title: Glutathione redox regulates airway hyperresponsiveness and airway inflammation in mice.
abstract: Glutathione is the major intracellular redox buffer. We have shown that glutathione redox status, which is the balance between intracellular reduced (GSH) and oxidized (GSSG) glutathione, in antigen-presenting cells (APC) regulates the helper T cell type 1 (Th1)/Th2 balance due to the production of IL-12. Bronchial asthma is a typical Th2 disease. Th2 cells and Th2 cytokines are characteristic of asthma and trigger off an inflammation. Accordingly, we studied the effects of the intracellular glutathione redox status on airway hyperresponsiveness (AHR) and allergen-induced airway inflammation in a mouse model of asthma. We used gamma-Glutamylcysteinylethyl ester (gamma-GCE), which is a membrane-permeating GSH precursor, to elevate the intracellular GSH level and GSH/GSSG ratio of mice. In vitro, gamma-GCE pretreatment of human monocytic THP-1 cells elevated the GSH/GSSG ratio and enhanced IL-12(p70) production induced by LPS. In the mouse asthma model, intraperitoneal injection of gamma-GCE elevated the GSH/GSSG ratio of lung tissue and reduced AHR. gamma-GCE reduced levels of IL-4, IL-5, IL-10, and the chemokines eotaxin and RANTES (regulated on activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid, whereas it enhanced the production of IL-12 and IFN-gamma. Histologically, gamma-GCE suppressed eosinophils infiltration. Interestingly, we also found that gamma-GCE directly inhibited chemokine-induced eosinophil chemotaxis without affecting eotaxin receptor chemokine receptor 3 (CCR3) expressions. Taken together, these findings suggest that changing glutathione redox balance, increase in GSH level, and the GSH/GSSG ratio by gamma-GCE, ameliorate bronchial asthma by altering the Th1/Th2 imbalance through IL-12 production from APC and suppressing chemokine production and eosinophil migration itself.
authors.affiliation: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Koike
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hisada
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Utsugi
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Ishizuka
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ono
authors.forename: Yukie
authors.initials: Y
authors.lastname: Murata
authors.forename: Junji
authors.initials: J
authors.lastname: Hamuro
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
authors.forename: Kunio
authors.initials: K
authors.lastname: Dobashi
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction; D054397:Receptors, CCR3 / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: C515351:Ccr3 protein, mouse; D018925:Chemokines; D016207:Cytokines; D004151:Dipeptides; D054397:Receptors, CCR3; C067744:N-gamma-glutamylcysteine ethyl ester; D005978:Glutathione; D019803:Glutathione Disulfide