PROTEIN KINASE-A ACTIVATORS INHIBIT AGONIST-INDUCED PROSTAGLANDIN PRODUCTION IN HUMAN AMNION

Prostaglandin (PG) production by human amnion has been postulated to h ave a role in the onset of labor. Previous work by ourselves and other s has demonstrated that oxytocin, phorbol esters and epidermal growth factor (EGF) increase PGE, production in human amnion cells by activat ion of the Phospholipase C/Protein Kinase C (PKC) cascade system. The present study was undertaken to determine the effect of prior activati on of the Adenylate Cyclase cascade system upon subsequent stimulation of PGE2 production by oxytocin, phorbol 12-myristate-13-acetate (PMA) or EGF in amnion cells and membrane discs. Isoproterenol, forskolin a nd dibutyryl cyclic adenosine monophosphate (dbcAMP) were utilized to activate the Adenylate Cyclase system at the-receptor, enzyme and seco nd messenger level. In control amnion cells, oxytocin, PMA and EGF eac h provoked dose dependent increases in PGE2 production. In cells prein cubated with dbcAMP, forskolin or isoproterenol, agonist stimulated PG E2 production was markedly (50-90%) inhibited (p < 0.01). Inhibition w as dose dependent upon preincubator concentrations. Maximal inhibition by adenylate cyclase activators occurred with 2-4 h of preincubation. In membrane discs, forskolin preincubation also inhibited oxytocin, P MA and EGF stimulation of PGE2 production. Activation of the Adenylate Cyclase system in human amnion cells or membrane discs inhibits the s ubsequent action of potent stimulators of PGE2 production in human amn ion.