BETA-ADRENOCEPTOR-MEDIATED INHIBITION OF IFN-GAMMA, IL-3, AND GM-CSF MESSENGER-RNA ACCUMULATION IN ACTIVATED HUMAN T-LYMPHOCYTES IS SOLELY MEDIATED BY THE BETA(2)-ADRENOCEPTOR SUBTYPE

Cytokine gene expression in T lymphocytes is a strictly regulated proc ess, involving both stimulatory and inhibitory signals. beta-Adrenocep tor (beta AR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses aft er binding to their specific receptors. In this study, the characteriz ation of beta AR subtype(s) (beta(1), beta(2), and beta(3)) involved i n the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage c olony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mR NA accumulation was studied by using various beta AR agonists and anta gonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mR NAs are dose-dependently inhibited by the nonselective beta AR agonist isoproterenol and by the selective beta(2)AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to beta AR stimulation. The obse rved inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective beta(2)AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta(1)AR antagon ist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM CSF protein in the presence of increasing concentrations of isoprotere nol followed a similar pattern as observed for GM-CSF mRNA. In additio n, the beta AR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumul ation of intracellular cyclic adenosine monophosphate (cAMP) levels. A lthough beta(3)AR mRNA was detectable in Con A-activated T lymphocytes , we could not demonstrate a functional activity in the regulation of cytokine expression: the beta(3)AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significan tly affect cellular cAMP levels. These data demonstrate that beta-agon ist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulatio n is solely mediated by beta(2)-adrenoceptors.