Resistance of rat hepatocytes against bile acid-induced apoptosis in cholestatic liver injury is due to nuclear factor-kappa B activation
Resistance of rat hepatocytes against bile acid-induced apoptosis in cholestatic liver injury is due to nuclear factor-kappa B activation
复制标题
DOI：
10.1016/s0168-8278(03)00214-9
复制
发表时间：
2003-08-01
影响因子：
25.7
通讯作者：
Moshage, H
中科院分区：
文献类型：
--
作者：
Schoemaker, MH;Gommans, WA;Moshage, H
背景/目标：探讨胆汁淤积性肝损伤中细胞凋亡的程度和机制，以及转录因子核因子-κ B在胆汁酸诱导的细胞凋亡中的保护作用。此外，将大鼠肝细胞原代培养物暴露于甘氨鹅去氧胆酸（GCDCA）、牛磺熊去氧胆酸（TUDCA）、牛磺鹅去氧胆酸（TCDCA）和细胞因子。TUNEL染色、caspase-3活性染色、caspase-8、caspase-9和caspase-3活性检测细胞凋亡。结果：胆汁淤积大鼠肝细胞凋亡有限，NF-κ B调控的抗凋亡基因A1和cIAP 2表达增加。Bcl-2仅表达于胆管上皮。与TCDCA和TUDCA相反，GCDCA在肝细胞中诱导具有死亡结构域的Fas相关蛋白（FADD）非依赖性途径的凋亡。虽然胆汁酸不能激活NF-κ B，但胆汁淤积时细胞因子激活NF-κ B可通过上调A1和cIAP 2而保护GCDCA诱导的体外细胞凋亡。结论：GCDCA诱导的细胞凋亡是一个由caspase-8激活的非FADD依赖性途径。然而，胆汁酸诱导的细胞凋亡在胆汁淤积是有限的。这可能是由于尼古丁诱导的NF-κ B调节的抗凋亡基因如A1和cIAP 2的激活。(C)2003年欧洲肝脏研究协会。由Elsevier Science B. V.出版，版权所有。
Background/Aims: To examine the extent and mechanisms of apoptosis in cholestatic liver injury and to explore the role of the transcription factor nuclear factor-kappa B in protection against bile acid-induced apoptosis.Methods: Cholestatic liver injury was induced by bile duct ligation in Wistar rats. Furthermore, primary cultures of rat hepatocytes were exposed to glycochenodeoxycholic acid (GCDCA), tauroursodeoxycholic acid (TUDCA), taurochenodeoxycholic acid (TCDCA) and to cytokines. Apoptosis was determined by TUNEL-staining, active caspase-3 staining, activation of caspase-8, -9 and -3.Results: Limited hepatocyte apoptosis and an increased expression of NF-kappaB-regulated anti-apoptotic genes A1 and cIAP2 were detected in cholestatic rat livers. Bcl-2 expression was restricted to bile duct epithelium. In contrast to TCDCA and TUDCA, GCDCA induced apoptosis in a Fas-associated protein with death domain (FADD)-independent pathway in hepatocytes. Although bile acids do not activate NF-kappaB, NF-kappaB activation by cytokines (induced during cholestasis) protected against GCDCA-induced apoptosis in vitro by upregulating A1 and cIAP2.Conclusions: GCDCA induces apoptosis in a mitochondria-controlled pathway in which caspase-8 is activated in a FADD-independent manner. However, bile acid-induced apoptosis in cholestasis is limited. This could be explained by cytokine-induced activation of NF-kappaB-regulated anti-apoptotic genes like A1 and cIAP2. (C) 2003 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.