Interferon-γ-mediated hepatocarcinogenesis in mice treated with diethylnitrosamine
Interferon-γ-mediated hepatocarcinogenesis in mice treated with diethylnitrosamine
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DOI：
10.1038/labinvest.3700257
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发表时间：
2005-05-01
影响因子：
5
通讯作者：
Kaneko, S
中科院分区：
文献类型：
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作者：
Matsuda, M;Nakamoto, Y;Kaneko, S
肝癌的发生是一个复杂的多因素过程，其中持续的肝内炎症起主要作用。虽然在化学诱导的肝癌发生过程中观察到炎症细胞的浸润，但炎症反应的病理生理作用还不是很清楚。为了探讨这个问题，我们监测了小鼠在接触化学致癌物质二乙基亚硝胺(DEN)的过程中的分子和细胞反应，这些小鼠暴露在饮用水中(50微克/L)。肝内I型和II型干扰素(分别为干扰素-β和干扰素-γ)的mRNA表达在肝细胞癌发生前2个月被诱导。通过监测干扰素-α/β受体(干扰素-α/βR-KO)或干扰素-伽马受体(干扰素-γR-KO)基因缺陷小鼠的肿瘤发展情况，确定了干扰素-α/β受体基因缺陷小鼠的致病重要性。与干扰素-α/βR-KO和野生型(Wt)小鼠相比，干扰素-伽马R-KO小鼠发生的肿瘤较少，尽管肿瘤直径在三个谱系之间没有显著差异。有趣的是，免疫组织化学研究显示，在干扰素-γR-KO小鼠的肝脏中，单核/巨噬细胞在浸润性单核细胞中的比例显著减少，这与肝内细胞因子的表达减少和DNA氧化损伤程度较小的事实相一致。结论：II型干扰素，而不是I型干扰素，可能通过促进单核/巨噬细胞活化和最终肝细胞DNA损伤而在DEN诱导的肝癌发生的初始阶段而不是促进阶段起关键作用。
Hepatocarcinogenesis is a complex multifactorial process in which continuous intrahepatic inflammation plays a major role. Although inflammatory cell infiltration is observed in the process of chemical-induced hepatocarcinogenesis, the pathophysiological role of the inflammatory response is not well defined. To approach this question, molecular and cellular responses were monitored during the development of liver tumors in mice exposed to a chemical hepatocarcinogen, diethylnitrosamine (DEN), in drinking water (50 mu g/l). Intrahepatic type I and type II interferon (IFN-beta and IFN-\gamma, respectively) mRNA expression was found to be induced 2 months before the appearance of hepatocellular carcinomas. The pathogenetic importance of IFNs was determined by monitoring tumor development in mice genetically deficient in the IFN-alpha/beta receptor (IFN-alpha/beta R KO) or the IFN-gamma receptor (IFN-gamma R KO). IFN-gamma R KO mice developed fewer tumors than IFN-alpha/beta R KO and wild-type (wt) mice, although the tumor diameters did not differ significantly among the three lineages. Interestingly, immunohistochemical studies demonstrated that the percentage of monocytes/macrophages in infiltrating mononuclear cells was reduced greatly in the livers of IFN-gamma R KO mice, which is consistent with the facts that intrahepatic cytokine expression was diminished and oxidative DNA damage was induced to a lesser extent. In conclusion, type II IFN, but not type I IFNs, may be involved critically in the initiation stage, but not the promotion stage, of DEN-induced hepatocarcinogenesis by enhancing monocytes/macrophages activation and eventual hepatocyte DNA damage.