title: Glutathione inhibits antibody and complement-mediated immunologic cell injury via multiple mechanisms.
abstract: 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.
authors.affiliation: Divison of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Divison of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Xiling
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Divison of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan; School of public health, Inner Mongolia Medical University, Huhhot, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Niimi
authors.affiliation: Divison of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Yanru
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Divison of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Honglan
authors.initials: H
authors.lastname: Piao
authors.affiliation: Divison of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Jianglin
authors.initials: J
authors.lastname: Fan
authors.affiliation: Divison of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan. Electronic address: yao@yamanashi.ac.jp.
authors.forename: Jian
authors.initials: J
authors.lastname: Yao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003167:Complement Activation; D015938:Complement Membrane Attack Complex / Q000494:pharmacology; D003165:Complement System Proteins / Q000494:pharmacology*; D005978:Glutathione / Q000494:pharmacology*; D007518:Isoantibodies / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D050527:Mesangial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D051381:Rats
chemical_list: D015938:Complement Membrane Attack Complex; D007518:Isoantibodies; C035678:anti-Thy antibody; D003165:Complement System Proteins; D005978:Glutathione
keywords: Antibody; Cell lysis; Complement; Glutathione; Mesangial cells; p38