IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis
IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis
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DOI：
10.1016/j.cell.2005.04.014
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发表时间：
2005-07-01
期刊：
影响因子：
64.5
通讯作者：
Karin, M
中科院分区：
文献类型：
--
作者：
Maeda, S;Kamata, H;Karin, M
NF-κ B活化所需的I κ B激酶β（IKK β）将慢性炎症与致癌作用联系起来。我们研究了IKK β是否参与化学诱导的肝癌，一个不涉及明显炎症的模型。令人惊讶的是，仅在肝细胞中缺乏IKK β的小鼠（Ikk β（Delta hep）小鼠）表现出由二乙基亚硝胺（DEN）引起的肝癌发生显著增加。这与增强的活性氧（ROS）产生，增加JNK激活，肝细胞死亡，引起增强的代偿性增殖的存活肝细胞。在DEN暴露的时间附近短暂口服抗氧化剂阻断了延长的JNK激活和代偿性增殖，并防止了Ikk β（Delta hep）小鼠中DEN诱导的过度致癌作用。在肝细胞和造血来源的枯否细胞中缺乏IKKP的小鼠中也发现肝癌发生减少。这些小鼠表现出肝细胞再生减少和肝有丝分裂原诱导减少，而Ikk β（Delta hep）小鼠则没有改变。因此，IKK β协调肝细胞和造血衍生细胞之间的炎症串扰，促进化学性肝癌发生。
I kappa B kinase beta (IKK beta), required for NF-kappa B activation, links chronic inflammation with carcinogenesis. We investigated whether IKK beta is involved in chemically induced liver cancer, a model not involving overt inflammation. Surprisingly, mice lacking IKK beta only in hepatocytes (Ikk beta(Delta hep) mice) exhibited a marked increase in hepatocarcinogenesis caused by diethylnitrosamine (DEN). This correlated with enhanced reactive oxygen species (ROS) production, increased JNK activation, and hepatocyte death, giving rise to augmented compensatory proliferation of surviving hepatocytes. Brief oral administration of an antioxidant around the time of DEN exposure blocked prolonged JNK activation and compensatory proliferation and prevented excessive DEN-induced carcinogenesis in Ikk beta(Delta hep) mice. Decreased hepatocarcinogenesis was also found in mice lacking IKKP in both hepatocytes and hematopoietic-derived Kupffer cells. These mice exhibited reduced hepatocyte regeneration and diminished induction of hepatomitogens, which were unaltered in Ikk beta(Delta hep) mice. IKK beta, therefore, orchestrates inflammatory crosstalk between hepatocytes and hematopoietic-derived cells that promotes chemical hepatocarcinogenesis.