| Co-Investigator(Kenkyū-buntansha) |
MIYAMOTO Yoichi Kumamoto University School of Medicine, Research Associate, 医学部, 助手 (20295132)
SAWA Tomohiro Kumamoto University School of Medicine, Research Associate, 医学部, 助手 (30284756)
AKAIKE Takaaki Kumamoto University School of Medicine, Associate Professor, 医学部, 助教授 (20231798)
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| Research Abstract |
Matrix metalloproteases (MMPs) are secreted by numerous mammalian cells as inactive proenzymes (proMMPs). After activation they are involved in tissue remodeling and facilitate cancer metastasis. In view of microbial infection and inflammation, two distinct proMMPs, proMMP-8 with 85 kDa and proMMP-9 with 92-kDa, known to be secreted by human polymorphonuclear leukocytes, are of special interest. Macrophages as well as fibroblasts can also produce proMMP-1 with 52 kDa and proMMP-9 known as progelatinases which cleave denatured collagen preferentially. We have previously reported that microbial proteases can activate various endogenous protease cascade systems of the infected hosts. Among them, we studied the kinin (or bradykinin) generating cascade most extensively and demonstrated processing of Hageman factor to its active form or prekallikrein to kallikrein or direct generation of kinin from kininogen, and activation of the clotting cascade involving factors XII, X, II, etc. In the pr
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esent study, we further found that human MMPs can be processed from 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. In this case, peroxynitrite (ONOOィイD1-ィエD1) or nitrogen dioxide radical (NOィイD22ィエD2), the reaction products of either superoxide (OィイD3-(/)2ィエD3) or molecular oxygen (OィイD22ィエD2) and nitric oxide (NO), are the key reactants. Both OィイD3-(/)2ィエD3 and NO are generated by activated macrophages and leukocytes as a result of immunologic responses involving various proinflammatory cytokines. NOィイD22ィエD2 or ONOOィイD1-ィエD1 seems to interact with a single cysteine residue in the propeptide autoinhibitory domain or so-called cysteine switch of proMMPs thus transforming proMMPs to their active conformation. Furthermore, we found a quite unique and novel MMP activation mechanism: Specifically, peroxynitrite-mediated MMP activation is remarkably potentiated by glutathione (GSH), in which nitrated GSH (NOィイD22ィエD2-GS) produced by peroxynitrite appears to be directly involved in the MMP activation. It is thus concluded that bacterial proteases and free radical species such as NO derived from host's inflammatory responses may contribute to the bacterial pathogenesis via activation of MMP activation particularly during bacterial intrusion into the host. Less
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