Loza Matthew J, Foster Susan, Peters Stephen P, Penn Raymond B
Department of Internal Medicine, Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA.
Blood. 2006 Mar 1;107(5):2052-60. doi: 10.1182/blood-2005-08-3265. Epub 2005 Nov 8.
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.
尽管β2-肾上腺素能受体（β2AR）是特征描述最为广泛的G蛋白偶联受体（GPCR），但β-激动剂对T细胞亚型功能的影响仍知之甚少。与关于2型T细胞缺乏β2AR表达的研究相反，我们证明人外周血淋巴细胞（PBL）中的2型白细胞介素-13+（IL-13+）T细胞（CD4+或CD8+）可直接对β-激动剂作出反应，其作用包括诱导蛋白激酶A（PKA）活性以及相关抑制CD3刺激的CD25表达；CD3刺激的IL-13、干扰素-γ（IFN-γ）和IL-2产生；以及p38丝裂原活化蛋白激酶（MAPK）磷酸化。前列腺素E2（PGE2）在激活PKA和抑制细胞因子产生方面比β-激动剂更有效。β-激动剂和PGE2还抑制佛波酯肉豆蔻酸酯乙酸酯（PMA）+离子霉素刺激的IFN-γ和IL-2（但不包括IL-13）产生，这表明上游CD3启动的信号传导不是PKA作用的唯一位点。PMA刺激的p38、p42/p44和核因子κB的差异调节解释了PGE2和β-激动剂抑制IFN-γ但不抑制IL-13产生的能力。β-激动剂和PGE2对CD3 + CD28刺激的IL-13产生的抑制在低激动剂浓度下被逆转，导致IL-13产生增强，但IFN-γ或IL-2不增强。这些发现确定了β2AR激活对T细胞亚型的直接作用，并表明GPCR和PKA活性在调节T细胞功能中具有复杂作用。
