Induction of hepatitis by JNK-mediated expression of TNF-alpha.
Induction of hepatitis by JNK-mediated expression of TNF-alpha.
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DOI：
10.1016/j.cell.2008.11.017
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发表时间：
2009-01-23
期刊：
影响因子：
64.5
通讯作者：
Davis RJ
中科院分区：
文献类型：
--
作者：
Das M;Sabio G;Jiang F;Rincón M;Flavell RA;Davis RJ
CJun NH2末端激酶(JNK)信号通路参与了肿瘤坏死因子(TNF)依赖型肝炎的发病过程。的确，在体内肿瘤坏死因子刺激的细胞死亡过程中，JNK可能在肝细胞中发挥关键作用。为了验证这一假设，我们研究了JNK1和JNK2基因复合破坏的小鼠的表型。肝细胞JNK1/2表达缺失的小鼠与对照组小鼠相比，在肝炎的发生过程中没有发现缺陷。相反，在造血室中失去JNK1/2的小鼠表现出肝炎的严重缺陷，这与肿瘤坏死因子α的表达显著降低有关。综上所述，这些数据表明，JNK是肿瘤坏死因子α表达所必需的，而JNK不是肿瘤坏死因子α刺激的肝细胞死亡所必需的。事实上，肿瘤坏死因子α在肝细胞特异性JNK1/2缺乏症小鼠和对照组小鼠中引起了类似的肝损伤。这些观察证实了JNK在肝炎发展中的作用，但确认造血细胞是JNK基本功能的部位。
The cJun NH2-terminal kinase (JNK) signaling pathway has been implicated in the development of tumor necrosis factor (TNF) -dependent hepatitis. Indeed, JNK may play a critical role in hepatocytes during TNF-stimulated cell death in vivo. To test this hypothesis, we examined the phenotype of mice with compound disruption of the Jnk1 and Jnk2 genes. Mice with loss of JNK1/2 expression in hepatocytes exhibited no defects in the development of hepatitis compared with control mice. In contrast, mice with loss of JNK1/2 in the hematopoietic compartment exhibited a profound defect in hepatitis that was associated with markedly reduced expression of TNFα. Together, these data indicate that JNK is required for TNFα expression, but JNK is not required for TNFα-stimulated death of hepatocytes. Indeed, TNFα-induced similar hepatic damage in mice with hepatocyte-specific JNK1/2-deficiency and control mice. These observations confirm a role for JNK in the development of hepatitis, but identify hematopoietic cells as the site of the essential function of JNK.
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