Structure and function of interleukin-1 beta converting enzyme.
An overwhelming body of evidence has shown that IL-1 beta is a major mediator of inflammatory disease (Tocci and Schmidt, 1996). The discovery of ICE, a unique processing enzyme involved in the production of active IL-1 beta, has provided a new approach to specifically block the production of this potent cytokine. Consequently, the discovery and development of inhibitors against the enzyme could hold great promise therapeutically. Potent inhibitors of the enzyme would be useful in the treatment of a number of important inflammatory diseases and potentially in the management of leukemia (Arend, 1993b; Estrov and Talpaz, 1996). A number of key questions must be answered before the therapeutic potential of such inhibitors can be realized. The development of a pharmaceutically acceptable cysteine proteinase inhibitor will almost certainly involve new chemical strategies gauged at safely inactivating the enzyme. For such inhibitors, it will be necessary to achieve selectivity for ICE from among the growing number of ICE family members while retaining potency. It will also be important to establish the level of inhibition of IL-1 beta required to achieve therapeutic efficacy. The studies comparing IL-1 beta- and ICE-deficient mice suggest that complete abrogation of IL-1 beta is required to achieve efficacy in models of inflammation. It is not known if this is the case in humans. Understanding the source of the residual IL-1 beta produced in ICE-deficient mice will be important in order to ascertain if a similar mechanism could generate active IL-1 beta in patients receiving if a ICE inhibitor. As for ICE itself, a number of formidable questions remain regarding its regulation and mechanism of activation. Answering these questions experimentally will present a major challenge due to the extremely low levels of enzyme present in cells. Studies on other family members may provide easier access to some of these questions and provide clues that can be applied to ICE. The components of the pathway involved in IL-1 trafficking and secretion are unknown, as are the mechanisms of ICE activation and regulation. Clearly other cellular proteins that have yet to be discovered will be involved in each of these processes, opening up new avenues of research in this field.
Tocci
M J
MJ
Department of Molecular Immunology, Merch Research Laboratories, Rahway, New Jersey 07065, USA.
D000818:Animals; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011480:Protease Inhibitors; D013379:Substrate Specificity
D007375:Interleukin-1; D011480:Protease Inhibitors; D003546:Cysteine Endopeptidases; D020170:Caspase 1