Modulation of cell proliferation and cytokine production in acute myeloblastic leukemia by interleukin-1 receptor antagonist and lack of its expression by leukemic cells

Abstract

Interleukin-1 (IL-1) is spontaneously produced by acute myeloblastic leukemia (AML) cells. IL-1 also induces synthesis of colony-stimulating factors (CSFs) and sustains leukemic growth. An IL-1-specific inhibitor has been recently purified and cloned; this molecule binds to IL-1 receptors but has no IL-1 activity, fulfilling the characteristics of an IL-1 receptor antagonist (IL-1ra). Because high-affinity binding sites for IL-1ra were shown on AML cells by radioligand binding studies, we studied the effect of IL-1ra on the proliferative activity of blast cells isolated from 16 cases of AML. In each case, spontaneous proliferation was inhibited by addition of the IL-1ra in a dose-dependent manner (1 to 100 ng/mL). Culture supernatants of unstimulated leukemic cells contained IL-1 beta and granulocyte-macrophage CSF (GM-CSF), but when incubated with the IL-1ra, a reduction or disappearance of GM-CSF was observed in 8 of 10 cases, whereas spontaneous IL-1 production was reduced in four of seven cases. By Northern hybridization, IL-1 beta gene transcripts were shown in 20 of 23 AML cases, whereas IL-1ra-specific messenger RNA was present in only two of the patients studied. These data show a role for IL-1 in the spontaneous proliferation and cytokine production of AML cells and suggest that an imbalanced synthesis of IL-1 and of its natural receptor antagonist may contribute to the unrestricted growth of AML cells.