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Evidence for a Functional Link between the Heme Oxygenase-Carbon Monoxide Pathway and Corticotropin-Releasing Hormone Release from Primary Cultures of Human Trophoblast Cells¹

Institutes of Pharmacology (G.T., P.N.) and Obstetrics and Gynecology (A.L., Fi.M., Fr.M., M.G.P., R.A., S.M.), Catholic University Medical School, Largo Francesco Vito 1-00168 Rome, Italy

Address all correspondence and requests for reprints to: Prof. Pierluigi Navarra, Institute of Pharmacology, Catholic University Medical School, Largo Francesco Vito 1-00168 Rome, Italy. E-mail pnavarra{at}rm.unicatt.it

The gene expression and synthesis of both constitutive and inducible heme oxygenase (HO) isoforms have been recently described in human placental cells, but the functional role(s) of this biochemical pathway in placental physiology and pathology is still unclear. In the present study, we have investigated whether HO activity is involved in the control of CRH secretion from trophoblast cells. Fluctuations in HO activity were induced in primary cultures of human trophoblast cells using well-known activators and inhibitors of HO, and the subsequent changes in CRH secretion were monitored measuring CRH immunoreactivity released into the incubation medium. It was found that the increase in HO activity induced by hemin or cobalt chloride (CoCl₂) was associated with parallel significant increases in CRH release. This effect was probably caused by the gaseous HO end-product, carbon monoxide (CO), because it was blocked by the HO inhibitor tin-mesoporphyrin-9, but it was not mimicked by stable HO end-products, biliverdin and bilirubin. We have also investigated whether stimulation of CRH release induced by HO was mediated by the cyclooxygenase (COX) pathway. Indeed, hemin also caused significant increases in PGE2 release in this experimental paradigm. However, CoCl₂, which also enhances CRH release, had no stimulatory effect and actually inhibited PG secretion; moreover, a nonselective COX inhibitor, indomethacin, failed to counteract hemininduced CRH release. Taken collectively, these findings suggested that modulation of CRH secretion by the HO-CO system occurs through a mechanism independent of COX activity.

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