Nitrosative stress-induced apoptosis through inhibition of NF-κB
Nitrosative stress-induced apoptosis through inhibition of NF-κB
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DOI：
10.1074/jbc.m201638200
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发表时间：
2002-09-13
影响因子：
4.8
通讯作者：
Stamler, JS
中科院分区：
文献类型：
--
作者：
Marshall, HE;Stamler, JS
由细胞因子产生的亚硝化应激倾向于凋亡性细胞死亡。然而，这种情况发生的分子机制还不清楚。我们以前已经表明，一氧化氮（NO）调节抗凋亡转录因子NF-κ B的活性。在这里，我们证明了通过NO抑制NF-κ B使A549和Jurkat T细胞对肿瘤坏死因子-α（TNF α）诱导的凋亡敏感。NF-κ B抑制的分子基础在两种细胞类型中是不同的。在A549细胞中，NO在核水平上通过S-亚硝基化作用抑制NF-κ B。在Jurkat细胞中，NO在接近IkappaB α降解的步骤中抑制细胞质中的NF-κ B活化途径。NF-κ B的抑制反映在细胞内S-亚硝基硫醇的水平上，S-亚硝基硫醇是组成性代谢的。这些数据表明，NO可以通过调节NF-κ B活性来影响细胞死亡，抑制位点具有细胞类型特异性。数据还显示NO生物活性调节肿瘤坏死因子-α信号传导。
Nitrosative stress produced by cytokines predisposes to apoptotic cell death. However, the molecular mechanism by which this occurs is not well understood. We have shown previously that nitric oxide (NO) regulates the activity of the anti-apoptotic transcription factor NF-kappaB. Here we demonstrate that the inhibition of NF-kappaB by NO sensitizes A549 and Jurkat T cells to tumor necrosis factor-alpha (TNFalpha)-induced apoptosis. The molecular basis of NF-kappaB inhibition is different in the two cell types. In A549 cells, NO functions at the nuclear level to inhibit NF-kappaB by S-nitrosylation. In Jurkat cells, NO inhibits the NF-kappaB activating pathway in the cytoplasm at a step proximal to the degradation of IkappaBalpha. The inhibition of NF-kappaB is reflected in the level of intracellular S-nitrosothiols, which are constitutively metabolized. These data suggest that NO can influence cell death by modulating NF-kappaB activity with the sites of inhibition being cell type-specific. The data also show that NO bioactivity regulates tumor necrosis factor-a signaling.