Human matrix metalloprotease activation by insults of bacterial infection involving proteases and free radicals.
We found that human matrix metalloproteases (MMPs) may be processed from their proenzyme forms (proMMP) to their active forms by two new and unique mechanisms: Firstly, by bacterial proteases such as Pseudomonas elastase and Vibrio cholerae protease, which cleave off the N-terminal autoinhibitory domain (so-called cysteine switch) from proMMPs. The second mechanism depends on free radical generation by activated polymorphonuclear leukocytes (PMNs). In this case, peroxynitrite (ONOO-) or nitrogen dioxide radical (.NO2), the reaction products of either superoxide (O2.-) or molecular oxygen (O2) and nitric oxide (.NO), are the key reactants. Both O2.- and .NO are generated by activated macrophages and PMNs as a result of immunologic responses involving various proinflammatory cytokines. .NO2 or ONOO- seems to interact with a single cysteine residue in the propeptide autoinhibitory domain, or so-called cysteine switch of proMMPs, thus transforming proMMPs into their active conformation. Furthermore, reactive oxygen species are known to inactivate the alpha1-protease inhibitor (alpha1-PI), a potent neutrophil elastase inhibitor in plasma. In addition, we found that such radicals activate MMPs which degrade and inactivate alpha1-PI by proteolysis. Thus, the activation of MMPs, accompanied by the inactivation of alpha1-PI, will bring about enhanced proteolytic damage to the matrix tissues of the infected sites by both MMPs and elastase.
Maeda
H
H
Department of Microbiology, Kumamoto University School of Medicine, Honjo, Japan.
Okamoto
T
T
Akaike
T
T
D001426:Bacterial Proteins / Q000378:metabolism; D001665:Binding Sites; D002729:Chloromercuribenzoates / Q000494:pharmacology; D017364:Collagenases / Q000187:drug effects / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000187:drug effects / Q000378:metabolism*; D005033:Ethylmaleimide / Q000494:pharmacology; D005609:Free Radicals; D006801:Humans; D006868:Hydrolysis; D020781:Matrix Metalloproteinase 1; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D010455:Peptides / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D020245:p-Chloromercuribenzoic Acid
D001426:Bacterial Proteins; D002729:Chloromercuribenzoates; D004792:Enzyme Precursors; D005609:Free Radicals; D010455:Peptides; D011480:Protease Inhibitors; D013439:Sulfhydryl Reagents; D020245:p-Chloromercuribenzoic Acid; D010450:Endopeptidases; D017364:Collagenases; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; D005033:Ethylmaleimide