Suppression of COUP-TFII by Proinflammatory Cytokines Contributes to the Pathogenesis of Endometriosis

Endometriosis is one of the most common gynecological diseases in women with a prevalence rate of approximately 10%. Chronic pelvic inflammation has been observed in patients with endometriosis and is associated with disease severity. However, how pelvic inflammation promotes endometriosis progression remains unknown. The objective of the study was to investigate the regulatory network of proinflammatory cytokines in endometriosis progression. Immunostaining of human endometrial (n = 21) and endometriotic (n = 36) sections, quantitative RT-PCR, Western blotting, chromatin immunoprecipitation, and luciferase reporter assays in primary culture human endometrial stromal cells were performed. Autologous transplantation of uterine endometrium from control chicken ovalbumin upstream promoter-transcription factor II [(COUP-TFII) flox/flox] and uterus-specific COUP-TFII knockout mice was performed. Expression of COUP-TFII was significantly reduced in endometriotic stroma. Reduction of COUP-TFII in endometriotic stromal cells was mediated by proinflammatory cytokines including IL-1β, TNF-α, and TGF-β1 via a common effector, microRNA-302a. Treatment with these proinflammatory cytokines increased the expression of microRNA-302a, which targets the 3′untranslated region of COUP-TFII to cause its down-regulation. Intriguingly, down-regulation of COUP-TFII in endometrial stromal cells resulted in de-repression of cyclooxygenase-2 (COX-2). Further investigation demonstrated that COUP-TFII directly binds to COX-2 promoter to inhibit its transcription. Forced expression of COUP-TFII inhibited IL-1β-induced COX-2 up-regulation, whereas the knockdown of COUP-TFII augmented this effect. Because overexpression of COX-2 has been demonstrated to be a master regulator in endometriosis progression, our data demonstrate the critical function of proinflammatory cytokines and the COUP-TFII regulatory gene network in the progression of endometriosis.