Role of protein kinase C in the inhibitory action of trophoblast interferons on expression of the oxytocin receptor in sheep endometrium.

PhosphoIipid/Ca(2+) -dependent protein kinase C (PKC) and oxytocin receptor were measured in sheep endometrial explants after culture for up to 96 h. Oxytocin receptor binding and PKC activity were reduced by up to 90% in explants exposed to recombinant ovine trophoblast interferon (rolFN-τ), recombinant bovine IFN-α(1) or ovine conceptus secretory proteins (a source of IFN-τ). Inhibition occurred in both caruncular and intercaruncular endometrium taken between days 7 and 10 of the oestrous cycle and in intercaruncular (but not caruncular) endometrium on day 6. Down-regulation of PKC by continued exposure of expiants to 4β-phorbol myristate acetate, or treatment with PKC inhibitors reduced both oxytocin receptor binding and PKC activity by up to 70%. Tyrosine kinase inhibitors were ineffective. Addition of oxytocin or progesterone, which reduce oxytocin receptor bindingin vivo, also lowered oxytocin receptor bindingin vitro in the absence of any effect on PKC. The data indicate that IFN-τ inhibits oxytocin receptor synthesis by a mechanism involving PKC inhibition, but that a non-PKC pathway also operates to control oxytocin receptor binding in non-pregnant animals. These conclusions were supported by measuring PKC activity and oxytocin receptor binding in endometrium without culture. Prolonged exposure of the endometrium to IFN-τin vivo may lead to PKC down regulation by a mechanism analogous to that involved in the action of continuous activation by agonist, and this may represent one function of the prolonged secretion of IFN-τ over a 10-day period in early pregnancy.