TY - JOUR
T1 - Expression of progesterone receptor A form and its role in the interaction of progesterone with cortisol on cyclooxygenase-2 expression in amnionic fibroblasts
AU - Guo, C. M.
AU - Zhu, X. O.
AU - Ni, X. T.
AU - Yang, Z.
AU - Myatt, L.
AU - Sun, Kang
N1 - Funding Information:
This work was supported by the Natural Science Foundation of China (30570680 and 30870935) and Shanghai Leading Academic Discipline Project (B111).
PY - 2009/12
Y1 - 2009/12
N2 - Context: Human amnion fibroblasts produce abundant prostaglandins toward the end of gestation, which is believed to be one of the major events leading to parturition. Glucocorticoids have been shown to up-regulate cyclooxygenase-2 (COX-2) expression, the crucial enzyme catalyzing prostaglandin synthesis, in human amnion fibroblasts. Although a major propregnancy hormone, the effect of progesterone and the associated progesterone receptor subtypes in the regulation of both basal and glucocorticoid-induced COX-2 expression in human amnion fibroblasts have not been resolved. Methods and Results: Cultured human amnion fibroblasts prepared from the fetal membranes at term pregnancy without labor mainly expressed the progesterone receptor A form (PRA). Inhibition of endogenous progesterone production with trilostane or knockdown of PRA expression with small interfering RNA significantly enhanced the glucocorticoid receptor (GR)-mediated COX-2 induction by cortisol, whereas overexpression of PRA attenuated the induction by cortisol. Co-immunoprecipitation assay revealed PRA in the GR protein complex. Although exogenous progesterone did not alter COX-2 expression under basal conditions, it attenuated cortisol-induced COX-2 expression at concentrations about 10- to 50-fold higher, which might be achieved by competition with cortisol for GR. Conclusions: We demonstrated in this study that endogenous progesterone might counteract the induction of prostaglandin synthesis by cortisol via PRA transdominant repression of GR function, whereas high levels of progesterone might further inhibit the induction by cortisol via competitive binding to GR in human amnion fibroblasts. These inhibitory actions of progesterone and PRA on glucocorticoids and GR may partly explain the inconsistent effects of glucocorticoids on parturition in humans.
AB - Context: Human amnion fibroblasts produce abundant prostaglandins toward the end of gestation, which is believed to be one of the major events leading to parturition. Glucocorticoids have been shown to up-regulate cyclooxygenase-2 (COX-2) expression, the crucial enzyme catalyzing prostaglandin synthesis, in human amnion fibroblasts. Although a major propregnancy hormone, the effect of progesterone and the associated progesterone receptor subtypes in the regulation of both basal and glucocorticoid-induced COX-2 expression in human amnion fibroblasts have not been resolved. Methods and Results: Cultured human amnion fibroblasts prepared from the fetal membranes at term pregnancy without labor mainly expressed the progesterone receptor A form (PRA). Inhibition of endogenous progesterone production with trilostane or knockdown of PRA expression with small interfering RNA significantly enhanced the glucocorticoid receptor (GR)-mediated COX-2 induction by cortisol, whereas overexpression of PRA attenuated the induction by cortisol. Co-immunoprecipitation assay revealed PRA in the GR protein complex. Although exogenous progesterone did not alter COX-2 expression under basal conditions, it attenuated cortisol-induced COX-2 expression at concentrations about 10- to 50-fold higher, which might be achieved by competition with cortisol for GR. Conclusions: We demonstrated in this study that endogenous progesterone might counteract the induction of prostaglandin synthesis by cortisol via PRA transdominant repression of GR function, whereas high levels of progesterone might further inhibit the induction by cortisol via competitive binding to GR in human amnion fibroblasts. These inhibitory actions of progesterone and PRA on glucocorticoids and GR may partly explain the inconsistent effects of glucocorticoids on parturition in humans.
UR - http://www.scopus.com/inward/record.url?scp=73249150366&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=73249150366&partnerID=8YFLogxK
U2 - 10.1210/jc.2009-0832
DO - 10.1210/jc.2009-0832
M3 - Article
C2 - 19837932
AN - SCOPUS:73249150366
SN - 0021-972X
VL - 94
SP - 5085
EP - 5092
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 12
ER -