Divergent effects of methylxanthines and adenylate cyclase agonists on monocyte cytotoxicity and cyclic AMP levels

Abstract

The effects of theophylline, isobutylmethylxanthine (IBMX), prostaglandin E1 (PGE1) and isoproterenol on [human] monocyte antibody-dependent cytotoxicity (ADCC) were compared to their effects on monocyte cAMP levels. Theophylline (2 mmol/l) halved ADCC and gave a 2-fold increase in cAMP levels. At concentrations not elevating cAMP, theophylline inhibited ADCC significantly. Incubation of monocytes with IBMX, PGE1 and isoproterenol ADCC was only modestly inhibited, while these agents gave larger increments (3- to 8-fold) in cAMP levels than theophylline did. Low concentrations of IBMX (50 .mu.mol/l) elevated cAMP without affecting monocyte ADCC, whereas PGE1 and isoproterenol inhibited ADCC dose-dependently comparable to increases in cAMP. In doses giving similar inhibition of ADCC, addition of PGE1 resulted in larger cAMP increments than did isoproterenol. The effects of IBMX, PGE1 and isoproterenol were dependent on target cell to effector cell ratio and increased during preincubation with the agents. The inhibition of ADCC by the agents was accompanied by a depressed monocyte lysozyme release and depressed activation of hexose monophosphate shunt. Only theophylline affected monocyte attachment to sensitized target cells. These results argue against the general inverse relationship between cAMP content and inhibition of monocyte ADCC and demonstrate that theophylline, independent of increases in cAMP, inhibits ADCC probably by abrogation of monocyte binding activity.