Enhancement of Interferon-γ–Induced Differentiation of Human Monoblastic Leukemia U-937 Cells by cAMP-Inducing Agents

The effects of combinations of interferons (IFNs) and cAMP-inducing agents on the induction of differentiation of human monocytic leukemia U-937 cells were examined. IFN-γ induced nitro blue tetrazolinum (NBT) reducing activity of U-937 cells in a dose-dependent manner, while cAMP-inducing agents such as cholera toxin, prostaglandin E₁, forskolin, and isoproterenol only marginally induced NBT reducing activity. However, they all synergistically increased IFN-γ induction of NBT reducing activity. Cholera toxin was the most potent of the cAMP-inducing agents. Combination effects of IFN-γ and cholera toxin on other differentiation-associated markers of α-naphthyl acetate esterase activity, morphological maturation, Fc receptors, and surface phenotype were also observed. IFN-α and -β, either alone or in combination with cAMP-inducing agents, did not induce NBT reducing activity. IFN-γ and cholera toxin also synergistically induced differentiation-associated markers in another human monocytic leukemia cell line, THP-1, and a human myeloblastic leukemia cell line, ML-1. These results suggest that cAMP/ A-kinase may be an important but insufficient signal for the maturation process of myelogenous leukemia cells.