子宮內膜異位症是目前最常見的婦科疾病，它的發生率大約為10~15%並且好發於生育年齡的女性。過去研究指出，過度表現環氧酵素二型 (cyclooxygenase-2，COX-2)導致前列腺素E2 (prostaglandin E2， PGE2)異常增加，我們的研究也發現PGE2前列腺素E2在子宮內膜異位症的發生過程中扮演不可或缺的角色。然而，在子宮內膜異位症的病人身上大量表現環氧酵素二型的機制目前尚未明瞭。雞卵蛋白上游驅動子-轉錄因子II (Chicken ovalbumin upstream promoter-transcription factor II ，COUP-TFII)是一個未知配體(ligand)的受體(receptor)，因此被歸類於孤兒核受體(orphan nuclear receptor)的一員。雞卵蛋白上游驅動子-轉錄因子II具有兩個高度保留的鋅指結構(Zn-finger motif)，顯示其為具有去氧核醣核酸結合位(DNA binding domain，DBD)的核受體(nuclear receptor)。藉由先前的文獻已知雞卵蛋白上游驅動子-轉錄因子II有參與抑制固醇類生成基因的表現，而這些固醇類生成基因被發現與子宮內膜異位症的發生有關，因此研究雞卵蛋白上游驅動子-轉錄因子II在子宮內膜異位症中扮演什麼樣的角色是相當重要的。在我們研究結果中發現異位的子宮內膜基質細胞，其雞卵蛋白上游驅動子-轉錄因子II的表現是明顯的少於原位的子宮內膜基質細胞。接著我們又利用原位子宮內膜基質細胞給與介白素-1β (interlukin-1β，IL-1β) 處理的實驗證明，介白素-1β可以抑制雞卵蛋白上游驅動子-轉錄因子II的表現，此發現可用來解釋在患有子宮內膜異位症的病人腹腔液中高濃度的介白素-1β有可能是造成雞卵蛋白上游驅動子-轉錄因子II表現量在異位子宮內膜基質細胞低下的原因；更進一步的實驗我們發現介白素-1β抑制雞卵蛋白上游驅動子-轉錄因子II 的表現量是藉由抑制其驅動子的活性。另外，我們在原位基質細胞上利用降低雞卵蛋白上游驅動子-轉錄因子II基因表現(knock-down)的方法證明在原位基質細胞表現較少的雞卵蛋白上游驅動子-轉錄因子II可以增加介白素-1β刺激而導致環氧酵素二型的大量表現；相反的，於異位基質細胞上過度表現雞卵蛋白上游驅動子-轉錄因子II基因(Over-expression)則證明了雞卵蛋白上游驅動子-轉錄因子II會抑制環氧酵素二型基礎表現量及介白素-1β刺激後環氧酵素二型的表現量。最後，染色質-免疫沉澱-聚合酶連鎖反應(chromatin immunoprecipitation- PCR)的結果指出雞卵蛋白上游驅動子-轉錄因子II會與環氧酵素二型基因的驅動子結合在一起，這樣的結果證明了雞卵蛋白上游驅動子-轉錄因子II會直接抑制環氧酵素二型基因的表現。總括以上的結果，我們發現介白素-1β抑制雞卵蛋白上游驅動子-轉錄因子II表現導致原本對於環氧酵素二型的抑制效果被解除，這使得環氧酵素二型基因對於介白素-1β的敏感度上升。過去已經知道前列腺素E2濃度提高的是因為過度表現的環氧酵素二型，而前列腺素E2會刺激固醇類荷爾蒙生成急性調節蛋白(steroidogenic acute regulatory protein)及苯環化酵素(aromatase)的表現，進而造成對於控制子宮內膜細胞增生很重要的雌激素異常生成。我們的結果證明了雞卵蛋白上游驅動子-轉錄因子II在子宮內膜異位症中的關鍵功能，並且為研究子宮內膜異位症的病原學開啟了另一扇門。

Endometriosis is one of the most common gynecological diseases in women with a prevalence rate of 10-15%. Overexpression of cyclooxygenase-2 (COX-2) and thus aberrant production of prostaglandin (PG) E2 has been shown to play an indispensable role in the development of endometriosis. However, the underlying mechanism of COX-2 overexpression remains largely unknown. Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) is an orphan nuclear receptor, which contains two conserved Zn-finger motifs, signified the presence of the DNA binding domain (DBD) of a nuclear receptor. COUP-TFII has been shown to inhibit expression of genes involving in steroidogenesis. Since aberrant expression of steroidogenic genes has been implicated in the development of endometriosis, we are interested in investigating the role of COUP-TFII in endometriosis. Here, we found that the expression of COUP-TFII was significantly reduced in endometriotic stromal cells compared to the eutopic endometrial stromal cells. Our data also demonstrated that reduced expression of COUP-TFII in endometrial stromal cells was mediated by elevated concentration of interleukin-1β (IL-1β) in the peritoneal fluid as treatment with IL-1β inhibited COUP-TFII expression. A further study revealed that IL-1β inhibited COUP-TFII promoter activity. Reduced expression of COUP-TFII leads to overexpression of COX-2 in endometriotic stromal cells as demonstrated by COUP-TFII knockdown assay. In contrast, forced expression of COUP-TFII inhibited basal and IL-1β-induced COX-2 expression in ectopic endometriotic stromal cells. A result from chromatin immunoprecipitation-PCR assay demonstrated that COUP-TFII binds to cox-2 promoter, providing the evidence that COUP-TFII directly inhibits cox-2 promoter activity. Taken together, we showed that IL-1β inhibits COUP-TFII expression, leading to de-repression of COX-2 expression and increased the sensitivity of cox-2 gene to IL-1β. It is known that elevated PGE2, due to overexpression of COX-2, stimulates the expression of steroidogenic acute regulatory protein and aromatase leading to aberrant production of estrogen, an important steroid in controlling endometrial cells proliferation. Our data demonstrate the critical function of COUP-TFII in the development of endometriosis that may shed lights on investigating novel molecular mechanisms of the etiology of endometriosis.

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