Induction of PGF2α Synthesis by Cortisol Through GR Dependent Induction of CBR1 in Human Amnion Fibroblasts

Abundant evidence indicates a pivotal role of prostaglandin F2 alpha (PGF2 alpha) in human parturition. Both the fetal and maternal sides of the fetal membranes synthesize PGF2 alpha. In addition to the synthesis of PGF2 alpha from PGH2 by PGF synthase (PGFS), PGF2 alpha can also be converted from PGE2 by carbonyl reductase 1 (CBR1). Here, we showed that there was concurrent increased production of cortisol and PGF2 alpha in association with the elevation of CBR1 in human amnion obtained at term with labor versus term without labor. In cultured primary human amnion fibroblasts, cortisol (0.01-1 mu M) increased PGF2 alpha production in a concentration-dependent manner, in parallel with elevation of CBR1 levels. Either siRNA-mediated knockdown of glucocorticoid receptor (GR) expression or GR antagonist RU486 attenuated the induction of CBR1 by cortisol. Chromatin immunoprecipitation (ChIP) showed an increased enrichment of both GR and RNA polymerase II to CBR1 promoter. Knockdown of CBR1 expression with siRNA or inhibition of CBR1 activity with rutin decreased both basal and cortisol-stimulated PGF2 alpha production in human amnion fibroblasts. In conclusion, CBR1 may play a critical role in PGF2 alpha synthesis in human amnion fibroblasts, and cortisol promotes the conversion of PGE2 into PGF2 alpha via GR-mediated induction of CBR1 in human amnion fibroblasts. This stimulatory effect of cortisol on CBR1 expression may partly explain the concurrent increases of cortisol and PGF2 alpha in human amnion tissue with labor, and these findings may account for the increased production of PGF2 alpha in the fetal membranes prior to the onset of labor.