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Analysis of action mechanism of intracellular glutathione redox to control lung inflammation and application to asthma treatment of glutathione modulator

细胞内谷胱甘肽氧化还原控制肺部炎症作用机制分析及谷胱甘肽调节剂在哮喘治疗中的应用

基本信息

批准号：
16590974
负责人：
DOBASHI Kunio
金额：
$ 1.86万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590974/
关键词：
redox glutathione IL-12 oxidative stress Th1 Th2 balance macrophage MAP kinase asthma TH1 TH2 オゾン

项目摘要

We recently demonstrated that balance of reduced and oxidized glutathione level (GSH/GSSG) in macrophage (MΦ) play a central role in determining which of the TH1 and TH2 cytokine responses predominate during immune states through IL-12 production. And we showed that glutathione redox regulated LPS-induced IL-12 production through p38 MAP kinase activation. On the other hand, c-jun N-terminal kinase negatively regulated LPS-induced IL-12 production from MΦ, and glutathione redox regulates LPS-induced IL-12 production through the opposite control of JNK and p38 MAP kinase activation.In this project, we revealed that oxidative stress affected intracellular. glutathione redox status in airway epithelial cells and increased production of cytokine. (ref1) And, Our data suggest that the involvement of RhoA/ROCK pathway in TCR-mediated secretion of IFN-gamma and IL-4 in patients with bronchial asthma differed from that in healthy persons. (ref2) Furthermore, we revealed that sphingosine 1-phosphate (S1P_2) attenuated cell migration by inhibiting a Racl-dependent signaling pathway and decreased RANTES production by stimulating a Gαq-dependent mechanism both possibly through the S1P_2 receptors.(ref3) We also revealed that glutathione modulator improved airway hyper responsiveness in OVA induced mouse asthma model and are preparing publication.

我们最近发现，在免疫状态下，巨噬细胞（MΦ）中还原型和氧化型谷胱甘肽水平（GSH/GSSG）的平衡通过IL-12的产生在决定TH 1和TH 2细胞因子应答中的哪一种占主导地位方面起着核心作用。我们发现谷胱甘肽氧化还原通过激活p38 MAP激酶调节LPS诱导的IL-12产生。另一方面，c-jun N-末端激酶负性调节LPS诱导的MΦ产生IL-12，谷胱甘肽氧化还原通过JNK和p38 MAP激酶的相反调控来调节LPS诱导的M Φ产生IL-12。气道上皮细胞谷胱甘肽氧化还原状态和细胞因子产生增加。此外，我们的数据表明，RhoA/ROCK通路参与TCR介导的IFN-γ和IL-4的分泌在支气管哮喘患者中与健康人不同。（参考文献2）此外，我们发现1-磷酸鞘氨醇（S1P_2）通过抑制Racl依赖的信号通路而减弱细胞迁移，通过刺激Gα q依赖的机制而减少RANTES的产生，这两种机制可能都是通过S1P_2受体实现的。（参考文献3）我们还发现谷胱甘肽调节剂改善了OVA诱导的小鼠哮喘模型的气道高反应性，并正在准备发表。