Biomol Ther.  2014 Sep;22(5):414-419. 10.4062/biomolther.2014.099.

Comparison of the Effects of Matrix Metalloproteinase Inhibitors on TNF-alpha Release from Activated Microglia and TNF-alpha Converting Enzyme Activity

• Lee EJ
• Moon PG
• Baek MC
• Kim HS

• KMID: 2380318
• DOI: http://doi.org/10.4062/biomolther.2014.099

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.

Keyword

Microglia; Inflammation; MMP inhibitor; TNF-alpha; TACE

MeSH Terms

Chemokines
Cytokines
Endopeptidases
Inflammation
Matrix Metalloproteinase Inhibitors*
Matrix Metalloproteinases
Microglia*
Neuroprotective Agents
Tumor Necrosis Factor-alpha*
Chemokines
Cytokines
Endopeptidases
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases
Neuroprotective Agents
Tumor Necrosis Factor-alpha