Shih-Chieh Lin1, Yo-Hua Li, Meng-Hsing Wu, Yu-Fan Chang, Dong-Kee Lee, Sophia Y Tsai, Ming-Jer Tsai, Shaw-Jenq Tsai. 1. Department of Physiology (S.-C.L., Y.-F.C., S.-J.T.), Institute of Basic Medical Sciences (Y.-H.L., S.-J.T.), and Department of Obstetrics and Gynecology (M.-H.W.), College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; and Department of Molecular and Cellular Biology (D.-K.L., S.Y.T., M.-J.T.), Baylor College of Medicine, Houston, Texas 77030.
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.
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.
Authors: Emily Evans-Hoeker; Bruce A Lessey; Jae Wook Jeong; Ricardo F Savaris; Wilder A Palomino; Lingwen Yuan; David P Schammel; Steven L Young Journal: Reprod Sci Date: 2016-05-24 Impact factor: 3.060
Authors: Dustin M Brown; Hsiu-Chi Lee; Shi Liu; Charles M Quick; Lorenzo M Fernandes; Frank A Simmen; Shaw-Jenq Tsai; Rosalia C M Simmen Journal: J Endocr Soc Date: 2018-05-25