子宮內膜異位症對於生殖年齡的婦女是常見的婦科疾病，雖然目前對於病理發展及機制都尚未釐清，但已有許多研究文獻證明細胞激素及生長激素參與在子宮內膜異症的形成過程中。在病患的腹膜液中，有高度表現的細胞激素，例如：腫瘤壞死因子、介白素-1β、介白素-6、介白素-8。在本實驗室已發表的研究文獻，子宮內膜異位症形成過程中，雙特異性去磷酸酶-2在受到缺氧誘導因子-1α的抑制下，增加有絲分裂活化蛋白質激酶的活性，促進介白素-1β刺激前列腺素合成酶-2，進而造成前列腺素E2生成。然而，對於其他細胞激素在子宮內膜異位症參與的機制，目前還是無法下定論。因此，本篇論文將探討在子宮內膜異位症，雙特異性去磷酸酶-2是否參與調控介白素-6/JAK-STAT3及細胞的功能性。本篇論文實驗結果顯示，比較子宮內膜原位及異位的基質細胞，活化態的STAT3高度表現在異位的基質細胞；而原位基質細胞經過介白素-6刺激後，活化態的STAT3亦有高度表現的情形。若將原位子宮內膜基質細胞中之雙特異性去磷酸酶-2的表現量抑制掉，則介白素-6的表現量會因而增加。另外，在細胞功能性測試實驗中，介白素-6的刺激促使原位基質細胞具有抗細胞凋亡的能力，但並未促進細胞增生。從以上實驗結果得知，缺氧前透過降低雙特異性去磷酸酶-2的表現量，進而促進介白素-6的生成，透過JAK-STAT3的訊息傳遞路徑，使細胞具有抗細胞凋亡的能力。這樣的機制將有助於異位組織在氧氣不足的情況下仍保有存活的能力。本研究結果對於在子宮內膜異位的發生提供了一個新的病理機制。

Endometriosis is a common gynecologic disease of reproductive age women. Despite the complicated and largely unknown etiology, a growing body of evidence indicates that cytokines and growth factors are involved in the pathogenesis of endometriosis. Elevated concentration of several cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-8 in peritoneal fluid of women with endometriosis have been reported. We have previously demonstrated that dual specificity phosphatase 2 (DUSP-2), a Mitogen-activated protein kinase (MAPK) specific phosphatase, was downregulated by hypoxia inducible factor-1α (HIF-1α). Downregulation of DUSP-2 promotes IL-1β-induced cyclooxygenase-2 (COX-2) expression leading to overproduction of prostaglandin E2, which plays important roles in the development of endometriosis. However, the regulation and pathological function of other cytokines remain largely uncharacterized. Herein, we aimed to investigate the regulation and function of IL-6 in women with endometriosis. Our results show that treatment of endometrial stromal cells with IL-6 triggers phosphorylation of signal transducer and activator of transcription 3 (STAT3). Concordance with this notion, phosphorylated STAT3 was evident in stromal cells isolated from endometriotic lesion compared to those isolated from normal endometrium. In addition, IL-6 expression was mediated via downregulation of DUSP2 as knockdown of DUSP2 was sufficient to induce the expression of IL-6. Pre-treatment with IL-6 protected stromal cells from etoposide-induced apoptosis but had no effect on promoting stromal cells proliferation. In conclusion, aberrant activation of IL-6-STAT3 signaling pathway was due to downregulation of DUSP2. Aberrant expression of IL-6 protects ectopic stromal cells from apoptosis through JAK-STAT3 signaling pathway, which may play an important role in the progression of endometriosis.

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