| Budget Amount *help |
¥11,900,000 (Direct Cost: ¥11,900,000)
Fiscal Year 2004: ¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 2003: ¥6,100,000 (Direct Cost: ¥6,100,000)
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| Research Abstract |
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.
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