TRANSCRIPTIONAL REGULATION OF INFLAMMATORY MEDIATORS IN ENDOMETRIOSIS

Endometriosis affects more than 7 million women in North America and accounts for ∼$1 billion in medical and surgical health expenses annually. A variety of theories has been promulgated to explain the derivation of extrauterine implants of endometrial tissue that define this syndrome, but the precise pathogenic mechanisms responsible for pelvic pain and infertility associated with endometriosis remain unknown. Investigations from our laboratory have supported the hypothesis that recruitment of immune cells is a critical etiological step in disease establishment. The implantation of endometriosis lesions on ectopic peritoneal surfaces requires attachment and invasion of stromal and epithelial cells into the extracellular matrix of the host tissue. These proliferating cells attract immune cell infiltrates, particularly macrophages, via the selective production of chemokines. Recruitment of macrophages exacerbates implant growth and fibrosis via paracrine secretion of mitogens, cytokines, oxygen free radicals and prostaglandins. In addition, environmental endocrine disruptors have been invoked as putative etiologic agents. We observed that peritoneal concentrations of RANTES (Regulated on Activation Normal T cell Expressed and Secreted) was highly correlated with the presence of endometriosis in women and this protein accounts for ∼70% of monocyte chemotaxis in Boyden chamber assays containing pelvic fluid from endometriosis patients. Endometriosis stromal cells are a potent source of RANTES secretion and RANTES mRNA expression. Proinflammatory cytokines, particularly IL-1beta and TNF-alpha, activate RANTES gene transcription in these cells through an NF-kappaB-dependent mechanism. Estradiol enhances this effect at transcriptional and post-transcriptional levels. An environmental toxicant, 2,3,7,8-TCDD (dioxin), also appears to activate RANTES gene expression directly in endometriosis stromal cells. RANTES mRNA production also can be negatively regulated in these cells. PPAR-gamma ligands inhibit RANTES expression. Prolonged exposure to medroxyprogesterone acetate or treatment with the non-steroidal anti-inflammatory drug, sulindac, represses RANTES transcription via interference with NF-kappaB. It is hoped that identification and characterization of the latter pathways will provide opportunities for new drug discovery and refinement of the treatment of endometriosis. Supported by NIH grant HD37321.