Evidence for a functional link between the heme oxygenase-carbon monoxide pathway and corticotropin-releasing hormone release from primary cultures of human trophoblast cells
P. Navarra et al., Evidence for a functional link between the heme oxygenase-carbon monoxide pathway and corticotropin-releasing hormone release from primary cultures of human trophoblast cells, J CLIN END, 86(1), 2001, pp. 317-323
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.