TNF a converting enzyme TACE

The TNF gene maps to chromosome 6p21.3, is about 3 kB in size and contains four exons. TNF is primarily produced as a 212-amino acid transmembrane protein a soluble homotrimeric cytokine is released via proteolytic cleavage by the metaUoprotease TNF-a-converting enzyme (TACE, also called ADAM 17). 

Spiro hydantoins such as 225-227 (Table 19) were tested for their inhibitory activity against tumor necrosis factor a (TNF-a) converting enzyme (TACE) [82]. The compounds exhibited strong inhibitory activity against porcine TACE and excellent selectivity over MMPs (Table 11). For compound 226, the (55, 6R) enantiomer was more than 80-fold less active against pTACE. Boc or isopropylacetyl pyrrolidine derivatives of 227 were also equipotent with 227. 

There are more than 25 ADAMs proteases identified so far. ADAM 17 has been shown to be TNF-a converting enzyme (TACE) (114). Inhibition of TACE slows the production of TNF-a, a potent cytokine involved in inflammatory responses to infection. Normally TNF-a produces a useful response, but in some cases, too much TNF-a is released and inhibition of TNF-a production would be ther-... 

FIGURE 1 Production and function of lymphotactin and fractalkine. Phorbol ester (PM A) induces the expression of lymphotactin in T-cells and NK cells, and lymphotactin is secreted and activates T-cells and NK cells that express the receptor CRXl. Proinflammatory cytokines induce the expression of fractalkine in endothelial cells. Fractalkine is produced as a membrane-bound form, which works as an adhesion molecule for T-cells (T) and monocytes (M) expressing the receptor CX3CR1. The secreted form is released by processing by TNF—a converting enzyme (TACE) and functions as a chemotactic factor. 

ProTNF-a is initially produced as a membrane-bound form that is processes by TNF-a converting enzyme (TACE), a type I membrane-bound metalloproteinase (Black et al. 1997, Moss et al. 1997). TACE represents a potential target for the development of a therapeutic agent for inflammation and related diseases (Patel et al. 1998). TACE is inhibited by TIMP-3 but not by TIMP-1, -2 and -4 (Amour et al. 1998). 

TNF-a converting enzyme (TACE) is a newly discovered enzyme in the disintegrin and metalloproteinase (ADAM) family (78). This enzyme releases the 17-kD mature TNF-a fiom membrane-bound TNF-a by cleaving Ala 76 and Val 77 linkage. TACE has also been shown to be involved with other cell surface protein shedding events such as the p55 and p75 TNF-a receptors (79). Our laboratory has previously shown that acute administration of alcohol (EtOH)to rats suppresses TNF-a production posttranscriptionally in the lung and blood (20,80). Recently, we have further defined the mechanism of TNF-a inhibition by EtOH, which revealed... 

IL-1 is stable, and it diffuses to and activates receptors (IL-1 receptors) on adjacent and distant cells. The IL-1 receptor of endothelial cells is especially important (Fig. 13.5a). In all cells, the IL-1 ligand bound to its receptor causes surface expression of a second cytokine, tumor necrosis factor-a (TNF-a). TNF-a was originally described as a factor that kills (causes necrosis of) mouse fibrosarcoma (cancer) cells but not normal mouse fibroblasts. TNF-a is released from the cell surface by an adamalysin protease, TNF alpha converting enzyme (TACE). TACE is also known as ADAM 17, one of more than 40 cell surface bound adamalysins related to the ADAM-TS2 subfamily (Sect. 8.2.1). Unlike IL-1, TNF-a is unstable and can only activate TNF receptors on nearby cells. It usually produces responses that supplement those from IL-1 activation (Fig. 13.5b). 

Another approach is the inhibition of the TNF-converting enzyme (TACE), which converts proTNF into its mature, proinflammatory form. Also, numerous inhibitors of P38 and Erk-MAP kinases have been synthesized and some have reached the clinical trial stage. MAP-p38 kinase occupies a central role in the signaling network responsible for the up-regulation of proinflammatory cytokines like interleukin 1 and TNFa. The pathway of Erk-MAP kinase is often up-regulated in human tumors and as such represents an attractive target for the development of anticancer drugs. ... 

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