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J Clin Endocrinol Metab. 2014 Mar;99(3):E427-37. doi: 10.1210/jc.2013-3717. Epub 2014 Jan 1.

Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis.

Author information

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.

PMID:
24423359
PMCID:
PMC5393480
DOI:
10.1210/jc.2013-3717
[Indexed for MEDLINE]
Free PMC Article

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