Prostaglandins differentially modulate progesterone receptor-A and -B expression in human myometrial cells: Evidence for prostaglandin-induced functional progesterone withdrawl

We tested the hypothesis that the prostaglandins (PGs), PGE(2) and PGF(2alpha), <LF>stimulate labor and delivery in women, in part, by inducing functional progesterone withdrawal in myometrial cells by increasing the progesterone receptor (PR)-A/PR-B expression ratio. PHM1-31 cells (an immortal pregnant human myometrial cell line) were exposed to PGE(2), PGF(2alpha), cyclic-8-<LF>bromoadenosine monophosphate (8-Br-cAMP) and phorbol 12-myristate 13-acetate (PMA) at various concentrations for 24h. Effects on PR-A and PR-B expression were then assessed by quantitative RT-PCR. PGF(2alpha) dose dependently increased PR-A mRNA and the PR-A/PR-B expression ratio but did not affect PR-B mRNA. PGE(2) dose-dependently increased mRNAs encoding PR-A and PR-B. The PGE(2) dose-threshold for PR-A (0.01 nM) <LF>was lower than that for PR-B (0.1 nM), which resulted in an initial rise and then a gradual fall in the PR-A/PR-B expression ratio to basal levels in response to PGF(2). Activation of the protein kinase (PK)-A signaling pathway with 8-Br-cAMP coordinately increased expression of PR-A and PR-B and therefore did not alter the PR-A/PR-B expression ratio. In contrast, activation of the PKC signaling pathway with PMA increased expression of PR-A without affecting PR-B and therefore significantly (P<0.05) increased the PR-A/PR-B expression ratio. These data demonstrate differential control of myometrial PR-A and PR-B expression by PGE(2) and PGF(2 alpha) and by specific intracellular signaling pathways. We conclude that PGs acting via the PKC pathway facilitate functional progesterone withdrawal by increasing the myometrial PR-A/PR-B expression ratio.