Oxytocin and Interferon tau Regulation of Prostaglandin Transporter (PGT) and Multidrug Resistant associated Protein 4 (MRP4) in the Bovine Endometrium

Abstract

Prostaglandins (PG) are involved in many female reproductive processes and are regulated at the levels of biosynthesis, secretion and catabolism. Transmembrane transport of PGs is also an important site of regulation and we have shown the requirement of PG transporter (PGT/SLCO21) for functional luteolysis in the bovine. A comprehensive screening of the endometrial expression of different PGTs indicated that MRP4/ABCC4 of ATP Binding Cassette (ABC) family was regulated during the bovine estrous cycle apart from the previously studied PGT/SLCO21 of Solute Carrier Organic Anion family. Accordingly, we have confirmed the expression of these carriers in our recently developed endometrial epithelial and stromal cell lines bEEL and CSC. Using these models, we have studied the effect of oxytocin (OT) and/or interferon tau (IFNt) and phorbol myristoyl acetate (PMA) on the regulation of PGT and MRP4 in relation with PGs production. Downregulation of MRP4 expression using siRNA induced a significant increase of PGF2α accumulation relative to PGE2 in the culture medium of CSC. Treatment of bEEL cells with OT stimulated COX2 expression and PGF2αproduction. These responses correlated well with upregulation of MRP4/ABCC4 but not PGT/SLCO2A1. In contrast, IFNt at a concentration that stimulated COX-2 without a corresponding increase in PG accumulation stimulated the expression of PGT/SLCO2A1 but not that of MRP4/ABCC4. Inhibition of OT induced PG production by the COX2 inhibitior NS-398 did not affect the induction of ABCC2 or COX2 expression in bEEL cells. Since OT at the origin of luteolytic PGF2α regulates MRP4 and IFNt, the embryonic antiluteolytic signal, regulates PGT, it is possible that these modulators are involved in selective or preferential transport of terminal PGs like PGE2 and PGF2α.