ROLE OF PROTEIN-KINASE-C IN THE INHIBITORY-ACTION OF TROPHOBLAST INTERFERONS ON EXPRESSION OF THE OXYTOCIN RECEPTOR IN SHEEP ENDOMETRIUM

Phospholipid/Ca2+-dependent protein kinase C (PKC) and oxytocin recept or were measured in sheep endometrial explants after culture for up to 96 h. Oxytocin receptor binding and PKC activity were reduced by up t o 90% in explants exposed to recombinant ovine trophoblast interferon (roIFN-tau), recombinant bovine IFN-alpha(1) or ovine conceptus secret ory proteins (a source of IFN-tau). Inhibition occurred in both carunc ular and intercaruncular endometrium taken between days 7 and 10 of th e oestrous cycle and in intercaruncular (but not caruncular) endometri um on day 6. Down-regulation of PKC by continued exposure of explants to 4 beta-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 p rogesterone, which reduce oxytocin receptor binding in vivo, also lowe red oxytocin receptor binding in vitro in the absence of any effect on PKC. The data indicate that IFN-tau inhibits oxytocin receptor synthe sis by a mechanism involving PKC inhibition, but that a non-PKC pathwa y also operates to control oxytocin receptor binding in non-pregnant a nimals. These conclusions were supported by measuring PKC activity and oxytocin receptor binding in endometrium without culture. Prolonged e xposure of the endometrium to IFN-tau in vivo may lead to PKC down reg ulation by a mechanism analogous to that involved in the action of con tinuous activation by agonist, and this may represent one function of the prolonged secretion of IFN-tau over a 10-day period in early pregn ancy.