title: Oxidative stress potentially enhances FcεRI-mediated leukotriene C4 release dependent on the late-phase increase of intracellular glutathione in mast cells.
abstract: Cysteinyl leukotrienes (cysLTs), which include leukotriene C4 (LTC4), are the predominant class of LTs synthesized by mast cells. CysLTs can induce many of the abnormalities seen in asthma. LTC4 is generated by the conjugation of LTA4 with reduced glutathione (GSH) by LTC4 synthase. During screening of the effects of prostanoids on high-affinity IgE receptor (FcεRI)-mediated LTC4 release from mast cells, we realized that some prostanoids, including ONO-AE1-259-01 and ONO-AE-248, inhibited LTC4 release, which was associated with a decrease in the amount of intracellular total GSH. We ascertained that l-buthionine-S,R-sulfoximine (BSO), a selective inhibitor of glutamate-cysteine ligase, inhibited LTC4 release. In addition, cell-permeable GSH, the glutathione reduced form ethyl ester (GSH-OEt), enhanced LTC4 release in accordance with the change in intracellular total GSH. Depletion of intracellular total GSH induced by ONO-AE-248 or BSO enhanced FcεRI-mediated LTB4 release in contrast to LTC4. Oxidative stress contributes to many pathological conditions including asthma. GSH is a major soluble antioxidant and a cofactor for several detoxifying enzymes including GSH peroxidase. Exposure of mast cells to hydrogen peroxide (H2O2) or diamide to mimic oxidative stress unexpectedly increased rather than decreased the intracellular reduced GSH content as well as total GSH in the late phase (i.e., 24 or 48 h after exposure), which was accompanied by an increase in LTC4 release. In conclusion, FcεRI-mediated LTC4 release from mast cells is mainly regulated by the amount of intracellular GSH. In some cases, oxidative stress may induce a late-phase increase in intracellular GSH, resulting in enhanced LTC4 release from mast cells.
authors.affiliation: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Seki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hisada
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Kawata
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kamide
authors.forename: Kunio
authors.initials: K
authors.lastname: Dobashi
authors.forename: Masanobu
authors.initials: M
authors.lastname: Yamada
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Okajima
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Ishizuka
mesh_terms: D000818:Animals; D001491:Basophils / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005978:Glutathione / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000276:immunology / Q000378:metabolism; D017997:Leukotriene C4 / Q000276:immunology / Q000378:metabolism*; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress; D011453:Prostaglandins / Q000276:immunology / Q000378:metabolism; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism*
chemical_list: D011453:Prostaglandins; D017455:Receptors, IgE; D017997:Leukotriene C4; D006861:Hydrogen Peroxide; D005978:Glutathione
keywords: BSO; EP; FcεRI; GSH; GSH-OEt; GSSG; Glutathione; LT; Leukotriene C(4); Mast cell; Oxidative stress; glutathione; glutathione reduced form ethyl ester; high-affinity IgE receptor; l-buthionine-S,R-sulfoximine; leukotriene; oxidized glutathione; prostaglandin E(2) receptor