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Nuclear Peroxisome Proliferator-Activated Receptors and Have Opposing Effects on Monocyte Chemotaxis in Endometriosis

Center for Reproductive Sciences (D.H., L.L.W., E.A.R., F.B., R.N.T.), University of California, San Francisco, California 94143; and Department of Obstetrics and Gynecology (D.H., D.W.), Tuebingen 72076, Germany

Address all correspondence and requests for reprints to: Robert N. Taylor, M.D., Ph.D., Center for Reproductive Sciences, HSE 1689, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California 94143-0556.

Abstract

The peroxisome proliferator-activated receptors (PPARs) and are nuclear receptors that play important roles in inflammatory diseases like ulcerative colitis and arthritis. In this study, we examined the possible role of PPARs in macrophage attraction into the peritoneal cavity of patients with endometriosis. We identified PPAR- and - messenger RNA by RT-PCR and protein by immunoblotting of lysates of peritoneal macrophages and monocytic U937 cells. Using immunocytochemistry, we localized PPAR- and - within the nuclei of both cell types. Monocyte chemotactic activity of peritoneal fluid from patients with endometriosis was quantified in Boyden chambers. Migration of U937 cells was increased by WY 14643 and reduced by rosiglitazone. Peritoneal fluid from patients with endometriosis activated U937 cells transiently transfected with a PPAR-/GAL4 luciferase reporter. By contrast, peritoneal fluid did not cause significant activation of PPAR-/GAL4 constructs. The U937 cells transiently transfected with a PPAR response element luciferase reporter showed disease stage-dependent up-regulation when treated with peritoneal fluid from patients with endometriosis. Treatment with peritoneal fluid from healthy controls down-regulated PPAR response element transactivation. We conclude that peritoneal fluid of endometriosis patients contains activators of PPAR- that stimulate macrophage chemotaxis. Inhibitors of PPAR- or activators of PPAR- could be developed for the treatment of inflammation associated with endometriosis.

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