Combination Effects of Interferon-γ and Cholera Toxin on Induction of Differentiation of an Insensitive U-937 Clone

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Abstract
We examined the combination effect of interferon-.gamma. (IFN-.gamma.) and cholera toxin and the role of cAMP in the induction of differentiation of a differentiation-insensitive U-937 clone, in which the reactivity to differentiation-inducers was decreased. IFN-.gamma. (100 units/ml) or cholera toxin (10-9 M) alone only marginally induced various differentiation-associated characteristics such as NBT-reducing activity, phagocytic activity, .alpha.-naphthyl acetate esterase activity and surface markers. However, when combined with each other, they significantly induced these markers. Other cAMP-inducing agents such as prostaglandin E2, forskolin, epinephrine and isoproterenol did not induce NBT-reducing activity, either alone or in combination with IFN-.gamma.. However, all these cAMP-inducing agents significantly increased intracellular cAMP levels. Tumor necrosis factor, interleukin 6 or granulocyte/macrophage colony-stimulating factor alone did not induce NBT-reducing activity, but they could induce activity when combined with cholera toxin. These results suggest that enhancement of induction of differentiation by cholera toxin in combination with IFN-.gamma. or other cytokines may not be merely due to increased cAMP levels. There seems to be a transduction signal other than cAMP coupling with cholera toxin to stimulate induction of differentiation of an insensitive U-937 clone.