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.

我们最近证明，巨噬细胞（Mφ）中降低和氧化的谷胱甘肽水平（GSH/GSSG）的平衡在确定通过IL-12通过IL-12的生产在免疫状态下占主导的Th1和Th2细胞因子反应中的哪种核心作用。我们表明，谷胱甘肽氧化还原通过p38 MAP激酶激活调节LPS诱导的IL-12产生。另一方面，C-JUN N末端激酶对LPS诱导的Mφ产生的IL-12产生，而谷胱甘肽氧化还原通过JNK和p38 MAP激酶激活的相反控制来调节LPS诱导的IL-12产生。在这个项目中，我们揭示了氧化应激影响的胞内细胞内的氧化应激。气道上皮细胞中的谷胱甘肽氧化还原状态和细胞因子的产生增加。（参考文献1），我们的数据表明，在具有支气管哮喘的患者中，RhoA/Rock途径参与IFN-GAMMA和IL-4的TCR介导的分泌，与健康人不同。（Ref2）此外，我们透露，鞘氨酸1-磷酸（S1P_2）通过抑制RACL依赖性信号通路并改善RANTES产生的细胞迁移，通过刺激GαQ依赖性机制，既可以通过S1P_2受体来刺激GαQ依赖机制。准备出版。