Effect of the phosphodiesterase III inhibitor amrinone on cytokine and nitric oxide production in immunostimulated J774.1 macrophages

The level of intracellular cyclic nucleotides is a regulatory factor in a variety of immune processes. Increases in intracellular cyclic AMP (cAMP) and/or cyclic GMP (cGMP) concentration by the inhibition of phosphodiesterase have been shown to modulate the inflammatory response. Amrinone is a clinically used positive inotropic agent which elevates intracellular cAMP and cGMP levels by selective inhibition of the phosphodiesterase III isoenzyme. In the current study, we investigated the effect of various concentrations (1-300 mu M) of amrinone on lipopolysaccharide-induced production of pro- and anti-inflammatory cytokines and of nitric oxide (NO) in vitro. In cultured murine J774.1 macrophages, 1 ng/ml-10 mu g/ml of lipopolysaccharide from Escherichia coli 055:B5 induced production of tumor necrosis factor-alpha (TNF-alpha), interleukin-10, and nitrite (breakdown product of NO). Pretreatment of cells with amrinone caused a dose-dependent suppression of TNF-alpha production in the concentration range of 1-100 mu M. Furthermore, this drug suppressed NO production in the range of 30-300 mu M. Similarly to the results in the J774.1 cells, amrinone also inhibited TNF-alpha and NO production in the range of 10-100 mu M in primary rat peritoneal macrophages. At 300 mu M, but not at lower concentrations, amrinone inhibited interleukin-10 production in lipopolysaccharide-treated J774.1 macrophages. Pretreatment of the macrophages with 100 and 300 mu M amrinone increased the Lipopolysaccharide-elicited translocation of nuclear factor-kappa B. Taken together, our results indicate that the phosphodiesterase In inhibitor amrinone modulates the activation/production of many pro- and anti-inflammatory factors in endotoxin-stimulated cells. It remains to be further investigated how such immunomodulatory effects contribute to the clinical profile of the agent. (C) 1997 Elsevier Science B.V.