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TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3
A Amour1, P M Slocombe, A Webster
1School of Biological Sciences, University of East Anglia, Norwich, UK. A.Amour@uea.ac.uk
FEBS Letters
|October 2, 1998
Summary
Tissue inhibitors of metalloproteinases (TIMPs) and synthetic inhibitors target TNF-alpha converting enzyme (TACE). TIMP-3 effectively inhibits TACE, suggesting its role in modulating inflammatory diseases involving TNF-alpha.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Tumor Necrosis Factor-alpha converting enzyme (TACE; ADAM-17) is a metalloproteinase crucial for processing proTNF-alpha into its soluble, active form.
- TACE's role in inflammatory diseases makes it a significant therapeutic target for inhibitor design.
Purpose of the Study:
- To investigate the inhibitory effects of tissue inhibitors of metalloproteinases (TIMPs) and synthetic metalloproteinase inhibitors on TACE.
- To characterize the inhibition profile of the catalytic domain of mouse TACE (rTACE).
Main Methods:
- Overexpression of the catalytic domain of mouse TACE (rTACE) as a soluble Ig fusion protein.
- Assessing inhibition of rTACE by various TIMPs (TIMP-1, -2, -3, -4) and peptide hydroxamate inhibitors.
Main Results:
- Recombinant mouse TACE (rTACE) was effectively inhibited by peptide hydroxamate inhibitors.
- TIMP-3 demonstrated significant inhibition of rTACE.
- TIMP-1, TIMP-2, and TIMP-4 showed minimal to no inhibitory activity against rTACE.
Conclusions:
- TIMP-3 plays a distinct role in TACE inhibition compared to other TIMPs.
- These findings suggest TIMP-3's potential importance in regulating pathological processes driven by TNF-alpha secretion.