EFFECT OF INTERLEUKIN-1, TUMOR-NECROSIS-FACTOR-ALPHA, AND INTERFERON-ALPHA ON THE BLAST CELLS OF ACUTE MYELOBLASTIC-LEUKEMIA

In this study, we further established the role of interleukin-1-alpha (IL-1-alpha), interleukin-1-beta, tumor necrosis factor-alpha (TNF-alpha), and interferon-alpha (IFN-alpha) as regulators of proliferation of acute myeloid leukemia (AML) cells. AML cells from 8 of 15 patients incorporated high levels of H-3-thymidine (H-3-TdR) in the absence of exogenous growth factors. The spontaneous DNA synthesis could be abrogated with monospecific antibodies directed toward IL-1-alpha, IL-1-beta, or TNF-alpha, as well as with antigranulocyte-macrophage colony-stimulating factor (GM-CSF). Human recombinant GM-CSF reversed the inhibitory action of each of these antibodies and reinduced DNA synthesis in AML cells. Thus, in these cases, constitutively produced IL-1 or TNF-alpha had stimulated the synthesis of GM-CSF, which resulted in GM-CSF-dependent proliferation of AML blasts. Exogenous IL-1 up-regulated the endogenous production of GM-CSF, suggesting a positive regulation of autocrine growth factor production. We also present evidence that TNF-alpha may exert both stimulative as well as inhibitory effects on DNA synthesis in AML cells. The enhancing effect of TNF-alpha was mediated through the induction of GM-CSF production, as stimulation of DNA synthesis in AML blasts could be abrogated with anti-GM-CSF antibody. A concentration-dependent inhibitory effect of TNF-alpha on H-3-TdR incorporation into AML blasts was observed only when these cells were grown in the absence of GM-CSF. Finally, we show that human recombinant IFN-alpha is a potent inhibitor of AML cell proliferation in vitro.