title: Stimulation of β₂-adrenergic receptors inhibits calcineurin activity in CD4(+) T cells via PKA-AKAP interaction.
abstract: The sympathetic nervous system (SNS) is able to modulate immune functions via adrenoceptor-dependent mechanisms. Activation of β₂-adrenergic receptors (AR) on CD4(+) T lymphocytes has been shown to inhibit Th1-cytokine production and cell proliferation. Here, we investigated the role of the calcium/calmodulin-dependent protein phosphatase calcineurin (CaN), a key element of the T cell receptor (TCR)-signaling pathway, in β₂-AR-mediated suppression of T cell function. Purified rat splenic CD4(+) T cells were stimulated with anti-CD3/anti-CD28 in presence or absence of the β₂-AR agonist terbutaline (TERB). Treatment with TERB induced a dose-dependent inhibition of cellular CaN activity, along with a reduction in IL-2 and IFN-γ production, and T cell proliferation. Co-administration of the β-AR antagonist nadolol abolished these effects. Blockade of the cAMP-dependent protein kinase A (PKA) with the inhibitor H-89 completely prevented TERB-induced CaN inhibition. However, a receptor-independent rise in the second messenger cAMP was not sufficient to suppress CaN activity. Disruption of the interaction between PKA and A-kinase anchoring protein (AKAP) by the inhibitor peptide St-Ht31 fully blocked TERB-induced CaN inhibition, demonstrating that PKA-AKAP interaction is essential for the β₂-AR-mediated CaN inhibition. Taken together, this study provides evidence for a link between the β₂-AR and TCR signaling pathways since expression of IL-2 and IFN-γ in activated T cells largely depends on dephosphorylation of the transcription factor NFAT by CaN, and identifies a novel intracellular mechanism that can lead to downregulation of T cell function after SNS activation.
authors.affiliation: Laboratory of Psychology and Behavioral Immunobiology, Institute for Behavioral Sciences, ETH Zurich, 8092 Zurich, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Riether
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
authors.forename: Timo
authors.initials: T
authors.lastname: Wirth
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pacheco-López
authors.forename: Raphael
authors.initials: R
authors.lastname: Doenlen
authors.forename: Hanneke
authors.initials: H
authors.lastname: Willemen
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.forename: Manfred
authors.initials: M
authors.lastname: Schedlowski
authors.forename: Harald
authors.initials: H
authors.lastname: Engler
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D019703:Calcineurin / Q000494:pharmacology; D065095:Calcineurin Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000097:blood*; D016207:Cytokines / Q000097:blood; D007202:Indicators and Reagents; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D013726:Terbutaline / Q000494:pharmacology; D018417:Th1 Cells / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D018106:CD28 Antigens; D017252:CD3 Complex; D065095:Calcineurin Inhibitors; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D007202:Indicators and Reagents; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D010744:Phosphoric Monoester Hydrolases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D013726:Terbutaline