Leukotriene production and inactivation by normal, chronic granulomatous disease and myeloperoxidase-deficient neutrophils.
Appropriately stimulated neutrophils release peroxidase and undergo a respiratory burst to form hydrogen peroxide (H2O2) and hydroxyl radicals (OH). We report here that both the myeloperoxidase-H2O2-halide system and OH released in this way can degrade the leukotrienes (LT) formed by neutrophils. More LTB4 and LTC4 were recovered from the supernatants of chronic granulomatous disease neutrophils (which are unable to respond to stimulation with a respiratory burst) than from normal or myeloperoxidase-deficient neutrophils when stimulated with the calcium ionophore A23187. When radiolabeled LTC4 was added, 72% of the LTC4 was recovered from the chronic granulomatous disease cells in contrast to 0% from the myeloperoxidase-deficient and normal cells. Inhibitor studies using catalase, superoxide dismutase, azide, mannitol, or ethanol suggested that LTC4 degradation was mediated primarily by the myeloperoxidase system in normal cells and by OH in myeloperoxidase-deficient cells. LTC4 degradation by the cell-free myeloperoxidase-H2O2-halide system and the OH -generating acetaldehyde-xanthine oxidase-Fe2+ system had inhibitor profiles comparable to normal and myeloperoxidase-deficient neutrophils, respectively. LTC4 degradation products formed by the stimulated neutrophils and model systems included the 5-(S), 12-(R)- and 5-(S), 12-(S)-6-trans-isomers of LTB4. Thus phagocytes may modulate LT activity in inflammatory sites by the inactivation of these potent biologic mediators by at least two oxidative mechanisms.
D005260:Female; D006105:Granulomatous Disease, Chronic / Q000276:immunology / Q000503:physiopathology*; D006801:Humans; D007700:Kinetics; D007975:Leukotriene B4 / Q000096:biosynthesis* / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D009195:Peroxidase / Q000097:blood / Q000172:deficiency*; D010544:Peroxidases / Q000172:deficiency*; D013189:SRS-A / Q000096:biosynthesis* / Q000378:metabolism
D013189:SRS-A; D007975:Leukotriene B4; D010544:Peroxidases; D009195:Peroxidase