β-adrenergic modulation of human type-1/type-2 cytokine balance

Background: Neuroendocrine mediators are increasingly recognized as immunomodulatory agents. Lymphocytes and monocytes express receptors for a variety of neuroendocrine mediators, including catecholamines, It has been reported that beta-adrenergic agonists decrease IFN-gamma production, with varying effects on IL-4 and 1L-5 production. Objective: Our purpose was to determine the effects of catecholamines (including beta-adrenergic agonists) on the type-1/type-2 cytokine balance in tetanus-stimulated human PBMCs. Method: Human PBMCs were stimulated with tetanus in the presence of epinephrine (EPI), norepinephrine, or terbutaline, IFN-gamma, IL-4, IL-5, and IL-10 levels in the supernatants were determined by ELISA. Results: PBMCs stimulated in the presence of EPI produced decreased levels of IFN-gamma and increased levels of IL-10, IL-4, and 1L-5. A small decrease in IFN-gamma production and an increase in IL-10, IL-4, and IL-5 production were also observed with norepinephrine. Terbutaline induced similar alterations in the type-1/type-2 cytokine balance compared with EPI, indicating that the beta(2)adrenergic receptor is involved in these cytokine alterations. Furthermore, these cytokine alterations were blocked by propranolol. Finally, IL-12p70 prevented the cytokine alterations, suggesting that the mechanism of beta-adrenergic-induced cytokine alterations involves a decrease in IL-12. Conclusion: beta-Adrenergic agonists induce a shift in the human type-1/type-2 cytokine balance toward a type-2 response. These data provide a potential mechanism to explain the paradoxical increase in asthma morbidity and mortality associated with the chronic use of scheduled dosing of short-acting beta-adrenergic agonists.