Role of Interleukin-1β Converting Enzyme (ICE) in Acute Myelogenous Leukemia Cell Proliferation and Programmed Cell Death

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Abstract
The proinflammatory cytokine interleukin (IL)-1 has been shown to play a pivotal role in stimulating acute myelogenous leukemia (AML) cell proliferation. The gene for its prominent IL-1b˜ form produces a 31-kDa precursor protein (pro-IL-1b˜) that is biologically inactive unless cleaved to its mature form by a cytoplasmic cysteine protease termed IL-1b˜ converting enzyme (ICE). Although ICE was first thought to be a unique enzyme with a single biologic activity, several investigators have demonstrated that ICE shares sequence homology with the protein product of ced-3, the gene for cell death of the nematode Caenorhabditis elegans, and induces apoptosis in different experimental models. It was therefore hypothesized that ICE may either augment the production of mature IL-1b˜ and stimulate the proliferation of cells, in which IL-1b˜ acts as an autocrine growth factor, or induce apoptosis. Recent data indicate that ICE is a member of an increasingly recognized family of cysteine proteases. Unlike ICE, the other members of this family do not cleave pro-IL-1b˜ but are effective inducers of apoptotic cell death, whereas ICE acts primarily as an IL-1b˜ converting enzyme. Because IL-1b˜ serves as either an autocrine or paracrine growth factor in AML, we recently investigated the effect of ICE inhibition on AML colony growth and found that ICE inhibition reduced the production of mature IL-1b˜ and suppressed AML progenitor proliferation. Our data suggest that ICE does not function as an apoptosis gene in AML but rather increases mature IL-1b˜ production and AML cell proliferation. It is possible, therefore, that ICE inhibitors may be beneficial in AML therapy.