Interleukin‐6 production by the blast cells of acute myeloblastic leukemia: Regulation by endogenous interleukin‐1 and biological implications

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Abstract
Coordinate production of interleukin‐1β (IL‐1β) and granulocyte macrophagecolony stimulating factor (GM‐CSF) or IL‐6 by the blast cells of acute myeloblastic leukemia (AML) and normal peripheral blood leukocytes have been previously reported (van der Shoot et al.: Blood 74:2081–2087, 1989; Bradbury et al.: Leukemia 4:44–47 1990a, British Journal of Haematology 16:(in press), 1990b; Rodriguez‐Cimadevilla et al.: Blood 76:1481–1489, 1990; Schindler et al.: Blood 75:40–47, 1990). In the present study, we show that IL‐6 production by AML blasts is up‐regulated by endogenously produced IL‐1α. Neutralization of the endogenous source of IL‐1 results in a significant decrease in IL‐6 production, as determined by ELISA. Conversely, exposure of AML blasts to IL‐1α results in a significant increase in IL‐6 production in 10 of 16 patient samples. Antibodies against IL‐1α and ‐β also cause a drastic decrease in IL‐6 and GM‐CSF gene expression by the cells, suggesting that cytokine gene expression in AML blasts is driven, at least in part, by endogenous IL‐1. The biologic significance of IL‐6 production in culture of AML blasts has been addressed using a neutralizing antibody against IL‐6. Our data indicate that IL‐6 is important for the survival of clonogenic blasts in culture. In contrast, the survival of the total population of blasts is IL‐6‐independent, as assessed by the integrity of cellular DNA, even in the presence of anti‐IL‐6. These observations are consistent with the view that AML blasts might be organized as a lineage, with comparable hierarchy as in normal hemopoiesis and, perhaps, increased heterogeneity despite a homogenous appearance (McCulloch and Till: Blood Cells 7:63‐77, 1981; Buick and McCulloch: Control of Animal Cell Proliferation. Academic Press, New York, vol. 1, pp. 25–57, 1985). Buick and McCulloch have identified a subpopulation of AML clonogenic cells with stem‐cell‐like properties, and suggested that the majority of blasts may have undergone a determination‐like step. Our data indicate a marked difference in IL‐6 requirement for cell survival between precursors and the majority of blasts, suggesting that IL‐6 responsiveness may decrease following a determination‐like event, i.e., the reduction in proliferative capacity.