Tumor necrosis factor signaling in hepatocyte apoptosis
Tumor necrosis factor signaling in hepatocyte apoptosis
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DOI：
10.1111/j.1440-1746.2006.04645.x
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发表时间：
2007-06-01
影响因子：
4.1
通讯作者：
Hatano, Etsuro
中科院分区：
文献类型：
--
作者：
Hatano, Etsuro
死亡受体介导的肝细胞凋亡与多种肝脏疾病有关，包括病毒性肝炎、酒精性肝炎、缺血/再灌注损伤、暴发性肝衰竭、淤胆性肝损伤和癌症。我们的目的是阐明死亡受体介导的肝细胞凋亡的保护途径以及细胞凋亡在肝损伤中的意义。体外：AdI-kappa BSR联合肿瘤坏死因子-α/Jo2可迅速诱导小鼠肝细胞凋亡，而单独应用肿瘤坏死因子-α/Jo2对小鼠肝细胞几乎无细胞毒作用。线粒体通透性转换(MPT)抑制剂环孢素A和三氟拉嗪的联合使用可保护Adi kappa BSR感染的肝细胞免受肿瘤坏死因子-α的影响，但不能保护Fas介导的细胞凋亡。一氧化氮供体S-亚硝基-N-乙酰青霉胺可抑制Bid裂解、MPT和caspase的激活，减少肿瘤坏死因子-α和Fas介导的细胞杀伤。LY294002对PI3K的抑制和显性-负性Akt减弱了由TNF-α或Jo2激活的NF-kappa B，使肝细胞对TNF-α或Jo2敏感。体内：细胞凋亡和坏死可能在肝脏缺血/再灌注损伤中起重要作用。腺病毒转导myrAkt可通过Bad而不是NF-kappaB抑制大鼠肝细胞凋亡和随后的肝缺血/再灌注损伤，胆汁酸通过诱导肝细胞凋亡而导致胆汁淤积时的肝损伤。肝细胞凋亡在胆管结扎性肝损伤中起重要作用。至少，胆管结扎所致的早期肝损伤涉及Fas介导和Bclxl不敏感的细胞凋亡途径。综上所述，细胞凋亡在各种肝病中的作用可能提供了可能的治疗方法。
Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, and cancer. Our aim was to clarify the protective pathway in death receptor-mediated hepatocyte apoptosis and the significance of apoptosis in liver injury. In vitro: AdI kappa Bsr plus tumor necrosis factor (TNF)-alpha/Jo2 rapidly induced apoptosis in mouse hepatocyte, whereas TNF-alpha/Jo2 alone produced little cytotoxicity. The combination of the mitochondrial permeability transition (MPT) inhibitors, cyclosporine A and trifluoperazine, protected AdI kappa Bsr-infected hepatocytes from TNF-alpha- but not Fas-mediated apoptosis. The TNF-alpha and Jo2 induced iNOS through NF-kappa B. Nitric oxide donor (S-nitroso-N-acetylpenicillamine) inhibited Bid cleavage, the MPT, and caspase activation and reduced TNF-alpha- and Fas-mediated cell killing. Inhibition of PI3K by LY294002 and a dominant-negative Akt, which attenuated NF-kappa B activation by TNF-alpha or Jo2, sensitized hepatocytes to TNF-alpha or Jo2. In vivo: apoptosis as well as necrosis may play an important role in hepatic ischemia/reperfusion injury. Adenoviral gene transfer of myrAkt could inhibit apoptotic cell death and subsequent hepatic ischemia/reperfusion injury in the rat, through Bad not NF-kappa B. Bile acids cause liver injury during cholestasis by inducing hepatocyte apoptosis. Hepatocyte apoptosis has a major role in hepatic injury by bile duct ligation. At least, early hepatic injury by bile duct ligation involved Fas-mediated and Bcl-xL insensitive apoptotic pathway. In conclusion, the role of apoptosis in various liver diseases may suggest possible treatments.