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Induction of PG G/H Synthase-2 in Bovine Myometrial Cells by Interferon- Requires the Activation of the p38 MAPK Pathway

Perinatal Research and Developmental Pharmacology Unit (F.D.-B.) and Terry Fox Molecular Oncology Group (A.E.K.), Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, Québec H3T 1E2, Canada; and Departments of Experimental Medicine (F.D.-B.), Oncology (A.E.K.), Cell Biology and Anatomy (F.D.-B.), Microbiology and Immunology (A.E.K.), McGill University, Montréal, Québec H36 1Y6, Canada

Address all correspondence and requests for reprints to: Dr. Florence Doualla-Bell, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte-Ste-Catherine, Montréal, Québec H3T 1E2, Canada. E-mail: fdoualla{at}ldi.jgh.mcgill.ca

PGs are regulators of a plethora of uterine functions during reproductive processes, including uterine contractility. In bovine uterus, the rate-limiting step in PG synthesis is catalyzed by the PG endoperoxide G/H synthase (PGHS) enzymes. It has previously been established that PGHS-2 isoform expression is affected by the ruminant-specific interferon (IFN)- in bovine endometrial cells. Here, we show that PGHS-2 mRNA and protein levels are induced by IFN- in primary cell cultures from bovine myometrium. Treatment with recombinant bovine IFN- induces the activation of the JAK-STAT and p38 MAPK pathways in bovine myometrial cells. Inhibition of the p38 pathway by the specific inhibitor SB203580 strongly decreases PGHS-2 mRNA and protein expression without affecting the phosphorylation and DNA-binding of transcription factors STAT-1 and STAT-2. The p38 pathway regulates PGHS-2 expression at the posttranscriptional level, because the presence of SB203580 results in the destabilization of IFN--induced PGHS-2 mRNA. Taken together, these data demonstrate the ability of IFN- to induce the activation of the JAK-STAT pathway in a manner similar to other types of IFN (i.e. , ß, and ) and to regulate PGHS-2 mRNA stability through the activation of the p38 pathway. These findings provide new insights into the physiological function of IFN-, in regard to regulation of specific genes associated with myometrial contractility.

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