Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis.
Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis.
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DOI：
10.1016/j.ccr.2008.06.016
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发表时间：
2008-08-12
期刊：
影响因子：
50.3
通讯作者：
Karin M
中科院分区：
文献类型：
--
作者：
Sakurai T;He G;Matsuzawa A;Yu GY;Maeda S;Hardiman G;Karin M
肝细胞IκB激酶β（IKKβ）通过抑制活性氧（ROS）的积累和肝损伤来抑制肝癌的发生，而JNK 1的激活则促进ROS的积累、肝损伤和肝癌的发生。我们研究了抑制肝癌发生的肝细胞p38α在控制ROS代谢和细胞死亡方面是否与IKKβ作用相似。肝细胞特异性p38α消融增强了ROS积累和肝损伤，这在给予抗氧化剂后得到了预防。除了活性氧积累增加外，IKKβ或p38α的缺失加剧的肝细胞死亡还与IL-1α的释放有关。抑制IL-1α作用或消除其受体可抑制致癌物诱导的代偿性增殖和肝肿瘤发生。因此，坏死肝细胞释放的IL-1α是肝肿瘤发生的重要介质。
Hepatocyte IκB kinase β (IKKβ) inhibits hepatocarcinogenesis by suppressing accumulation of reactive oxygen species (ROS) and liver damage, whereas JNK1 activation promotes ROS accumulation, liver damage and carcinogenesis. We examined whether hepatocyte p38α, found to inhibit liver carcinogenesis, acts similarly to IKKβ in control of ROS metabolism and cell death. Hepatocyte-specific p38α ablation enhanced ROS accumulation and liver damage, which were prevented upon administration of an antioxidant. In addition to elevated ROS accumulation, hepatocyte death, augmented by loss of either IKKβ or p38α, was associated with release of IL-1α. Inhibition of IL-1α action or ablation of its receptor inhibited carcinogen-induced compensatory proliferation and liver tumorigenesis. IL-1α release by necrotic hepatocytes is therefore an important mediator of liver tumorigenesis.
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