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Stimulation of Macrophage Migration Inhibitory Factor Expression in Endometrial Stromal Cells by Interleukin 1, beta Involving the Nuclear Transcription Factor NFB¹

Unité d'endocrinologie de la reproduction,³ Centre de Recherche, Hôpital Saint-François d'Assise, Centre Hospitalier Universitaire de Québec, Faculté de Médecine, Université Laval, Québec, Canada G1L 3L5 Institute for Medical Research at North Shore-LIJ,⁴ Manhasset, New York 11030

Endometriosis, the ectopic development of endometrial tissue, is, particularly in peritoneal endometriosis, believed to result from tubal reflux of menstrual tissue. The release of cytokines and growth factors by refluxed endometrial cells in response to peritoneal inflammatory stimuli may enhance the capability of endometrial cells to implant and grow into the peritoneal host tissue. Herein we report that interleukin 1 (IL1), a major proinflammatory cytokine that is overproduced by endometriosis women-derived peritoneal macrophages and found in elevated concentrations in the peritoneal fluid of patients with endometriosis, stimulates the synthesis and the secretion of macrophage migration inhibitory factor (MIF) by human endometrial stromal cells. IL1B (0.1–100 ng/ml) exerted dose- and time-dependent effects of MIF protein secretion and mRNA synthesis, as shown by ELISA and reverse transcription-polymerase chain reaction, respectively. IL1B appeared to induce MIF gene transcription via the B nuclear transcription factor (NFB), as shown by electrophoretic mobility shift assay and Western blot analysis of IB phosphorylation. Curcumin (10^–8 M), which is known for inhibiting NFB activation, inhibited IL1B-induced MIF secretion as well as NFB nuclear translocation and DNA binding. Taken together, these findings clearly show that IL1B up-regulates the expression of MIF in endometrial stromal cells in vitro and acts via NFB. This may play an important role in the physiology of the human endometrium and the pathophysiology of endometriosis considering the immunomodulatory properties of MIF as well as its role in cell growth, angiogenesis and tissue remodeling.

cytokines, endometrial cells, endometriosis, female reproductive tract, IL1B, menstrual cycle, MIF, NFB, uterus

² Correspondence: Ali Akoum, Laboratoire d'Endocrinologie de la Reproduction, Centre de Recherche, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, Local D0-711, Québec, Québec, Canada, G1L 3L5. FAX: 418 525 4195; ali.akoum{at}crsfa.ulaval.ca

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