Suppression of IL-12 production by phosphodiesterase inhibition in murine endotoxemia is IL-10 independent

Abstract

Phosphodiesterase (PDE) inhibitors are potent regulators of various immune processes. Immune cells contain type IV and type III PDE. Here we studied in mice the effects of rolipram, a selective PDE IV inhibitor, and amrinone, a selective PDE III blocker, on plasma levels of IL-12 (p70), IFN-gamma, IL-1, TNF-alpha, and nitric oxide (NO) induced by intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS) (80 mg/kg). Pretreatment of BALB/c mice with both rolipram (1-25 mg/kg) and amrinone (10-100 mg/kg) decreased plasma IL-12 levels in a dose-dependent manner. Similarly, LPS-elicited plasma IFN-gamma concentrations were suppressed by both rolipram and amrinone. However, LPS-induced plasma IL-1alpha levels were not affected by either of these compounds. In addition, rolipram inhibited IL-12, IFN-gamma, TNF-alpha and nitrite/nitrate (breakdown products of NO) production in C57BL/6 IL-10(+/+) mice as well as in their IL-10-deficient counterparts (C57BL/6 IL-10(-/-)). Our results suggest that rolipram and amrinone decrease the immune activation in endotoxemia through inhibition of the production of pro-inflammatory mediators IL-12, IFN-gamma, TNF-alpha and NO. These effects are not the consequences of the increase in IL-10 production by PDE inhibition.