Galle P R, Hofmann W J, Walczak H, Schaller H, Otto G, Stremmel W, Krammer P H, Runkel L
University Hospital, Department of Gastroenterology, Heidelberg, Germany.
J Exp Med. 1995 Nov 1;182(5):1223-30. doi: 10.1084/jem.182.5.1223.
Apoptosis occurs in the normal liver and in various forms of liver disease. The CD95 (APO-1/Fas) (CD95) receptor mediates apoptosis, and liver cells in animal models are acutely sensitive to apoptosis initiated by this receptor. We have used primary human hepatocytes as a model system to investigate CD95-mediated apoptotic liver damage. Treatment of fresh human hepatocytes with low concentrations of agonistic antibodies against CD95 resulted in apoptosis of > 95% of the cultured liver cells within 4 and 7.5 h. Immunohistology of a panel of explanted liver tissues revealed that hepatocytes in normal livers (n = 5) and in alcoholic cirrhosis (n = 13) expressed low constitutive levels of CD95. CD95 receptor expression was highly elevated in hepatocytes in hepatitis B virus-related cirrhosis (n = 9) and in acute liver failure (n = 8). By in situ hybridization CD95 ligand messenger RNA expression was absent in normal liver but detected at high levels in livers with ongoing liver damage. In cases of hepatitis B virus-related cirrhosis and acute hepatic failure, ligand expression was found primarily in areas with lymphocytic infiltration. In contrast, in patients with alcoholic liver damage, high CD95 ligand messenger RNA expression was found in hepatocytes. These findings suggest that liver destruction in hepatitis B may primarily involve killing of hepatocytes by T lymphocytes using the CD95 receptor-ligand system. In alcoholic liver damage, death of hepatocytes might occur by fratricide and paracrine or autocrine mechanisms mediated by the hepatocytes themselves.
细胞凋亡发生于正常肝脏及各种肝脏疾病中。CD95（APO-1/Fas）受体介导细胞凋亡，动物模型中的肝细胞对该受体引发的细胞凋亡极为敏感。我们使用原代人肝细胞作为模型系统来研究CD95介导的肝细胞凋亡损伤。用低浓度抗CD95激动性抗体处理新鲜人肝细胞，4至7.5小时内超过95%的培养肝细胞发生凋亡。一组移植肝组织的免疫组织学检查显示，正常肝脏（n = 5）和酒精性肝硬化（n = 13）中的肝细胞CD95组成性表达水平较低。在乙型肝炎病毒相关性肝硬化（n = 9）和急性肝衰竭（n = 8）的肝细胞中，CD95受体表达显著升高。通过原位杂交发现，正常肝脏中不存在CD95配体信使核糖核酸表达，但在有进行性肝损伤的肝脏中可检测到高水平表达。在乙型肝炎病毒相关性肝硬化和急性肝衰竭病例中，配体表达主要见于淋巴细胞浸润区域。相反，在酒精性肝损伤患者中，肝细胞中发现高CD95配体信使核糖核酸表达。这些发现表明，乙型肝炎中的肝破坏可能主要涉及T淋巴细胞利用CD95受体-配体系统杀伤肝细胞。在酒精性肝损伤中，肝细胞死亡可能通过肝细胞自身介导的自相残杀及旁分泌或自分泌机制发生。
