NFκB mediates apoptosis through transcriptional activation of Fas (CD95) in adenoviral hepatitis
NFκB mediates apoptosis through transcriptional activation of Fas (CD95) in adenoviral hepatitis
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DOI：
10.1074/jbc.275.9.6421
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发表时间：
2000-03-03
影响因子：
4.8
通讯作者：
Kubicka, S
中科院分区：
文献类型：
--
作者：
Kühnel, F;Zender, L;Kubicka, S
NF kappa B 是胚胎肝脏发育和肝脏再生等多种生理条件下的重要生存因子。然而，NF kappa B也是细胞对多种细胞外应激刺激反应的主要介质，并且已经表明，一些病毒诱导的宿主细胞凋亡似乎依赖于NF kappa B的激活。病毒感染后NF kappa B的激活可能是启动针对病毒颗粒的先天免疫反应的快速方式。我们使用裸鼠模型评估了NFkB在腺病毒肝炎早期阶段的作用。表达 I kappa B α 突变形式的腺病毒载体。在腺病毒肝炎的早期阶段，表达 LacZ 的腺病毒载体可诱导 NFkB DNA 并与 Fas (CD95) mRNA 的上调相关，但与 Fast (CD95L) mRNA 的上调无关。肝脏腺病毒感染后 NF kappa B DNA 结合的快速增加可以被 I kappa B α 非常有效地抑制。与 LacZ 对照病毒相比，表达 IκB α 的腺病毒载体抑制 Fas (CD95) mRNA 表达的增加，特别是在肝炎的早期阶段。在具有 Fas 启动子-荧光素酶构建体的肝癌细胞系中进行的报告基因实验表明，I kappa B α 对 Fas (CD95) mRNA 的抑制是转录介导的。通过 caspase 3 测定和末端 dUTP 缺口末端标记测试评估了 Fas (CD95) 转录中 NF kappa B 依赖性增加的功能相关性。与对照相比，I kappa B α腺病毒感染导致病毒性肝炎早期的caspase 3活性降低，并在腺病毒给药后24小时预防肝细胞凋亡。因此，我们的研究证明了 NF kappa B 在 Fas (CD95) 介导的肝细胞凋亡中具有新的促凋亡功能。有趣的是，即使在肿瘤坏死因子-α 已经被诱导的阶段，NF kappa B 也会在病毒感染时介导肝细胞凋亡，如肿瘤坏死因子-α 血清水平的时间曲线所示。因此，NF kappa B 的促凋亡或抗凋亡作用似乎更多地取决于死亡刺激的性质，而不是组织的起源。
NF kappa B is an essential survival factor in several physiological conditions such as embryonal liver development and liver regeneration. However, NF kappa B is also a main mediator of the cellular response to a variety of extracellular stress stimuli, and it has been shown that some viral-induced host cell apoptosis appears to be dependent on NF kappa B activation, The activation of NF kappa B upon viral infection may be a rapid way of initiating an innate immune response against the viral particles, We have assessed the role of NFkB during the early phase of adenoviral hepatitis in a nude mouse model using an adenoviral vector expressing a mutant form of I kappa B alpha. Administration of a LacZ-expressing adenoviral vector induces NFkB DNA and correlates with the up-regulation of Fas (CD95) mRNA, but not Fast (CD95L) mRNA, during the early phase of adenoviral hepatitis. The rapid increase in NF kappa B DNA binding after adenoviral infection of the liver could be very effectively inhibited by I kappa B alpha. Compared with the LacZ control virus, the I kappa B alpha-expressing adenoviral vector inhibits the increase of Fas (CD95) mRNA expression, in particular in the very early phase of the hepatitis. Reporter gene experiments in hepatoma cell Lines with a Fas promoter-luciferase construct indicated that the repression of Fas (CD95) mRNA by I kappa B alpha was transcriptionally mediated. The functional relevance of the NF kappa B-dependent increase in Fas (CD95) transcription was assessed by caspase 3 assays and terminal dUTP nick-end labeling tests. Compared with the control, I kappa B alpha adenoviral infection resulted in reduced caspase 3 activity during the early phase of viral hepatitis and in a prevention of Liver cell apoptosis 24 h after adenoviral administration. Therefore our study demonstrates a new pro-apoptotic function of NF kappa B in Fas (CD95)-mediated apoptosis of hepatocytes. Interestingly, NF kappa B mediates liver cell apoptosis upon viral infection even in a phase where tumor necrosis factor-alpha is already induced, as shown by the time curves of tumor necrosis factor-alpha serum levels, Therefore, the pro- or anti-apoptotic role of NF kappa B appears to be more determined by the nature of the death stimulus than by the origin of the tissue.