Involvement of Iron, Nuclear Factor-Kappa B (NF-κB) and Prostaglandins in the Pathogenesis of Peritoneal Endometriosis-Associated Inflammation: A Review

Abstract

Peritoneal endometriosis is a chronic pelvic inflammatory disease, characterized by increased numbers of peritoneal macrophages and their secreted products such as cytokines, growth and angiogenic factors in peritoneal fluid. Inflammation plays a major role in pain and infertility associated with endometriosis, but is also extensively involved in the molecular and cellular processes that lead to peritoneal endometriotic lesion development. Several inflammatory mediators have therefore been studied in the context of endometriosis over the last few years. The aim of this review is to focus on three that have been clearly implicated in the pathogenesis of endometriosis and may be linked: peritoneal iron metabolism, nuclear factor-kappa B (NF-κB) activation, and prostaglandin biosynthesis. Peritoneal iron overload has been conclusively demonstrated in endometriosis patients and may induce oxidative stress in the peritoneal cavity. Oxidative stress and proinflammatory cytokines are well known to be potent activators of the NF-κB pathway, which has recently been implicated in peritoneal endometriosis. Induced NF-κB activation leads to expression of numerous proinflammatory genes such as cytokines, which may provide positive feedback to the pathway, self-perpetuating the inflammatory response. Other important NF-κB-regulated molecules are prostaglandin biosynthesis enzymes, and cyclooxygenase-2 (COX-2) in particular. Increased concentrations of prostaglandins have been evidenced in the peritoneal fluid of endometriosis patients and COX-2 inhibitors have proved to be effective in ‘in vitro’ and ‘in vivo’ experimental models. In the light of available data collected from patient biopsies, as well as ‘in vitro’ and ‘in vivo’ studies, the respective implication and potential molecular association of iron, NF-κB and prostaglandins in the pathogenesis of endometriosis are discussed. The key role of peritoneal macrophages is emphasized and potential therapeutic targets are examined.