Peroxisome proliferator-activated receptor-γ ligand inhibition of RANTES production by human endometriotic stromal cells is mediated through an upstream promoter element

Abstract

Objective To investigate the effect of peroxisome proliferator activated receptor-γ (PPAR-γ) ligands on transcription and secretion of regulated upon activation normal T-cell expressed and secreted (RANTES) in endometriotic stromal cells. Design Controlled laboratory study. Setting Academic research laboratory. Patient(s) Women in the follicular phase of the menstrual cycle undergoing laparoscopic resection for endometriosis. Intervention(s) [1] Transient transfection of endometriotic stromal cells with RANTES promoter vectors with and without a mutagenized PPAR-γ response element (PPRE), then treatment with PPAR-γ ligands; [2] co-incubation of cells with PPAR-γ ligands. Main outcome measure(s) RANTES promoter activity and RANTES secretion. Result(s) In endometriotic stromal cells, addition of PPAR-γ ligands (rosiglitazone and 15 deoxy-Δ 12,14 prostaglandin J 2) inhibited RANTES promoter activity by 51% and 50%, respectively. In cells transfected with the same promoter after site-directed mutagenesis of the 5′ PPRE, addition of PPAR-γ ligands failed to inhibit promoter activity. When endometriotic stromal cells were treated with PPAR-γ ligands, a decrease in RANTES secretion by 51% and 20%, respectively, was observed. Conclusion(s) The PPAR-γ ligands inhibit RANTES transcription and protein production in endometriotic stromal cells. Transcriptional repression appears to be mediated through a specific PPRE at −344 to −322 bp upstream from the RNA polymerase start site.