Prostaglandin F2α (PGF2α) and Prolactin Signaling: PGF2α-Mediated Inhibition of Prolactin Receptor Expression in the Corpus Luteum

Abstract

Abstract It is well established that prolactin (PRL) sustains, whereas prostaglandin F2α (PGF2α) curtails, progesterone production by the rodent corpus luteum (CL). We have previously shown that PGF2α inhibits the expression of several luteal genes stimulated by PRL, whereas it stimulates other genes inhibited by this hormone. We have also found that PGF2α stimulation of 20α-hydroxysteroid dehydrogenase (20αHSD), an enzyme that catabolizes progesterone, at the end of pregnancy is accompanied by a dramatic decrease in PRL receptor (PRL-R) expression. These findings, and the fact that the factors that inhibit PRL-R are not known, led us to examine in vivo whether the decline in PRL-R at the end of pregnancy is due to PGF2α and to also find out whether PGF2α opposes PRL action by inhibiting PRL-R expression. Using the PGF2α receptor (PGF2α-R) knockout, we examined whether the absence of the PGF2α-R prevents the decline in the expression of both the short and long forms of the PRL-R in the CL. We found that, in sharp contrast to the wild-type mice, in which both forms of the PRL-R decline to low levels between d 18–20 of pregnancy, expression of these receptors remained elevated in the PGF2α-R null mice. Furthermore, administration of PGF2α to pregnant rats inhibited PRL-R expression. Time-course analysis revealed that PGF2α treatment decreases both isoforms of PRL-R within 1 h of treatment in vivo, whereas its stimulatory effect on 20αHSD expression was further delayed. Similar results were obtained with luteinized granulosa cells in culture. To examine whether the decline in PRL-R is involved/necessary for PGF2α action, cells were transfected with a constitutively active PRL-R. The expression of this receptor did not prevent PGF2α effect on PRL-R or 20αHSD expression. Taken together, these results demonstrate that PGF2α inhibits the expression of the PRL-R and that the decline in both forms of the PRL-R that occurs at the end of pregnancy in the CL is due to PGF2α. The results further suggest that PGF2α-mediated stimulation of 20αHSD is independent from PGF2α inhibition of PRL signaling in luteal cell.