Molecular mechanism for activation and regulation of matrix metalloproteinases during bacterial infections and respiratory inflammation

Tatsuya Okamoto, Teruo Akuta, Fumio Tamura, Albert van der Vliet, Takaaki Akaike

Research output: Contribution to journalReview articlepeer-review

81 Citations (Scopus)

Abstract

Matrix metalloproteinases (MMPs) are critical mediators of tissue remodeling. Inappropriate regulation of MMPs causes many pathological events, including microbial invasion and inflammatory tissue damage. Some of the bacterial exoproteinases can effectively activate pro-MMPs (inactive zymogens) via limited proteolysis around their autoinhibitory domains. In addition, overproduction of nitric oxide (NO) may contribute to respiratory inflammation via the formation of reactive nitrogen species (RNS). Several studies have identified regulatory properties of NO/RNS on biomolecules due to functional modification of their cysteine residues. In fact, NO/RNS can mediate activation and expression of MMPs, because RNS can interact with a cysteine switch in the autoinhibitory domain, thus converting proMMPs into their active forms without proteolysis. Many studies have indicated that NO/RNS can participate in expression of various genes that affect immune-inflammatory responses, including MMPs. Although NO in some cases upregulates MMPs, S-nitrosothiols downregulate MMP-9 expression by suppressing the NF-κB pathway. While microbial proteinases cause excessive activation of MMPs and contribute to microbial pathogenesis, NO/RNS may modulate expression and activation of MMPs as well as various inflammatory mediators, depending on the redox status at sites of inflammation. Therefore, appropriate regulation of MMPs may be of potential therapeutic value for various infections and inflammatory lung diseases.

Original languageEnglish
Pages (from-to)997-1006
Number of pages10
JournalBiological Chemistry
Volume385
Issue number11
DOIs
Publication statusPublished - 2004 Nov 1
Externally publishedYes

Keywords

  • Bacterial proteinase
  • Matrix metalloproteinase (MMP)
  • Nitric oxide (NO)
  • Nuclear factor κB (NF-κB)
  • Peroxynitrite (ONOO)
  • Reactive nitrogen species (RNS)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry

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