A series of experiments were undertaken to examine the effects of interferon (IFN)-τ on regulation of prostaglandin H synthase (PGHS)-2 mRNA in bovine endometrial (BEND) cells as a means to elucidate the actions of IFN-τ to maintain pregnancy. The objective was to determine if IFN-τ mediates posttranscriptional regulation of PGHS-2 mRNA. Cells were treated with phorbol 12,13-dibutyrate (PdBu) for 3 h to induce PGHS-2 mRNA expression. Actinomycin D (0 or 1 μg/ml) or the p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580 (1 μM), were added at 3 h, followed by addition of IFN-τ (0 or 50 ng/ml) at 3.5 h and extraction of RNA at 4.5 h. The concentrations of PGHS-2 mRNA were stable between 3 and 4.5 h regardless of actinomycin D. Simultaneous treatment of PdBu-treated cells with actinomycin D and SB203580 (1 μM) decreased PGHS-2 mRNA. Addition of IFN-τ (50 ng/ml) reduced PGHS-2 mRNA, which was not observed when actinomycin D was present. Concurrent treatments of cells with SB203580 and IFN-τ (5 ng/ml) decreased concentrations of PGHS-2 mRNA in an additive manner. Although IFN-τ reduced PGHS-2 mRNA concentrations, phosphorylation of p38 MAPK was induced by IFN-τ, PdBu, and PdBu combined with IFN-τ after 10 min of treatment. Both the p38 MAPK inhibitor and IFN-τ decreased prostaglandin F_2α secretion, and decreases were additive when the two were given together. In summary, activation of p38 MAPK by PdBu is required for continued presence of PGHS-2 mRNA and secretion of prostaglandin F_2α in BEND cells. Interferon-τ mediates a transcription-dependent mechanism, which induces degradation of PGHS-2 mRNA. However, the consequences of an IFN-τ-induced activation of p38 MAPK warrant further investigation, because inhibition of p38 MAPK caused a degradation of PGHS-2 mRNA.