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Elucidation of the mechanism of TNF-induced reactive oxygen species-dependent cytotoxicity and development of its clinical application

TNF诱导的活性氧依赖性细胞毒性机制的阐明及其临床应用的开发

基本信息

批准号：
15390131
负责人：
NAKANO Hiroyasu
金额：
$ 7.62万
依托单位：
Juntendo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

By using NF-κB activation-deficient cells, we demonstrate that TNFα stimulation leads to accumulation of reactive oxygen species(ROS), which is essential for prolonged mitogen-activated protein kinase(MAPK) activation and necrotic cell death. Moreover, microarray analysis shows that several antioxidant enzymes are induced by TNFα in an NF-κB-dependent manner. Collectively, a novel function of NF-κB is to suppress TNF-induced ROS accumulation by upregulating anti-oxidant enzymes.Accumulation of unfolded proteins in the endoplasmic reticulum(ER) causes ER overload, resulting in ER stress. To cope with ER stress, mammalian cells trigger a specific response known as the unfolded protein response(UPR). By using murine fibrosarcoma L929 cells, in which tumor necrosis factor(TNF)α induces accumulation of reactive oxygen species(ROS) and cell death, we show that TNFαTh induces the UPR in a ROS-dependent fashion. In contrast to TNFα, oxidative stresses by H_2O_2 or arsenite only induce eIF2α phosphorylation, but not activation of PERK- or IRE1-dependent pathways, indicating the specificity of downstream signaling induced by various oxidative stresses. Conversely, the UPR induced by tunicamycin substantially suppresses TNFα-induced ROS accumulation and cell death. Collectively, some, but not all, oxidative stresses induce the UPR, and preemptive UPR counteracts TNFα-induced ROS accumulation.

通过使用NF-κB激活缺陷细胞，我们证明了TNFα刺激导致活性氧（ROS）的积累，这是延长丝裂原活化蛋白激酶（MAPK）激活和坏死细胞死亡所必需的。此外，微阵列分析显示，TNFα以NF-κ b依赖的方式诱导几种抗氧化酶。总的来说，NF-κB的一个新功能是通过上调抗氧化酶来抑制tnf诱导的ROS积累。未折叠蛋白在内质网（ER）中的积累导致内质网超载，从而导致内质网应激。为了应对内质网应激，哺乳动物细胞会触发一种称为未折叠蛋白反应（UPR）的特定反应。通过使用肿瘤坏死因子(TNF)α诱导活性氧（ROS）积累和细胞死亡的小鼠纤维肉瘤L929细胞，我们发现TNFα th以ROS依赖的方式诱导UPR。与TNFα相比，H_2O_2或亚砷酸盐氧化应激只诱导eIF2α磷酸化，而不激活PERK-或ire1依赖性通路，表明各种氧化应激诱导的下游信号通路的特异性。相反，tunicamycin诱导的UPR显著抑制tnf α诱导的ROS积累和细胞死亡。总的来说，一些（但不是全部）氧化应激诱导UPR，抢先UPR抵消tnf α诱导的ROS积累。