IRF-1 is an essential mediator in IFN-γ-induced cell cycle arrest and apoptosis of primary cultured hepatocytes
IRF-1 is an essential mediator in IFN-γ-induced cell cycle arrest and apoptosis of primary cultured hepatocytes
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DOI：
10.1006/bbrc.1999.0276
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发表时间：
1999-04-21
影响因子：
3.1
通讯作者：
Watanabe, Y
中科院分区：
文献类型：
--
作者：
Kano, A;Haruyama, T;Watanabe, Y
IFN-γ诱导原代培养的肝细胞中的细胞周期停滞和p53非依赖性凋亡。然而，目前还不清楚是什么分子调节该机制。我们在这里报告，干扰素调节因子1（IRF-1）是一个重要的分子在这些现象。IRF-1基因缺陷小鼠肝细胞对IFN-γ完全耐受，表现为LDH释放、DNA断裂和caspase-3家族激活等3种不同的凋亡标志。在肝细胞中几乎没有检测到Caspase-1表达，在野生型和IRF-1缺陷肝细胞之间，Fas或Caspase-3的组成性和IFN-γ诱导的mRNA表达没有变化。IFN-γ诱导的caspase-11的表达也没有改变。因此，这些分子不太可能直接调节这些机制。有趣的是，IRF-1缺陷型肝细胞也对IFN-γ诱导的细胞周期停滞具有抗性，尽管IFN-γ诱导的细胞周期停滞和细胞凋亡是由独立的途径调节的。通过北方印迹分析的结果表明，IFN-γ诱导的p53 mRNA表达受IRF-1调节，但不受组成性p53 mRNA表达的调节。事实上，IFN-γ在p53缺陷肝细胞中不诱导细胞周期停滞。总之，IRF-1介导IFN-γ信号传导至原代肝细胞中，用于通过p53表达的细胞周期停滞和细胞凋亡。(C)北京：科学出版社.
IFN-gamma induces cell cycle arrest and p53-independent apoptosis in primary cultured hepatocytes. However, it is not yet understood what molecules regulate the mechanism. We report here that interferon regulatory factor 1 (IRF-1) is an essential molecule in these phenomena. Hepatocytes from IRF-1-deficient mice were completely resistant to IFN-gamma in apoptosis indicated by three different hallmarks such as LDH release, DNA fragmentation and the activation of caspase-3 family. Caspase-1 expression was little detected in hepatocytes, and constitutive and IFN-gamma-induced mRNA expression of Fas or caspase-3 did not change in between wild type and IRF-1-deficient hepatocytes. Expression of IFN-gamma-inducible caspase, caspase-11, did not change either. Thus, it is unlikely that these molecules directly regulate the mechanisms. Interestingly, IRF-1-deficient hepatocytes were also resistant to IFN-gamma-induced cell cycle arrest despite IFN-gamma-induced cell cycle arrest and apoptosis are regulated by independent pathways. Results by Northern blot analysis showed that IFN-gamma-induced but not constitutive p53 mRNA expression was regulated by IRF-1. In fact, IFN-gamma did not induce cell cycle arrest in p53-deficient hepatocytes. Taken together, IRF-1 mediates IFN-gamma signaling into primary hepatocytes for cell cycle arrest via p53 expression and for apoptosis. (C) 1999 Academic Press.