Stimulation of beta-adrenergic receptors inhibits calcineurin activity in CD4(+) T cells via PKA-AKAP interaction.

摘要

The sympathetic nervous system (SNS) is able to modulate immune functions via adrenoceptor-dependent mechanisms. Activation of beta-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 beta-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 beta-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-gamma production, and T cell proliferation. Co-administration of the beta-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 beta-AR-mediated CaN inhibition. Taken together, this study provides evidence for a link between the beta-AR and TCR signaling pathways since expression of IL-2 and IFN-gamma 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.