Prostaglandins differentially modulate progesterone receptor-A and -B expression in human myometrial cells: evidence for prostaglandin-induced functional progesterone withdrawal.
We tested the hypothesis that prostaglandin (PGs), PGE2, and PGF2 alpha, 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 ration. PHM1-31 cells (an immortal pregnant human myometrial cell line) were exposed to PGE2, PGF2 alpha, cyclic-8-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. PGF2 alpha dose dependently increased PR-A mRNA and the PR-A/PR-B expression ration but did not effect PR-B mRNA. PGE2 dose-dependently increased mRNAs encoding PR-A and PR-B. The PGE2 dose-threshold for PR-A (0.01 nM) was lower than that for PR-B (0.1 nM), which resulted in an initial rise then a gradual fall in PR-A/PR-B expression ration to basal levels in response to PGE2. 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 ration. 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 ration. These data demonstrate differential control of myometrial PR-A and PR-B expression by PGE2 and PGF2 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.
Madsen
Gemma
G
Mothers and Babies Research Centre, University of Newcastle and John Hunter Hospital, Newcastle, NSW, Australia.
Zakar
Tamas
T
Ku
Chun Ying
CY
Sanborn
Barbara M
BM
Smith
Roger
R
Mesiano
Sam
S
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D002461:Cell Line, Transformed; D015237:Dinoprost / Q000008:administration & dosage / Q000502:physiology*; D015232:Dinoprostone / Q000008:administration & dosage / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D009215:Myometrium / Q000166:cytology / Q000378:metabolism*; D011374:Progesterone / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D012333:RNA, Messenger; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011374:Progesterone; D015237:Dinoprost; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate