A cell-type-specific requirement for IFN regulatory factor 5 (IRF5) in Fas-induced apoptosis
A cell-type-specific requirement for IFN regulatory factor 5 (IRF5) in Fas-induced apoptosis
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DOI：
10.1073/pnas.0712295105
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发表时间：
2008-02-19
影响因子：
11.1
通讯作者：
Tamura, Tomohiko
中科院分区：
文献类型：
--
作者：
Couzinet, Arnaud;Tamura, Kaoru;Tamura, Tomohiko
细胞凋亡是一种高度调控的细胞自杀过程，发生在发育、宿主防御和病理生理过程中。转录因子IFN调节因子5（IRF 5），已知参与先天免疫应答的激活，最近已被证明是DNA损伤诱导的细胞凋亡和肿瘤抑制的关键。在这里，我们报告的细胞类型特异性作用的IRF 5在促进细胞凋亡后，通过死亡受体Fas（CD 95/APO-1/TNFRSF 6）的信号。特别是，我们表明，在IRF 5基因缺陷的小鼠是抵抗肝细胞凋亡和致死性在体内给药的Fas激活单克隆抗体，和IRF 5参与的Fas信号传导的一个阶段，之前的caspase 8和c-Jun N-末端激酶（JNK）的激活。除肝细胞外，IRF 5也是由低甲基化CpG激活的树突状细胞凋亡所必需的，但在体外胸腺细胞和胚胎成纤维细胞中不需要。因此，这些发现揭示了IRF 5在死亡受体诱导的细胞凋亡的复杂调节机制中的细胞类型特异性功能。
Apoptosis is a highly regulated process of cell suicide that occurs during development, host defense, and pathophysiology. The transcription factor IFN regulatory factor 5 (IRF5), known to be involved in the activation of innate immune responses, recently has been shown to be critical for DNA damage-induced apoptosis and tumor suppression. Here, we report on a cell-type-specific role of IRF5 in promoting apoptosis upon signaling through the death receptor Fas (CD95/APO-1/TNFRSF6). In particular, we show that mice deficient in the Irf5 gene are resistant to hepatic apoptosis and lethality in response to the in vivo administration of a Fas-activating monoclonal antibody, and that IRF5 is involved in a stage of Fas signaling that precedes the activation of caspase 8 and c-Jun N-terminal kinase (JNK). In addition to hepatocytes, IRF5 is also required for apoptosis in dendritic cells activated by hypomethylated CpG but not in thymocytes and embryonic fibroblasts in vitro. Thus, these findings reveal a cell-type-specific function for IRF5 in the complex regulatory mechanism of death-receptor-induced apoptosis.