Estrogen Receptor β Modulates Apoptosis Complexes and the Inflammasome to Drive the Pathogenesis of Endometriosis.
Estrogen Receptor β Modulates Apoptosis Complexes and the Inflammasome to Drive the Pathogenesis of Endometriosis.
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DOI：
10.1016/j.cell.2015.10.034
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发表时间：
2015-11-05
期刊：
影响因子：
64.5
通讯作者：
O'Malley BW
中科院分区：
文献类型：
--
作者：
Han SJ;Jung SY;Wu SP;Hawkins SM;Park MJ;Kyo S;Qin J;Lydon JP;Tsai SY;Tsai MJ;DeMayo FJ;O'Malley BW
雌激素介导的细胞信号传导的改变在子宫内膜异位症的发病机制中发挥着重要作用。除了较高的雌激素受体 (ER)β 水平外，在子宫内膜异位组织中还检测到增强的 ERβ 活性，并且通过 ERβ 选择性拮抗剂抑制增强的 ERβ 活性，抑制了小鼠异位病变的生长。值得注意的是，ERβ功能的增强刺激了子宫内膜异位症的进展。作为逃避细胞生存内源性免疫监视的机制，ERβ 与细胞质中的细胞凋亡机制相互作用，抑制 TNFα 诱导的细胞凋亡。 ERβ 还与细胞质炎症小体的成分相互作用，增加白细胞介素 1β，从而增强其细胞粘附和增殖特性。此外，ERβ功能的增强增强了上皮-间质转化信号传导，从而增加了子宫内膜异位组织的侵袭活性，从而形成异位病变。总的来说，我们揭示了逆行月经产生的子宫内膜组织如何逃避免疫监视，并通过获得 ERβ 功能而发展为持续的异位病变。
Alterations in estrogen-mediated cellular signaling play an essential role in the pathogenesis of endometriosis. In addition to higher estrogen receptor (ER)β levels, enhanced ERβ activity was detected in endometriotic tissues, and the inhibition of enhanced ERβ activity by an ERβ-selective antagonist suppressed mouse ectopic lesion growth. Notably, gain of ERβ function stimulated the progression of endometriosis. As a mechanism to evade endogenous immune surveillance for cell survival, ERβ interacts with cellular apoptotic machinery in the cytoplasm to inhibit TNFα-induced apoptosis. ERβ also interacts with components of the cytoplasmic inflammasome to increase interleukin-1β and thus enhance its cellular adhesion and proliferation properties. Furthermore, this gain of ERβ function enhances epithelial-mesenchymal transition signaling, thereby increasing the invasion activity of endometriotic tissues for establishment of ectopic lesions. Collectively, we reveal how endometrial tissue generated by retrograde menstruation can escape immune surveillance and develop into sustained ectopic lesions via gain of ERβ function.