Chemotactic factor inactivation by the myeloperoxidase-hydrogen peroxide-halide system. An inflammatory control mechanism

Polymorphonuclear leukocytes may modulate the acute inflammatory response by the secretion of enzymes capable of inactivating mediators of inflammation. The ability of the myeloperoxidase-H₂O₂-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°C resulted in essentially complete loss of chemotactic activity. Inactivation was dependent on enzymatically active myeloperoxidase, H₂O₂ or a peroxide-generating enzyme system, and a halide cofactor. It was blocked by agents which inhibit peroxidase (azide) or degrade H₂O₂ (catalase). Inactivation of chemoattractants was time-dependent, reaching maximal levels within 1-5 min, and temperature-dependent with no significant inactivation occurring at 0°C. H₂O₂ alone had no significant inactivating ability of concentrations as high as 10 mM, whereas in the presence of myeloperoxidase and a halide, 0.1 μM, H₂O₂ showed significant activity and 10 μM H₂O₂ 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 membrane-perturbing agents secrete enzymatic constituents, including myeloperoxidase, and metabolic products such as H₂O₂. 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.