TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3

School of Biological Sciences, University of East Anglia, Norwich, UK.
FEBS Letters (Impact Factor: 3.17). 10/1998; 435(1):39-44.
Source: PubMed


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.

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    • "Among these genes, DAB2 (expressed in various tissues), which is detected at an early myogenic differentiation state [67], has lost or reduced expression in hyperproliferative cells [96]. Another gene in this group that is significantly down-regulated is a member of the tissue inhibitors of matrix metalloproteinases (TIMP) family, TIMP3, or metalloproteinase inhibitor 3. TIMP3 complexes with MMPs and is the only TIMP capable of inhibiting membrane bound MMP, transmembrane MMP and sheddases such as TNF-α converting enzyme (TACE), which is also known as disintegrin and metalloproteinase (ADAM-17) [97], [98]. Conversely, all MMPs detected in this study were highly up-regulated. "
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    • "Interestingly, the levels of TIMP-3 in group 2 and group 3 did differ significantly. TIMP-3 was found to be a strong inhibitor of TACE among other TIMPs [36] and TACE. Diabetic conditions can increase the expression of markers of systemic inflammation and Monroy et al. [37] showed that insulin-resistant conditions were associated with the increased level of TACE activity and such conditions were correlated with the down-regulation of TIMP-3 in human skeletal muscle. "
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    • "In general, all four TIMPs are broad-spectrum inhibitors of the MMP family, with some differences in specificity. TIMP-3 has been demonstrated to have a broader range of metalloproteinase substrates being particularly effective in uniquely inhibiting several members of the ADAM (a disintegrin and metalloprotease) and ADAMTS (ADAM with thrombospondin motifs) family [1], [2], [3], [4], [5], [6]. Although originally characterized for their functional property to inhibit MMP activity, TIMPs have more recently been shown to have additional biological activities that may be independent of their MMP-inhibitory functions [7]. "
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