Interferon-tau suppresses prostaglandin F-2 alpha secretion independently of the mitogen-activated protein kinase and nuclear factor kappa B pathways

Pregnancy is established in ruminants through inhibitory actions of interfe ron (IFN)-tau on the release of prostaglandin F-2 alpha (PGF), which allows the corpus luteum to survive and continue to produce progesterone. Experim ents were designed to 1) delineate the signal transduction pathway coordina ting the synthesis of PGE, 2) determine how rapidly recombinant bovine (rb) IFN-tau attenuated phorbol ester (PDBu)-induced secretion of PGF, and 3) e stablish the site at which rbIFN-tau attenuates the secretion of PGF in cul tured bovine endometrial (BEND) cells. BEND cells were untreated (control) or treated for 5, 10, 60, 180, or 300 min with PDBu (100 ng/ml), rbIFN-tau (50 or 500 ng/ml), PDBu + rbIFN-tau, or PDBu + PD98059 (MEK-1 inhibitor; 50 muM). Secretion of PGF was induced (P < 0.0001) by PDBu within 180 min, bu t induction was inhibited 74% by the addition of rbIFN-<tau> (P < 0.0001) a nd was ablated completely by PD98059. Parallel results were obtained for cy clooxygenase (COX)-2 protein expression. PDBu induced (P < 0.05) activation of the Raf-1/MEK-1/ERK-1/2 pathway, which was obligatory for the expressio n of COX-2 and secretion of PGF but was not altered by cotreatment with rbI FN-tau. PDBu induced (P < 0.05) transcription of c-jun and c-fos mRNAs with in 30 min; induction was inhibited (P < 0.05) by cotreatment with PD98059 b ut not by cotreatment with rbIFN-tau. Treatment of BEND cells with rbIFN-ta u also did not attenuate PDBu-induced degradation of I kappaB alpha, sugges ting that the I kappaB alpha /NF kappaB pathway is not a site of IFN-tau in hibition of PGF. However, rbIFN-tau did block transcription of the COX-2 ge ne induced by PDBu within 30 min. In conclusion, COX-2 expression and PGF s ecretion induced by PDBu is mediated through the Raf-1/MEK-1/ERK-1/2 pathwa y, but this pathway is not disrupted by rbIFN-tau. Because rbIFN-tau inhibi ts COX-2 mRNAs within 30 min, we hypothesized that transcription factors ac tivated by rbIFN-tau rapidly and directly attenuate COX-2 gene expression, thereby suppressing secretion of PGF.