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

Shih-Chieh Lin, Shih‐Chieh Lin, Yo-Hua Li, Meng-Hsing Wu, Meng‐Hsing Wu, Yu-Fan Chang, Dong-Kee Lee, Sophia Y Tsai, Ming‐Jer Tsai, Ming-Jer Tsai, Shaw‐Jenq Tsai, Shaw-Jenq Tsai
The Journal of clinical endocrinology and metabolism · 2014 · vol. 99(3) , pp. E427–E437 · doi:10.1210/jc.2013-3717 · PMID:24423359 · W2000299884
article OA: bronze CC0 ⤵ 27 in-corpus citations
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Proinflammatory cytokines suppress COUP-TFII expression in endometriotic stromal cells, increasing COX-2 and contributing to endometriosis pathogenesis.

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Abstract

CONTEXT: 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. OBJECTIVE: The objective of the study was to investigate the regulatory network of proinflammatory cytokines in endometriosis progression. DESIGN, SETTINGS, AND PATIENTS: 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. RESULTS: 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. CONCLUSION: 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.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

COUP Transcription Factor II Cytokines Endometriosis Inflammation Mediators Uterine Diseases Animals Cells, Cultured COUP Transcription Factor II COUP Transcription Factor II Cytokines Cytokines Down-Regulation Down-Regulation Down-Regulation Endometriosis Endometriosis Endometrium Endometrium Endometrium Female

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