. Human amnion fibroblasts produce cortisol, progesterone and express glucocorticoid receptor (GR), progesterone receptor A (PGRA) form at term. The roles of progesterone and PGRA in the induction of PLA2G4A by cortisol via GR in the amnion fibroblasts remain largely unknown. Using cultured human term amnion fibroblasts, we found that cortisol induced the expression of PGRA, which was attenuated by inhibiting PG synthesis with indomethacin. Knockdown of PGRA expression or inhibition of endogenous progesterone production with trilostane significantly enhanced the induction of PLA2G4A by cortisol, whereas overexpression of PGRA attenuated the induction of PLA2G4A by cortisol. Although exogenous progesterone did not alter PLA2G4A expression under basal conditions, it attenuated cortisol-induced PLA2G4A expression at concentrations about tenfold higher, which might be achieved by competition with cortisol for GR. In conclusion, PGRA in the presence of endogenous progesterone is a transdominant repressor of the induction of PLA2G4A by cortisol. High level of progesterone may compete with cortisol for GR, thus further inhibiting the induction of PLA2G4A by cortisol. Moreover, increased PG synthesis by cortisol may feed back on the expression of PGRA leading to attenuation of cortisolinduced PLA2G4A expression. The above findings may be pertinent to the inconsistent effects of glucocorticoids on parturition in humans.Reproduction (2010) 139 915-922

Exposure to Endocrine Disrupters and Nuclear Receptor Gene Expression in Infertile and Fertile Women from Different Italian Areas

“…BPA is considered an ER-agonist, as well as an AR antagonist [ 29 ]; MEHP may display anti-estrogenic and anti-androgenic activities acting on steroid synthesis rather than on ERs or AR [ 62 ]. Indeed, NR expression may be modulated by direct, as well as cross-talk or feed-back mechanisms [ 63 ]. The observed increase of AhR and PXR is consistent with the available evidence on both BPA and MEHP mechanisms [ 23 , 29 , 30 , 64 , 65 ].…”