Glutathione inhibits antibody and complement-mediated immunologic cell injury via multiple mechanisms.
Glutathione inhibits antibody and complement-mediated immunologic cell injury via multiple mechanisms.
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DOI：
10.1016/j.redox.2017.03.030
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发表时间：
2017-08
期刊：
影响因子：
11.4
通讯作者：
Yao J
中科院分区：
文献类型：
--
作者：
Zhang Z;Zhang X;Fang X;Niimi M;Huang Y;Piao H;Gao S;Fan J;Yao J
抗氧化剂谷胱甘肽（GSH）在免疫调节中起着重要作用。然而，其对体液免疫的作用，特别是对抗体和补体等效应分子的作用知之甚少。鉴于这些分子含有丰富的二硫键，我们推测谷胱甘肽可能通过其硫醇功能影响这些蛋白质的作用。利用抗体加补体诱导的肾小球系膜细胞（MC）裂解模型，我们解决了这一假设。大鼠MCs暴露于抗thy -1抗体加补体或抗mc兔血清，引起补体依赖性细胞裂解，并被谷胱甘肽完全阻断。此外，谷胱甘肽还能有效地阻止抗体介导的红细胞凝集和抗体致敏微球的聚集。进一步分析表明，谷胱甘肽抑制抗体与抗原的结合，并促进抗体转化为其还原形式。GSH还能有效抑制MCs中C5b-9的形成和沉积，并抑制经典补体激活途径和替代补体激活途径。最后，GSH减弱了P38的活化，P38是一种氧化敏感激酶，部分介导了抗体和补体依赖性的MC裂解。通过抑制γ -谷氨酰半胱氨酸合成酶或xCT转运体来消耗GSH增强P38的激活并使MCs对细胞裂解敏感。总之，我们的研究结果表明，谷胱甘肽通过抑制抗体与抗原结合、抑制补体激活和增强细胞防御机制来保护细胞免受免疫细胞损伤。我们的研究为谷胱甘肽在调节免疫反应中的作用提供了新的机制见解，并表明谷胱甘肽可能用于治疗某些免疫疾病。关于谷胱甘肽在体液免疫中的作用的信息很少。谷胱甘肽抑制抗体触发和补体介导的免疫反应。谷胱甘肽通过其硫醇功能干扰抗体与细胞表面抗原的结合。谷胱甘肽抑制经典和替代补体激活途径。谷胱甘肽通过抑制P38增强细胞对免疫损伤的抵抗力。
Antioxidant glutathione (GSH) plays an important role in the regulation of immunity. However, little is known about its effects on humoral immunity, especially its action on effector molecules like antibody and complement. Given that these molecules contain abundant disulfide bonds, we speculated that GSH might influence the action of these proteins via its thiol function. Using a model of a glomerular mesangial cell (MC) lysis induced by antibodies plus complement, we addressed this hypothesis. Exposure of rat MCs to anti-Thy-1 antibody plus complement or anti-MC rabbit serum caused a complement-dependent cell lysis, which was completely blocked by GSH. Moreover, GSH potently prevented the antibody-mediated agglutination of red blood cells and aggregation of antibody-sensitized microspheres. Further analysis revealed that GSH inhibited antibody binding to antigens and promoted the conversion of the antibodies to its reduced forms. GSH also potently inhibited the formation and deposition of C5b-9 in MCs and suppressed both the classic and alternative complement activation pathway. Lastly, GSH attenuated P38 activation, an oxidative sensitive kinase that partially mediated the antibody- and complement-dependent MC lysis. Depletion of GSH via inhibiting gamma-glutamylcysteine synthetase or xCT transporter augmented P38 activation and sensitized MCs to the cell lysis. Collectively, our results indicate that GSH protects cells from immunological cell damage via mechanisms involving inhibition of antibody binding to the antigens, suppression of complement activation and augmentation of cellular defense mechanism. Our study provides novel mechanistic insights into the actions of GSH in the regulation of immune responses and suggests that GSH might be used to treat certain immune disorders. Little information is available regarding the role of GSH on humoral immunity. GSH inhibited antibody-triggered and complement-mediated immune responses. GSH interfered with antibody binding to cell surface antigens via its thiol function. GSH inhibited both the classic and alternative complement activation pathways. GSH increased cell resistance to immunological injury via inhibition of P38.