Han Sang Jun, Jung Sung Yun, Wu San-Pin, Hawkins Shannon M, Park Mi Jin, Kyo Satoru, Qin Jun, Lydon John P, Tsai Sophia Y, Tsai Ming-Jer, DeMayo Francesco J, O'Malley Bert W
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Alkek Center for Molecular Discovery, Verna and Marrs McLean, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Cell. 2015 Nov 5;163(4):960-74. doi: 10.1016/j.cell.2015.10.034.
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 TNF-α-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.
雌激素介导的细胞信号改变在子宫内膜异位症的发病机制中起重要作用。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ERβ选择性拮抗剂对增强的ERβ活性的抑制作用抑制了小鼠异位病变的生长。值得注意的是，ERβ功能的获得促进了子宫内膜异位症的进展。作为一种逃避内源性免疫监视以实现细胞存活的机制，ERβ与细胞质中的细胞凋亡机制相互作用以抑制TNF-α诱导的细胞凋亡。ERβ还与细胞质炎性小体的成分相互作用以增加白细胞介素-1β，从而增强其细胞粘附和增殖特性。此外，ERβ功能的这种获得增强了上皮-间质转化信号，从而增加了子宫内膜异位组织的侵袭活性以建立异位病变。总的来说，我们揭示了逆行月经产生的子宫内膜组织如何通过ERβ功能的获得逃避免疫监视并发展为持续性异位病变。
