A novel mechanism for bradykinin production at inflammatory sites. Diverse effects of a mixture of neutrophil elastase and mast cell tryptase versus tissue and plasma kallikreins on native and oxidized kininogens.
Coprocessing of kininogens by a mixture of human mast cell tryptase and neutrophil elastase was explored as a potential substitute for the kallikrein-dependent pathway for kinin generation during inflammation. Tryptase easily excised bradykinin from the synthetic heptadecapeptide, ISLMKRPPGFSPFRSSR, but was unable to produce significant amounts of kinin by proteolysis of kininogens. However, a mixture of tryptase and elastase released bradykinin from each protein with a yield comparable to that of human plasma kallikrein. Significantly, neither plasma nor tissue kallikrein was able to effectively process N-chlorosuccinimide-oxidized high molecular weight kininogen, an effect attributed to the oxidation of a methionine residue upstream from the N terminus of the kinin domain. In support of these results the model heptadecapetide, ISL(MO)KRPPGFSPFRSSR, was also resistant to hydrolysis by either kallikrein. In contrast, the release of bradykinin from oxidized peptide or protein substrates by the tryptase/elastase mixture was not altered. Because kininogen modification may occur at inflammatory sites, as a result of the oxidative burst of recruited neutrophils and macrophages, these results suggest an alternative pathway for kinin production and the necessity for the novel utilization of two specific proteinases known to be released from these cells during inflammatory episodes.
Kozik
A
A
Institute of Molecular Biology, Jagiellonian University, Kraków, 31-120 Poland.
Moore
R B
RB
Potempa
J
J
Imamura
T
T
Rapala-Kozik
M
M
Travis
J
J
D000595:Amino Acid Sequence; D001920:Bradykinin / Q000096:biosynthesis*; D053818:Chymases; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007610:Kallikreins / Q000378:metabolism*; D007704:Kininogens / Q000378:metabolism*; D019272:Leukocyte Elastase / Q000378:metabolism*; D008407:Mast Cells / Q000201:enzymology; D008956:Models, Chemical; D008970:Molecular Weight; D010084:Oxidation-Reduction; D012697:Serine Endopeptidases / Q000378:metabolism*; D013379:Substrate Specificity; D053802:Tryptases
D007704:Kininogens; D007610:Kallikreins; D012697:Serine Endopeptidases; C083294:chymase 2; D019272:Leukocyte Elastase; D053818:Chymases; D053802:Tryptases; D001920:Bradykinin