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

The peroxisome proliferator-activated receptors (PPARs) a and g 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-a and -g messenger RNA by RT-PCR and protein by immunoblotting of lysates of peritoneal macrophages and monocytic U937 cells. Using immunocytochemistry, we localized PPAR-a and -g 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-a/GAL4 luciferase reporter. By contrast, peritoneal fluid did not cause significant activation of PPAR-g/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-a that stimulate macrophage chemotaxis. Inhibitors of PPAR-a or activators of PPAR-g could be developed for the treatment of inflammation associated with endometriosis. (J Clin Endocrinol Metab 86: 3108–3114, 2001) O THE PAST two decades, considerable evidence for a cell-mediated immunological etiology of endometriosis has accumulated. Resident leukocytes within endometriotic implants have been identified histologically (1–3). Furthermore, increased numbers of peritoneal leukocytes are found in women with endometriosis (4–6). Of these, the most numerous are the macrophages, and these cells manifest an activated phenotype in women with laparoscopic evidence of endometriosis (7–9). It has been proposed that the cytokines elaborated from activated peritoneal macrophages mediate many of the symptoms associated with the endometriosis syndrome (10). The attraction of inflammatory cells into the peritoneal cavity has been a major focus of our laboratory over the past decade. Shortly following the cloning and characterization of RANTES, a monocyte and T-cell chemokine (11), we reported its detection in peritoneal fluid from women with advanced stages of endometriosis (6). Indeed, a variety of chemokines have been identified in human peritoneal fluid. Most of these predominantly recruit monocytes [e.g. RANTES (6)], monocyte chemotactic protein-1 (12), and vascular endothelial growth factor (13, 14); however chemoattractants for neutrophils [e.g. interleukin-8 (15)], epithelial neutrophil-activating protein-78 (16)), and eosinophils [eotaxin (17)] also