Mundt B, Wirth T, Zender L, Waltemathe M, Trautwein C, Manns M P, Kühnel F, Kubicka S
Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover, Carl Neubergstrasse 1, 30625 Hannover, Germany.
Gut. 2005 Nov;54(11):1590-6. doi: 10.1136/gut.2004.056929.
Tumour necrosis factor related apoptosis inducing ligand (TRAIL) induces apoptosis in transformed cells and is considered as an agent for cancer therapy. As there is evidence that TRAIL is also essential for apoptosis in animal models of liver injury, we investigated the role of TRAIL in viral hepatitis and after alcohol consumption.
Expression of TRAIL was determined by western blot analysis in the liver of patients with chronic hepatitis C virus (HCV) infection as well as in experimental acute adenoviral hepatitis and after alcohol intake in the liver of mice. To investigate the effect of FasL and TRAIL expression, we used low dose adenoviral gene transfer. Apoptosis and steatosis were assessed by TUNEL and fat red staining, and by caspase assays.
TRAIL was overexpressed in the liver of patients with HCV associated steatosis while acute adenoviral hepatitis resulted in upregulation of TRAIL-DR5. In contrast with FasL, TRAIL expression was harmless to healthy livers. However, in virally infected livers, TRAIL expression induced apoptosis and steatosis whereas expression of FasL only resulted in apoptosis of hepatocytes without steatosis. After alcohol intake, TRAIL expression led to hepatic steatosis, without apoptosis of hepatocytes, indicating that TRAIL mediated apoptosis and steatosis may be independently modulated after viral infection and alcohol intake. In viral hepatitis and after alcohol intake, Ad-TRAIL mediated steatosis can be inhibited by injection of a neutralising TRAIL antibody.
We identified TRAIL as a new mediator of hepatic steatosis in viral hepatitis and after alcohol intake. Consequently, TRAIL mediated hepatotoxicity has to be considered in patients with viral hepatitis and alcoholic liver disease.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）可诱导转化细胞凋亡，被视为一种癌症治疗药物。鉴于有证据表明TRAIL在肝损伤动物模型的凋亡过程中也至关重要，我们研究了TRAIL在病毒性肝炎及饮酒后的作用。
通过蛋白质印迹分析确定慢性丙型肝炎病毒（HCV）感染患者肝脏中TRAIL的表达，以及实验性急性腺病毒性肝炎小鼠肝脏和饮酒后小鼠肝脏中TRAIL的表达。为研究FasL和TRAIL表达的影响，我们采用低剂量腺病毒基因转移。通过TUNEL和脂肪红染色以及半胱天冬酶检测评估细胞凋亡和脂肪变性。
TRAIL在HCV相关性脂肪变性患者的肝脏中过表达，而急性腺病毒性肝炎导致TRAIL-DR5上调。与FasL不同，TRAIL表达对健康肝脏无害。然而，在病毒感染的肝脏中，TRAIL表达诱导细胞凋亡和脂肪变性，而FasL表达仅导致肝细胞凋亡而无脂肪变性。饮酒后，TRAIL表达导致肝脏脂肪变性，但无肝细胞凋亡，这表明TRAIL介导的细胞凋亡和脂肪变性在病毒感染和饮酒后可能受到独立调节。在病毒性肝炎和饮酒后，注射中和性TRAIL抗体可抑制Ad-TRAIL介导的脂肪变性。
我们确定TRAIL是病毒性肝炎和饮酒后肝脏脂肪变性的新介质。因此，在病毒性肝炎和酒精性肝病患者中必须考虑TRAIL介导的肝毒性。
