Polymorphonuclear leukocyte inhibition by therapeutic concentrations of theophylline is mediated by cyclic-3',5'-adenosine monophosphate

Abstract

Although theophylline has been used for many years as a principal agent in treatment of reversible obstructive airway disease, the mechanism of drug activity at therapeutic concentrations remains unclear. Because inflammatory mediators generated by polymorphonuclear leukocytes (PMN) may be important in the pathogenesis of airway hyperreactivity, the effects of theophylline upon PMN activation were studied. Theophylline (9 micrograms/ml, 50 microM) inhibited PMN leukotriene B4 generation by 50%, oxygen metabolite generation by 60%, and decreased the concentration of isoproterenol required to cause 50% maximal inhibition (EC50) from 13 to 3.3 nM. The same theophylline concentration increased PMN cAMP by 196% at 45 s after cell activation. A higher theophylline concentrations (18 micrograms/ml, 100 microM) decreased leukotriene B4 generation by more than 90%. Eight healthy volunteers were studied before and after 1 wk of oral theophylline administration (mean plasma theophylline level achieved was 9.4 micrograms/ml). Basal and 1-min postactivation cAMP concentrations were increased 160 and 157%, respectively, in PMN specimens after theophylline administration. The EC50 for isoproterenol was reduced by 50%, and the cAMP elevation induced by isoproterenol was increased by 200%. Because theophylline inhibition of PMN function appeared to be associated with both an increase in cAMP and a decrease in intracellular calcium, these effects may be relevant to both the therapeutic and adverse pharmacologic actions of theophylline. Because inflammatory mediator release was reduced by low drug concentrations, inhibition of PMN function may be an effect of therapeutic theophylline administration.