Chemotactic factor inactivation by the myeloperoxidase-hydrogen peroxide-halide system.
Polymorphonuclear leukocytes may modulate the acute inflammatory response by the secretion of enzymes capable of inactivating mediators of inflammation. The ability of the myeloperoxidase-H(2)O(2)-halide system of the neutrophil to inactivate chemoattractants was examined using both a radioassay and a morphologic assay of chemotaxis. Incubation of either a complement-derived agent, C5a, or a synthetic formyl-methionyl peptide chemoattractant with the myeloperoxidase system for 15 min at 37 degrees C resulted in essentially complete loss of chemotactic activity. Inactivation was dependent on enzymatically active myeloperoxidase, H(2)O(2) or a peroxide-generating enzyme system, and a halide cofactor. It was blocked by agents which inhibit peroxidase (azide) or degrade H(2)O(2) (catalase). Inactivation of chemoattractants was time-dependent, reaching maximal levels within 1-5 min, and temperature-dependent with no significant inactivation occurring at 0 degrees C. H(2)O(2) alone had no significant inactivating ability at concentrations as high as 10 mM, whereas in the presence of myeloperoxidase and a halide, 0.1 muM H(2)O(2) showed significant activity and 10 muM H(2)O(2) caused complete inactivation. On a molar basis, the order of effectiveness of the halide cofactors was Br(-) > I(-) > Cl(-), although only chloride was fully active at physiologic concentrations. Neutrophils stimulated by phagocytosis or by membraneperturbing agents secrete enzymatic constituents, including myeloperoxidase, and metabolic products such as H(2)O(2). Thus, it is suggested that the myeloperoxidase system acting at an extracellular site serves as an inflammatory control mechanism by virtue of its ability to inactivate neutrophil chemoattractants.
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003182:Complement C5 / Q000276:immunology*; D003864:Depression, Chemical; D004285:Dogs; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D009504:Neutrophils / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology*; D009195:Peroxidase / Q000494:pharmacology*; D010544:Peroxidases / Q000494:pharmacology*; D013997:Time Factors
D003182:Complement C5; D010446:Peptide Fragments; D006861:Hydrogen Peroxide; D010544:Peroxidases; D009195:Peroxidase