Myeloperoxidase-mediated modulation of chemotactic peptide binding to human neutrophils.
Methionine-containing chemotactic peptides, such as formyl-methionyl-leucyl-phenylalanine (FMLP), are inactivated via a neutrophil-derived, myeloperoxidase-mediated oxidation of the methionine residue. We report that extracellular inactivation of FMLP by myeloperoxidase modulates the apparent binding of methionine-containing chemotactic peptides to their surface receptors. Inhibitors of myeloperoxidase enhanced FMLP binding. At subsaturating concentrations of 3H-FMLP (20 nM), 1 mM cyanide (KCN) increased the binding of 3H-FMLP to human neutrophils (PMN) by 51% +/- 12%. Similar increases occurred with 0.1 mM azide and 10 mM aminotriazole (ATZ). KCN had little effect on maximal 3H-FMLP binding to PMN at saturation (control-17,040 +/- 910 receptors/PMN; KCN-16,820 +/- 1,940 receptors/PMN), but decreased the concentration of 3H-FMLP required to half-saturate the PMN receptors (control-39 +/- 3 nM; KCN-17 +/- 1 nM). ATZ gave similar results. The binding to PMN of the non-methionine-containing chemotactic peptide 125I-formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine (125I-FNLPNTL) was unaltered by KCN. Also, the binding of 3H-FMLP to myeloperoxidase-deficient PMN was unaltered by KCN. Both KCN and ATZ decreased the oxidation of FMLP by PMN. Finally, ATZ (but not KCN) enhanced the chemotactic migration of PMN in response to submaximal concentrations of FMLP. These studies show that intact PMN inactivate methionine-containing chemotactic peptides by a pathway that is sensitive to myeloperoxidase inhibitors and is absent in myeloperoxidase-deficient PMN. This action results in an apparent decrease in the affinity of the chemotactic peptide receptor for methionine-containing chemotactic peptides, which may modulate chemotatic events in inflammatory loci.
D000640:Amitrole / Q000494:pharmacology; D001386:Azides / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism*; D009195:Peroxidase / Q000494:pharmacology*; D010544:Peroxidases / Q000494:pharmacology*; D011190:Potassium Cyanide / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects*
D001386:Azides; D009842:Oligopeptides; D009240:N-Formylmethionine Leucyl-Phenylalanine; C021642:F-chemotactic peptide; D010544:Peroxidases; D009195:Peroxidase; D011190:Potassium Cyanide; D000640:Amitrole