ROLE OF INTERLEUKIN-1-BETA CONVERTING-ENZYME (ICE) IN ACUTE MYELOGENOUS LEUKEMIA-CELL PROLIFERATION AND PROGRAMMED CELL-DEATH

The proinflammatory cytokine interleukin (IL)-1 has been shown to play a pivotal role in stimulating acute myelogenous leukemia (AML) cell p roliferation. The gene for its prominent IL-1 beta form produces a 31- kDa precursor protein (pro-IL-1 beta) that is biologically inactive un less cleaved to its mature form by a cytoplasmic cysteine protease ter med IL-1 beta converting enzyme (ICE). Although ICE was first thought to be a unique enzyme with a single biologic activity, several investi gators have demonstrated that ICE shares sequence homology with the pr otein product of ced-3, the gene for cell death of the nematode Caenor habditis elegans, and induces apoptosis in different experimental mode ls. It was therefore hypothesized that ICE may either augment the prod uction of mature IL-1 beta and stimulate the proliferation of cells, i n which IL-1 beta acts as an autocrine growth factor, or induce apopto sis. Recent data indicate that ICE is a member of an increasingly reco gnized family of cysteine proteases. Unlike ICE, the other members of this family do not cleave pro-IL-1 beta but are effective inducers of apoptotic cell death, whereas ICE acts primarily as an IL-1 beta conve rting enzyme. Because IL-1 beta serves as either an autocrine or parac rine 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-1 beta and suppressed AML progenitor proli feration. Our data suggest that ICE does not function as an apoptosis gene in AML but rather increases mature IL-1 beta production and AML c ell proliferation. It is possible, therefore, that ICE inhibitors may be beneficial in AML therapy.