Human matrix metalloprotease activation by insults of bacterial infection involving proteases and free radicals

Hiroshi Maeda, Tatsuya Okamoto, Takaaki Akaike

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)193-200
Number of pages8
JournalBiological Chemistry
Volume379
Issue number2
DOIs
Publication statusPublished - 1998 Feb
Externally publishedYes

Keywords

  • Bacterial proteases
  • Collagenase, PMN
  • Matrix metalloproteases (MMPs)
  • Nitric oxide
  • Peroxynitrite
  • Reactive oxygen species
  • α-Protease inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry

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