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

Cédric Carli, Christine N Metz, Yousef Al-Abed, Yousef Al‐Abed, Paul H Naccache, Ali Akoum
Endocrinology · 2009 · vol. 150(7) , pp. 3128–3137 · doi:10.1210/en.2008-1088 · PMID:19299454 · W2060063893
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Macrophage migration inhibitory factor up-regulates cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic cells via p38 and ERK MAPK pathways.

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Abstract

Cyclooxygenase (COX) is the rate-limiting enzyme in the metabolic conversion of arachidonic acid to prostaglandins (PGs), including prostaglandin E(2) (PGE(2)), 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 PGE(2). MIF treatment strongly activated p38 and ERK MAPK, and specific inhibitors of both pathways completely blocked basal and MIF-induced PGE(2) synthesis. Whereas p38 inhibitors negatively affected the stimulated synthesis of COX-2 and that of PGE(2), ERK inhibitors only decreased the production of PGE(2). These findings show for the first time a direct role for MIF in the up-regulation of COX-2 synthesis and PGE(2) 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 PGE(2) 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 PGE(2) 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.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Cyclooxygenase 2 Dinoprostone Endometriosis Macrophage Migration-Inhibitory Factors Signal Transduction Adult Antigens, Differentiation, B-Lymphocyte Antigens, Differentiation, B-Lymphocyte Cells, Cultured Cyclooxygenase 2 Dinoprostone Endometriosis Extracellular Signal-Regulated MAP Kinases Extracellular Signal-Regulated MAP Kinases Female Histocompatibility Antigens Class II Histocompatibility Antigens Class II Humans Macrophage Migration-Inhibitory Factors Signal Transduction

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