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.
J Clin Endocrinol Metab. 2014 Mar;99(3):E427-37. doi: 10.1210/jc.2013-3717. Epub 2014 Jan 1.
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.
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.
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.
子宫内膜异位症是女性最常见的妇科疾病之一，患病率约为 10%。在子宫内膜异位症患者中观察到慢性盆腔炎，且与疾病严重程度相关。然而，盆腔炎症如何促进子宫内膜异位症的进展尚不清楚。
本研究旨在探讨促炎细胞因子在子宫内膜异位症进展中的调控网络。
设计、环境和患者：对人子宫内膜（n=21）和子宫内膜异位症（n=36）切片进行免疫染色，对原代培养的人子宫内膜基质细胞进行定量 RT-PCR、Western blot、染色质免疫沉淀和荧光素酶报告基因检测，进行自体移植鸡卵清蛋白上游启动子转录因子 II（COUP-TFII） flox/flox 和子宫特异性 COUP-TFII 敲除小鼠的子宫内膜。
COUP-TFII 在子宫内膜异位症的基质中表达显著降低。促炎细胞因子（包括 IL-1β、TNF-α 和 TGF-β1）通过共同效应物 microRNA-302a 介导的 COUP-TFII 在子宫内膜异位症基质细胞中的减少。这些促炎细胞因子的处理增加了 microRNA-302a 的表达，其靶向 COUP-TFII 的 3'非翻译区导致其下调。有趣的是，子宫内膜基质细胞中 COUP-TFII 的下调导致环氧化酶-2（COX-2）去抑制。进一步的研究表明，COUP-TFII 直接结合 COX-2 启动子抑制其转录。COUP-TFII 的强制表达抑制了 IL-1β 诱导的 COX-2 上调，而 COUP-TFII 的敲低增强了这种效应。
因为 COX-2 的过度表达已被证明是子宫内膜异位症进展的主要调节因子，我们的数据表明促炎细胞因子和 COUP-TFII 调节基因网络在子宫内膜异位症进展中的关键作用。
