Modulatory in vitro effects of interleukin-1 receptor antagonist (IL-1Ra) or antisense oligonucleotide to interleukin-1 beta converting enzyme (ICE) on acute myeloid leukaemia (AML) cell growth

Abstract

We investigated the effects of interleukin-1 receptor antagonist (IL-1Ra) on the spontaneous proliferation and AML colony forming unit (CFU-AML) formation of bone marrow and peripheral blood cells in 50 acute myeloid leukaemia (AML) patients. Exposure to IL-1Ra (10 mu g/ml) caused either decreased, unaltered or increased AML cell proliferation, as well as of CFU-AML colony formation, depending on the individual patient, but the inhibitory effects were dominant. To evaluate the involvement of IL-1 beta converting enzyme (ICE) in the autonomous AML cell growth, the effects of an antisense oligonucleotide on ICE were examined in 19 of these patients. In a majority of patients, antisense ICE suppressed both AML cell proliferation and CFU-AML although a stimulatory effect was sometimes evident. The proportion of AML patients with suppression obtained by antisense ICE was higher than with IL-1Ra, suggesting the involvement of additional ICE-dependent cytokine(s) in AML cell growth besides IL-1. The presence of IL-1Ra or antisense ICE also suppressed the endogenous IL-1 beta production of AML cells, at both the level of pro-IL-1 beta and mature IL-1 beta. Although inhibition by IL-1Ra or antisense ICE on growth parameters of AML cells in vitro prevailed, indicating the importance of IL-1 activity in autonomous AML cell growth, stimulatory effects on the cells of some patients suggest that AML is a heterogenous disorder regarding IL-1 beta regulation.