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Regulation of 15-Hydroxy Prostaglandin Dehydrogenase by Corticotrophin-Releasing Hormone through a Calcium-Dependent Pathway in Human Chorion Trophoblast Cells

Canadian Institutes of Health Research Group in Fetal and Neonatal Health and Development, Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Canada M5S 1A8

Address all correspondence and requests for reprints to: Kevin McKeown, M.D., Department of Physiology Medical Sciences Building, Room 3344, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada. E-mail: kevin.mckeown{at}utoronto.ca.

Prostaglandins (PGs) play a crucial role in mediating parturition events, and their synthesis and metabolism are regulated by PG H synthase and 15-hydroxy-PG dehydrogenase (PGDH), respectively. Within the chorion tissue, it is the actions of PGDH that predominate. Throughout gestation, the fetal membranes secrete increasing amounts of CRH. We hypothesized that CRH, produced locally in the chorion, could act to modulate PGDH activity throughout gestation. To investigate this, we obtained Percoll-purified human chorion and placental trophoblast cells from uncomplicated term pregnancies and cultured them for 72 h. Activity of PGDH was assessed by incubation (4 h) with PGF₂ (282 nM) and measurement of conversion to 13,14-dihydro-15-keto PG F₂. Dose-response curves were constructed for the chorion cell cultures with CRH or 8-bromo-cAMP. To investigate the role of CRH and calcium, cells were treated with either astressin, a CRH antibody, BAPTA, or EGTA. CRH (0–1 µM) had no effect on PGDH activity; however, cells treated with astressin (10 µM), with or without exogenous CRH (1 µM), and cells treated with a CRH antibody showed a significant decrease in PGDH activity. 8-Bromo-cAMP (0–1 mM) had no effect on 13,14-dihydro-15-keto PG F₂ output in chorion trophoblast cells but significantly decreased output from placental trophoblast cells. Cells treated with either BAPTA-AM or EGTA had significantly reduced PGDH activity; and, at intermediate concentrations of chelator, exogenous CRH restored PGDH activity. We suggest that, in chorion trophoblast cells, endogenously produced CRH exerts a tonic stimulatory effect on PGDH activity and may help maintain a metabolic barrier, preventing the transfer of bioactive PGs from the chorioamnion to the myometrium.

Abbreviations: CREB, cAMP-responsive element-binding protein; PG, prostaglandin; PGDH, 15-hydroxy-PG dehydrogenase; PGFM, 13,14-dihydro-15-keto PG F₂; PGHS, PG H synthase.

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