Mechanisms of liver disease: cross-talk between the NF-kappaB and JNK pathways.
Mechanisms of liver disease: cross-talk between the NF-kappaB and JNK pathways.
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DOI：
10.1515/bc.2009.111
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发表时间：
2009-10
影响因子：
3.7
通讯作者：
Franzoso G
中科院分区：
文献类型：
--
作者：
Papa S;Bubici C;Zazzeroni F;Franzoso G
肝脏在内源性和外源性化学物质的转化和降解以及去除不需要的细胞（如受损的、遗传突变的或病毒感染的细胞）方面发挥着核心作用。由于这一功能，肝脏容易受到这些自然发生过程中产生的产物引起的毒性的影响。肝细胞死亡是肝损伤的主要特征。响应于肝损伤，启动特定的细胞内过程以维持肝脏完整性。包括肿瘤坏死因子（TNF）α和白细胞介素-6（IL-6）在内的炎性细胞因子是这些过程的关键介质，因为它们可以激活不同的细胞反应，例如增殖、存活和死亡。TNFα诱导肝细胞中的特异性信号传导途径，导致促存活介质或细胞死亡效应物的激活。虽然转录因子NF-κB的活化促进了存活，但c-Jun N-末端激酶（JNK）和半胱天冬酶的诱导代表了TNFα介导的信号通路中细胞死亡的战略效应物。本文综述了TNFα诱导肝细胞毒性机制的最新研究进展，提示NF-κB对JNK诱导的肝细胞死亡具有保护作用。需要鉴定调节NF-κB和JNK通路之间相互作用的机制以鉴定用于治疗肝病（包括肝炎和肝细胞癌）的新靶点。
The liver plays a central role in the transformation and degradation of endogenous and exogenous chemicals, and in the removal of unwanted cells such as damaged, genetically mutated or virus-infected cells. Because of this function, the liver is susceptible to toxicity caused by the products generated during these natural occurrences. Hepatocyte death is the major feature of liver injury. In response to liver injury specific intracellular processes are initiated to maintain the liver integrity. Inflammatory cytokines including tumour necrosis factor (TNF)α and interleukin-6 (IL-6) are key mediators of these processes as they can activate different cellular response such as proliferation, survival and death. TNFα induces specific signalling pathways in hepatocytes leading to the activation of either pro-survival mediators or effectors of cell death. While the activation of transcription factor NF-κB promotes survival, the induction of c-Jun N-terminal kinases (JNKs) and caspases represent the strategic effectors of cell death in the TNFα-mediated signalling pathway. This review summarizes recent advances in the mechanisms of TNFα-induced hepatotoxicity, suggesting that NF-κB plays a protective activity against JNK-induced hepatocyte death. The identification of the mechanisms regulating the interplay between the NF-κB and JNK pathways are required to identify novel targets for the treatment of liver disease, including hepatitis and hepatocellular carcinoma.