Comparison of the Effects of Matrix Metalloproteinase Inhibitors on TNF-alpha Release from Activated Microglia and TNF-alpha Converting Enzyme Activity.
10.4062/biomolther.2014.099
- Author:
Eun Jung LEE
1
;
Pyong Gon MOON
;
Moon Chang BAEK
;
Hee Sun KIM
Author Information
1. Department of Molecular Medicine, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul 158-710, Republic of Korea. hskimp@ewha.ac.kr
- Publication Type:Original Article
- Keywords:
Microglia;
Inflammation;
MMP inhibitor;
TNF-alpha;
TACE
- MeSH:
Chemokines;
Cytokines;
Endopeptidases;
Inflammation;
Matrix Metalloproteinase Inhibitors*;
Matrix Metalloproteinases;
Microglia*;
Neuroprotective Agents;
Tumor Necrosis Factor-alpha*
- From:Biomolecules & Therapeutics
2014;22(5):414-419
- CountryRepublic of Korea
- Language:English
-
Abstract:
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate cell-matrix composition and are also involved in processing various bioactive molecules such as cell-surface receptors, chemokines, and cytokines. Our group recently reported that MMP-3, -8, and -9 are upregulated during microglial activation and play a role as proinflammatory mediators (Lee et al., 2010, 2014). In particular, we demonstrated that MMP-8 has tumor necrosis factor alpha (TNF-alpha)-converting enzyme (TACE) activity by cleaving the prodomain of TNF-alpha and that inhibition of MMP-8 inhibits TACE activity. The present study was undertaken to compare the effect of MMP-8 inhibitor (M8I) with those of inhibitors of other MMPs, such as MMP-3 (NNGH) or MMP-9 (M9I), in their regulation of TNF-alpha activity. We found that the MMP inhibitors suppressed TNF-alpha secretion from lipopolysaccharide (LPS)-stimulated BV2 microglial cells in an order of efficacy: M8I>NNGH>M9I. In addition, MMP inhibitors suppressed the activity of recombinant TACE protein in the same efficacy order as that of TNF-alpha inhibition (M8I>NNGH>M9I), proving a direct correlation between TACE activity and TNF-alpha secretion. A subsequent pro-TNF-alpha cleavage assay revealed that both MMP-3 and MMP-9 cleave a prodomain of TNF-alpha, suggesting that MMP-3 and MMP-9 also have TACE activity. However, the number and position of cleavage sites varied between MMP-3, -8, and -9. Collectively, the concurrent inhibition of MMP and TACE by NNGH, M8I, or M9I may contribute to their strong anti-inflammatory and neuroprotective effects.
