Molecular mechanism for activation and regulation of matrix metalloproteinases during bacterial infections and respiratory inflammation.
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-kappaB 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.
Okamoto
Tatsuya
T
Department of Microbiology and Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Akuta
Teruo
T
Tamura
Fumio
F
van Der Vliet
Albert
A
Akaike
Takaaki
T
D000818:Animals; D001424:Bacterial Infections / Q000201:enzymology*; D004789:Enzyme Activation; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D011014:Pneumonia / Q000201:enzymology*
D020782:Matrix Metalloproteinases