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Blood, 1 March 2006, Vol. 107, No. 5, pp. 2052-2060.
Prepublished online as a Blood First Edition Paper on November 8, 2005; DOI 10.1182/blood-2005-08-3265.
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IMMUNOBIOLOGY
Beta-agonists modulate T-cell functions via direct actions on type 1 and type 2 cells
Matthew J. Loza,
Susan Foster,
Stephen P. Peters, and
Raymond B. Penn
From the Department of Internal Medicine, Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC.
Although the  2-adrenergic receptor (2AR) is the most extensively characterized G-protein-coupled receptor (GPCR), the effects of -agonists on T-cell subtype function remain poorly understood. In contrast to studies suggesting lack of 2AR 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 -agonist, with effects including induction of protein kinase A (PKA) activity and associated inhibition of CD3-stimulated CD25 expression; CD3-stimulated IL-13, interferon- (IFN-), and IL-2 production; and p38 mitogen-activated protein kinase (MAPK) phosphorylation. PGE2 was more efficacious than -agonist in activating PKA and inhibiting cytokine production. -agonist and PGE2 also inhibited phorbol myristate acetate (PMA) + calcimycin-stimulated IFN- 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- B explained the capacity of PGE2 and -agonist to inhibit IFN- but not IL-13 production. The inhibition of CD3 + CD28-stimulated IL-13 production by both -agonist and PGE2 was reversed at low agonist concentrations, resulting in enhanced IL-13, but not IFN- or IL-2, production. These findings identify direct effects of 2AR activation on T-cell subtypes and suggest a complex role for GPCRs and PKA activity in modulating T-cell functions.
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