Regulation of prostaglandin endoperoxide H synthase by glucocorticoids and activators of protein kinase C in the human amnion.
Since glucocorticoids decrease and protein kinase C (PKC) activators increase amniotic PGE2 production, the possibility that they regulate the activity of prostaglandin endoperoxide H synthase (PGHS), the rate-limiting enzyme of prostaglandin synthesis from arachidonate, was investigated. Glucocorticoids inhibited the production of PGE2 from exogenous arachidonate specifically and in a concentration dependent fashion. Furthermore, cortisol decreased PGHS activity and the amount of PGHS protein in amnion microsomes, and reduced the rate of recovery of PGHS after acetylsalicylic acid (ASA) pretreatment. Actinomycin D blocked the inhibition of PGHS recovery by cortisol, but did not suppress the spontaneous recovery of the enzyme, indicating that the glucocorticoid induced a post-transcriptional inhibitor of PGHS synthesis. PKC-activating phorbol esters, such as 12-tetradecanoyl phorbol 13-acetate (TPA) increased the synthesis of PGE2 from exogenous arachidonate, also in a specific and concentration dependent manner. PGHS recovery after ASA treatment was enhanced by TPA. PGHS activity and protein concentrations were increased by phorbol ester treatment; however, this was apparent only in tissues in which the concentrations of PGHS were initially low. These results show that the synthesis of PGHS is positively and negatively regulated in the human amnion by PKC and glucocorticoids, respectively, and suggest that effectors using these pathways may regulate the enzyme in vivo.
Zakar
T
T
University of Alberta Perinatal Research Centre, Department of Obstetrics and Gynaecology, Edmonton, Canada.
Teixeira
F J
FJ
Hirst
J J
JJ
Guo
F
F
MacLeod
E A
EA
Olson
D M
DM
D000650:Amnion / Q000187:drug effects / Q000201:enzymology*; D046508:Culture Techniques; D003609:Dactinomycin / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D005938:Glucocorticoids; D003609:Dactinomycin; D015735:Mifepristone; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D006854:Hydrocortisone