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 (O₂̇̄) or molecular oxygen (O₂) and nitric oxide (^.NO), are the key reactants. Both O₂̇̄ 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 cui-protease inhibitor (α₁-PI), a potent neutrophil elastase inhibitor in plasma. In addition, we found that such radicals activate MMPs which degrade and inactivate α₁-PI by proteolysis. Thus, the activation of MMPs, accompanied by the inactivation of α₁-PI, will bring about enhanced proteolytic damage to the matrix tissues of the infected sites by both MMPs and elastase.