Therapeutic concentrations of glucocorticoids suppress the antimicrobial activity of human macrophages without impairing their responsiveness to gamma interferon.

Abstract

By exposing human blood-derived macrophages and alveolar macrophages in vitro to dexamethasone, we showed in these studies that glucocorticoids markedly suppress the antimicrobial activity of macrophages but not macrophage activation by lym- phokines. As little as 2.5 X 10-8 mol/liter of dexamethasone prevented macrophages from inhibiting germination of Asper- gillus spores or from eliminating ingested bacteria such as Lis- teria, Nocardia, or Salmonella. Damage to macrophage function was inhibited by progesterone and appeared to be receptor-me- diated. In accordance with in vivo observations, dexamethasone required 24-36 h to suppress antimicrobial activity. While glu- cocorticoids interfered with base-line activity of macrophages, dexamethasone concentrations comparable to drug levels in pa- tients had no effect on macrophage activation. Proliferating lymphocytes and 'y-interferon thus increased the antimicrobial ac- tivity of phagocytes exposed to glucocorticoids over that of control cells. Macrophage activation and correction of the dexametha- sone effect by 'y-interferon, however, was dependent on the pathogen. The lymphokine enhanced the antimicrobial activity of dexamethasone-treated macrophages against Listeia and Salmonella but not against Aspergillus or Nocardia. Dexameth- asone-induced damage to the antimicrobial activity of human macrophages in vitro parallels observations that glucocorticoids render laboratory animals susceptible to listeriosis and asper- gillosis by damaging resident macrophages. Suppression of macrophage antimicrobial activity should thus be considered when treating patients with glucocorticoids; its prevention by - interferon might be beneficial for some but not all pathogens.