Regulation of MyD88-dependent signaling events by S nitrosylation retards toll-like receptor signal transduction and initiation of acute-phase immune responses
Regulation of MyD88-dependent signaling events by S nitrosylation retards toll-like receptor signal transduction and initiation of acute-phase immune responses
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DOI：
10.1128/mcb.01412-07
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发表时间：
2008-02-01
影响因子：
5.3
通讯作者：
Matsushita, Kenji
中科院分区：
文献类型：
--
作者：
Into, Takeshi;Inomata, Megumi;Matsushita, Kenji
一氧化氮（NO）被认为通过转录因子NF-κ B的S亚硝基化来调节免疫系统。然而，NO对先天免疫应答的调节作用尚不清楚。在这里，我们报告说，NO有能力控制Toll样受体介导的信号通过S亚硝基化。我们发现，衔接蛋白MyD 88主要是S亚硝基化，这取决于内皮NO合酶（eNOS）的存在。在MyD 88的TIR结构域内的特定半胱氨酸残基处的S亚硝基化导致NF-κ B活化性质的轻微降低。这种改变可以通过抗氧化剂谷胱甘肽来恢复。通过S亚硝基化，NO可以负调节MyD 88功能的多个步骤，包括LPS刺激后易位到细胞膜，与TIRAP相互作用，与TRAF 6结合，以及诱导I κ B α磷酸化。有趣的是，谷胱甘肽可以中和这种NO衍生的作用。我们还发现eNOS缺陷小鼠对LPS的急性发热反应，表明eNOS衍生的NO对炎症过程产生初始抑制作用。因此，NO有可能通过NO的可逆和氧化修饰来延迟MyD 88依赖性信号事件的诱导，从而缓解急剧的信号反应。这种作用可能反映了对活生物体中急性期炎症反应的适当调节。
Nitric oxide (NO) has been thought to regulate the immune system through S nitrosylation of the transcriptional factor NF-kappa B. However, regulatory effects of NO on innate immune responses are unclear. Here, we report that NO has a capability to control Toll-like receptor-mediated signaling through S nitrosylation. We found that the adaptor protein MyD88 was primarily S nitrosylated, depending on the presence of enclothelial NO synthase (eNOS). S nitrosylation at a particular cysteine residue within the TIR domain of MyD88 resulted in slight reduction of the NF-kappa B-activating property. This modification could be restored by the antioxidant glutathione. Through S nitrosylation, NO could negatively regulate the multiple steps of MyD88 functioning, including translocation to the cell membrane after LPS stimulation, interaction with TIRAP, binding to TRAF6, and induction of I kappa B alpha phosphorylation. Interestingly, glutathione could reversely neutralize such NO-derived effects. We also found that an acute febrile response to LPS was precipitated in eNOS-deficient mice, indicating that eNOS-derived NO exerts an initial suppressive effect on inflammatory processes. Thus, NO has a potential to retard induction of MyD88-dependent signaling events through the reversible and oxidative modification by NO, by which precipitous signaling reactions are relieved. Such an effect may reflect appropriate regulation of the acute-phase inflammatory responses in living organisms.