Evidence for a functional link between the heme oxygenase-carbon monoxide pathway and corticotropin-releasing hormone release from primary cultures of human trophoblast cells

The gene expression and syntheis of both constitutive and inducible heme ox ygenase (HO) isoforms have been recently described in human placental cells , but the functional role(s) of this biochemical pathway in placental physi ology and pathology is still unclear. In the present study, we have investi gated whether HO activity is involved in the control of CRH secretion from trophoblast cells. Fluctuations in HO activity were induced in primary cult ures 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 tha t the increase in HO activity induced by hemin or cobalt chloride (CoCl2) w as associated with parallel significant increases in CRH release. This effe ct 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 medi ated by the cyclooxygenase (COX) pathway. Indeed, hemin also caused signifi cant increases in PGE2 release in this experimental paradigm. However, CoCl 2, which also enhances CRH release, had no stimulatory effect and actually inhibited PG secretion; moreover, a nonselective COX inhibitor, indomethaci n, failed to counteract hemin-induced CRH release. Taken collectively, thes e findings suggested that modulation of CRH secretion by the HO-CO system o ccurs through a mechanism independent of COX activity.