Abstract
TNF-alpha converting enzyme (TACE; ADAM-17) is a membrane-bound disintegrin metalloproteinase that processes the membrane-associated cytokine proTNF-alpha to a soluble form. Because of its putative involvement in inflammatory diseases, TACE represents a significant target for the design of specific synthetic inhibitors as therapeutic agents. In order to study its inhibition by tissue inhibitors of metalloproteinases (TIMPs) and synthetic inhibitors of metalloproteinases, the catalytic domain of mouse TACE (rTACE) was overexpressed as a soluble Ig fusion protein from NS0 cells. rTACE was found to be well inhibited by peptide hydroxamate inhibitors as well as by TIMP-3 but not by TIMP-1, -2 and -4. These results suggest that TIMP-3, unlike the other TIMPs, may be important in the modulation of pathological events in which TNF-alpha secretion is involved.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins
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ADAM17 Protein
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Amino Acid Sequence
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Animals
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Catalysis
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Disintegrins / antagonists & inhibitors
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Enzyme Inhibitors / pharmacology
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Humans
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Hydrolysis
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Metalloendopeptidases / antagonists & inhibitors*
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Metalloendopeptidases / genetics
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Metalloendopeptidases / isolation & purification
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Mice
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Rats
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Recombinant Proteins / isolation & purification
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Recombinant Proteins / metabolism
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Substrate Specificity
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Tissue Inhibitor of Metalloproteinase-3 / antagonists & inhibitors
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Tissue Inhibitor of Metalloproteinase-3 / pharmacology*
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Disintegrins
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Enzyme Inhibitors
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Recombinant Proteins
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Tissue Inhibitor of Metalloproteinase-3
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Tumor Necrosis Factor-alpha
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ADAM Proteins
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Metalloendopeptidases
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ADAM17 Protein
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ADAM17 protein, human
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Adam17 protein, mouse
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Adam17 protein, rat