Beta-agonists modulate T-cell functions via direct actions on type 1 and type 2 cells.
Although the beta2-adrenergic receptor (beta2AR) is the most extensively characterized G-protein-coupled receptor (GPCR), the effects of beta-agonists on T-cell subtype function remain poorly understood. In contrast to studies suggesting lack of beta2AR expression on type 2 T cells, we demonstrate that type 2 interleukin-13+ (IL-13+) T cells (CD4+ or CD8+) in human peripheral blood lymphocytes (PBLs) can respond directly to beta-agonist, with effects including induction of protein kinase A (PKA) activity and associated inhibition of CD3-stimulated CD25 expression; CD3-stimulated IL-13, interferon-gamma (IFN-gamma), and IL-2 production; and p38 mitogen-activated protein kinase (MAPK) phosphorylation. PGE2 was more efficacious than beta-agonist in activating PKA and inhibiting cytokine production. beta-agonist and PGE2 also inhibited phorbol myristate acetate (PMA) + calcimycin-stimulated IFN-gamma and IL-2 (but not IL-13) production, suggesting that upstream CD3-initiated signaling is not the sole locus of PKA actions. Differential regulation of PMA-stimulated p38, p42/p44, and NF-kappaB explained the capacity of PGE2 and beta-agonist to inhibit IFN-gamma but not IL-13 production. The inhibition of CD3 + CD28-stimulated IL-13 production by both beta-agonist and PGE2 was reversed at low agonist concentrations, resulting in enhanced IL-13, but not IFN-gamma or IL-2, production. These findings identify direct effects of beta2AR activation on T-cell subtypes and suggest a complex role for GPCRs and PKA activity in modulating T-cell functions.
Loza
Matthew J
MJ
Department of Internal Medicine, Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA.
Foster
Susan
S
Peters
Stephen P
SP
Penn
Raymond B
RB
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D000001:Calcimycin / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D010120:Oxytocics / Q000276:immunology / Q000494:pharmacology; D011494:Protein Kinases / Q000276:immunology; D018343:Receptors, Adrenergic, beta-2 / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D015703:Antigens, CD; D002273:Carcinogens; D016207:Cytokines; D007476:Ionophores; D016328:NF-kappa B; D010120:Oxytocics; D018343:Receptors, Adrenergic, beta-2; D000001:Calcimycin; D011494:Protein Kinases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate