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

我们最近证明，巨噬细胞中还原性和氧化性谷胱甘肽水平（GSH/GSSG）的平衡（MΦ）在决定免疫状态下通过IL-12产生的TH1和TH2细胞因子反应中哪一个占主导地位方面发挥核心作用。我们发现谷胱甘肽氧化还原通过p38 MAP激酶激活来调节lps诱导的IL-12的产生。另一方面，c-jun n末端激酶通过MΦ负调控lps诱导的IL-12产生，谷胱甘肽氧化还原通过相反的JNK和p38 MAP激酶激活调控lps诱导的IL-12产生。在这个项目中，我们揭示了氧化应激对细胞内的影响。谷胱甘肽氧化还原状态在气道上皮细胞和细胞因子的生产增加。（参考文献1）并且，我们的数据表明，RhoA/ROCK通路参与支气管哮喘患者tcr介导的ifn - γ和IL-4分泌与健康人不同。（ref2）此外，我们发现鞘氨醇1-磷酸（S1P_2）通过抑制racl依赖的信号通路来减弱细胞迁移，并通过刺激g αq依赖的机制来减少RANTES的产生，这可能是通过S1P_2受体。（ref3）我们还发现谷胱甘肽调节剂改善OVA诱导小鼠哮喘模型的气道高反应性，并准备发表。

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.