Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype.
Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors.
Borger
P
P
Divisions of Allergology, Pulmonology, Molecular Pharmacology, and Hematology, Department of Internal Medicine and University Centre for Pharmacy, University of Groningen, Groningen, The Netherlands.
Hoekstra
Y
Y
Esselink
M T
MT
Postma
D S
DS
Zaagsma
J
J
Vellenga
E
E
Kauffman
H F
HF
D003208:Concanavalin A / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology; D005280:Fenoterol / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007377:Interleukin-3 / Q000235:genetics; D015847:Interleukin-4 / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors*; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D013999:Timolol / Q000494:pharmacology
D004983:Ethanolamines; D007377:Interleukin-3; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D003208:Concanavalin A; D015847:Interleukin-4; D005280:Fenoterol; C057368:BRL 37344; D013999:Timolol; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000242:Cyclic AMP; D007545:Isoproterenol