Neutrophil myeloperoxidase is a potent and selective inhibitor of mast cell tryptase.
Myeloperoxidase (MPO) is an important component of the neutrophil response to microbial infection. In this paper we report an additional activity of MPO, the potent and selective inhibition of human mast cell tryptase. MPO inhibits human mast cell tryptase in a time-dependent manner with an IC50 of 16 nM at 1 h. In contrast, MPO does not inhibit trypsin, thrombin, plasmin, factor Xa, elastase, or cathepsin G. It is the native protein conformation of MPO and not its enzyme activity that is responsible for tryptase inhibition. Heparin, at high concentrations, can prevent the inhibition of tryptase by MPO. We have shown by size-exclusion chromatography that MPO promotes the dissociation of active tryptase tetramer to inactive monomer. These data suggest that MPO inhibits tryptase by interfering with the heparin stabilization of tryptase tetramer. We have previously shown that lactoferrin (another neutrophil-associated protein) also inhibits tryptase activity by a similar mechanism. The finding that MPO is a potent inhibitor of tryptase lends further support to the hypothesis that neutrophil proteins, such as MPO and lactoferrin, may play a regulatory role as endogenous suppressers of tryptase enzyme activity.
Cregar
L
L
Departments of Biochemistry and Enzymology, Axys Pharmaceuticals, Inc., South San Francisco, California, 94080, USA.
Elrod
K C
KC
Putnam
D
D
Moore
W R
WR
D053818:Chymases; D006801:Humans; D018836:Inflammation Mediators; D008407:Mast Cells / Q000201:enzymology*; D009504:Neutrophils / Q000201:enzymology*; D009195:Peroxidase / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D053802:Tryptases
D018836:Inflammation Mediators; D015842:Serine Proteinase Inhibitors; D009195:Peroxidase; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases