Chemotactic factor inactivation by stimulated human neutrophils mediated by myeloperoxidase-catalyzed methionine oxidation.
Leukocyte chemoattractants were inactivated when exposed to human neutrophils and either ingestible particles or phorbol esters. Loss of biologic activity was time- and temperature-dependent, required physiologic concentrations of viable neutrophils and a halide, and was inhibited by azide or catalase. Neutrophils from patients with either hereditary myeloperoxidase deficiency or chronic granulomatous disease failed to inactivate the chemoattractants unless purified myeloperoxidase or H2O2, respectively, was added. Susceptibility to inactivation by neutrophils correlated with the presence of methionine in the attractant. Loss of chemotactic activity was blocked by low concentrations of methionine and by higher concentrations of other reducing agents, but was unaffected by oxidized methionine. Paper chromatography demonstrated that exposure of a formyl-methionyl peptide chemotactic factor to either the cellfree myeloperoxidase system or stimulated neutrophils resulted in its conversion to a molecular species whose location in the chromatographs was identical to that of the peptide containing oxidized methionine. Thus, stimulated human neutrophils inactivate peptide chemoattractants by secretion of myeloperoxidase and H2O2, which combine with halides to form oxidants that react with a critical methionine residue. We suggest that myeloperoxidase-catalyzed oxidation of thioethers may constitute an inflammatory control mechanism as well as a general means of modifying the functional properties of biologic mediators.
D000626:Aminopeptidases; D002177:Candidiasis / Q000201:enzymology; D002384:Catalysis; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003182:Complement C5 / Q000378:metabolism; D015936:Complement C5a; D006105:Granulomatous Disease, Chronic / Q000201:enzymology; D006801:Humans; D008715:Methionine / Q000378:metabolism*; D009239:N-Formylmethionine / Q000031:analogs & derivatives / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009504:Neutrophils / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism; D009195:Peroxidase / Q000494:pharmacology*; D010544:Peroxidases / Q000494:pharmacology*; D013440:Sulfides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology
D002630:Chemotactic Factors; D003182:Complement C5; D009842:Oligopeptides; D013440:Sulfides; C010073:chemotactic factor inactivator; D009239:N-Formylmethionine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a; D015054:Zymosan; D008715:Methionine; D010544:Peroxidases; D009195:Peroxidase; D000626:Aminopeptidases; D013755:Tetradecanoylphorbol Acetate