Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease
Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease
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DOI：
10.1073/pnas.0802702105
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发表时间：
2008-08-05
影响因子：
11.1
通讯作者：
Okumura, Ko
中科院分区：
文献类型：
--
作者：
Takeda, Kazuyoshi;Kojima, Yuko;Okumura, Ko
慢性胆汁淤积常导致肝纤维化性肝衰竭的过早死亡;然而，导致胆汁性肝硬化的分子机制尚未得到证实。在这篇文章中，我们表明，由肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体2/死亡受体5（DR 5）介导的死亡信号可能是胆汁淤积性肝损伤的关键调节因子。激动性抗DR 5单克隆抗体治疗引发胆管细胞凋亡，随后以小鼠品系特异性方式诱导胆管炎和胆汁淤积性肝损伤。TRAIL或DR 5缺陷小鼠对胆总管结扎诱导的胆汁淤积具有相对抗性，胆总管结扎增加了胆管细胞上DR 5的表达，使小鼠对DR 5介导的胆管炎敏感。值得注意的是，抗DR 5单克隆抗体诱导的胆管炎表现出典型的组织学外观，让人联想到人类原发性硬化性胆管炎。人原发性硬化性胆管炎和原发性胆汁性肝硬化患者的胆管细胞组成性表达DR 5，并且TRAIL表达和凋亡显著升高。因此，TRAIL/DR 5介导的细胞凋亡可能实质上有助于慢性胆汁淤积性疾病，特别是原发性硬化性胆管炎。
Chronic cholestasis often results in premature death from liver failure with fibrosis; however, the molecular mechanisms contributing to biliary cirrhosis are not demonstrated. In this article, we show that the death signal mediated by TNF-related apoptosis-inducing ligand (TRAIL) receptor 2/death receptor 5 (DR5) may be a key regulator of cholestatic liver injury. Agonistic anti-DR5 monoclonal antibody treatment triggered cholangiocyte apoptosis, and subsequently induced cholangitis and cholestatic liver injury in a mouse strain-specific manner. TRAIL- or DR5-deficient mice were relatively resistant to common bile duct ligation-induced cholestasis, and common bile duct ligation augmented DR5 expression on cholangiocytes, sensitizing mice to DR5-mediated cholangitis. Notably, anti-DR5 monoclonal antibody-induced cholangitis exhibited the typical histological appearance, reminiscent of human primary sclerosing cholangitis. Human cholangiocytes constitutively expressed DR5, and TRAIL expression and apoptosis were significantly elevated in cholangiocytes of human primary sclerosing cholangitis and primary biliary cirrhosis patients. Thus, TRAIL/ DR5-mediated apoptosis may substantially contribute to chronic cholestatic disease, particularly primary sclerosing cholangitis.