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Up-Regulation of Cyclooxygenase-2 Expression and Prostaglandin E₂ Production in Human Endometriotic Cells by Macrophage Migration Inhibitory Factor: Involvement of Novel Kinase Signaling Pathways

Laboratoire d’endocrinologie de la reproduction (C.C., A.A.), Centre de recherche-Hôpital Saint-François d’Assise, Centre Hospitalier Universitaire de Québec, Faculté de médecine, Université Laval, Québec, Canada G1L 3L5; Feinstein Institute for Medical Research (C.N.M., Y.A.-A.), Manhasset, New York 11030; and Centre de recherche en rhumatologie et immunologie (P.H.N.), Centre de recherche du Centre Hospitalier de l’ Université Laval, Centre Hospitalier Universitaire de Québec, Faculté de Médecine, Université Laval, Québec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Dr. Ali Akoum, Centre de recherche, Hôpital Saint-François d’Assise, 10, rue de l’Espinay, Local D0-711, Québec, Canada G1L 3L5. E-mail: ali.akoum{at}crsfa.ulaval.ca.

Cyclooxygenase (COX) is the rate-limiting enzyme in the metabolic conversion of arachidonic acid to prostaglandins (PGs), including prostaglandin E₂ (PGE₂), a major mediator of inflammation and angiogenesis. Herein, we report that macrophage migration inhibitory factor (MIF), a potent proinflammatory and growth-promoting factor found at elevated concentrations in the peritoneal fluid of women with endometriosis and active endometriosis lesions, acts directly on ectopic endometrial cells to stimulate the synthesis of COX-2, the inducible form of COX, and the release of PGE₂. MIF treatment strongly activated p38 and ERK MAPK, and specific inhibitors of both pathways completely blocked basal and MIF-induced PGE₂ synthesis. Whereas p38 inhibitors negatively affected the stimulated synthesis of COX-2 and that of PGE₂, ERK inhibitors only decreased the production of PGE₂. These findings show for the first time a direct role for MIF in the up-regulation of COX-2 synthesis and PGE₂ secretion in ectopic endometrial cells. They further indicate that whereas p38 and ERK MAPK signaling pathways both play a significant role in the regulation of basal and MIF-induced synthesis of PGE₂ by ectopic endometrial cells, only p38 kinase is involved in the regulation of COX-2 expression in these cells. This suggests that MIF acts at more than one level to stimulate the synthesis of PGE₂ and triggers the coordinate activation of multiple enzymes in the biosynthesis pathway. Our data provide evidence for a novel mechanism by which MIF can induce a proinflammatory phenotype in ectopic endometrial cells, and favor the establishment of endometriosis and its related clinical symptoms.