STIMULATION OF BETA-ADRENOCEPTORS INHIBITS ENDOTOXIN-INDUCED IL-12 PRODUCTION IN NORMAL AND IL-10 DEFICIENT MICE

Stimulation of beta-adrenoceptors has been shown to regulate the produ ction of various inflammatory mediators. In the present study, we inve stigated in mice whether ligation of beta-adrenoceptors, modulates lip opolysaccharide (LPS)-induced plasma levels of interleukin (IL)-12, in terferon-gamma (IFN-gamma), and IL-10. In BALB/c mice, isoproterenol ( 1-10 mg kg(-1), i.p.), a selective agonist of beta-adrenoceptors and a lso dexamethasone (10 mg kg(-1), i.p.) pretreatment 30 min before the administration of LPS suppressed plasma IL-12 (p40 and p70) concentrat ions as determined at various time points after the LPS challenge. The inhibition of IL-12 release by isoproterenol was prevented by the bet a-adrenoceptor antagonist propranolol confirming the involvement of be ta-adrenoceptors in the effect of isoproterenol. Furthermore, pretreat ment of the animals with propranolol alone enhanced LPS-induced plasma IL-12, suggesting that endogenous catecholamines inhibit IL-12 produc tion via the beta-adrenoceptors. In IL-10 deficient C57BL/6 IL-10(-/-) mice, plasma levels of IL-12 and IFN-gamma were significantly higher than in their counterparts, with more than 70-fold increase in IL-12. Furthermore, while augmenting the IL-10 response in C57BL/6 IL-10(+/+) , isoproterenol inhibited the production of IL-12 in both the C57BL/6 IL-10(+/+) and C57BL/6 IL-10-/- mice, suggesting that the inhibition o f IL-12 production by this compound is independent of the increased re lease of IL-10. Our results demonstrate, for the first time, that stim ulation of beta-adrenoceptors by isoproterenol or endogenous catechola mines suppresses IL-12 production in vivo. (C) 1998 Elsevier Science B .V. All rights reserved.