The relationship between intracellular cyclic AMP concentrations and the in vitro growth of macrophages

The addition of cholera toxin, prostaglandins, or one of a series of xanthine phosphodiesterase inhibitors to bone marrow-derived macrophages maintained in liquid culture caused a dose-dependent decrease in colony formation measured 7-10 days following seeding. The growth inhibitory effects of xanthines were in the same order of potency (caffeine less than theophylline less than isobutylmethylxanthine) as their reported ability to inhibit cyclic AMP phosphodiesterase. The relationship between the magnitude of the increases in intracellular concentrations of cyclic AMP observed following the addition of the drugs and the degree of growth inhibition was complex. Combinations of cholera toxin and phosphodiesterase inhibitors caused synergistic elevations in cyclic AMP levels after a lag of approximately 3 days. However, the growth rate was decreased immediately following the addition of the combination of drugs, and thus seemed to be independent of the nucleotide levels. A cyclic AMP-resistant variant of a cloned nontransformed macrophage cell line was found to be also resistant to the growth inhibitory actions of both cholera toxin and prostaglandins. However, resistance to the inhibitory effects of cyclic AMP did not render the cells resistant to a xanthine-induced growth inhibition.