Heijink I H, van den Berge M, Vellenga E, de Monchy J G R, Postma D S, Kauffman H F
Department of Allergology, University Hospital Groningen, Groningen, The Netherlands.
Clin Exp Allergy. 2004 Sep;34(9):1356-63. doi: 10.1111/j.1365-2222.2004.02037.x.
Airway inflammation in asthma is orchestrated by recruitment of T helper (Th)2 lymphocytes to the lung and subsequent production of Th2-like cytokines upon allergen challenge.
To examine whether allergen-induced dysfunction of the beta2-adrenergic receptor (beta2-AR) contributes to the enhanced T(h2) cell activity in asthma.
Beta2-adrenergic regulation of cytokine mRNA expression was studied in alpha-CD3/alpha-CD28-activated peripheral blood lymphocytes from seven asthma patients before and 6 h after allergen challenge, in conjunction with the effects of beta2-agonist fenoterol on T cell chemotaxis and signalling pathways.
A complete loss of beta2-AR control over expression of the Th2 cytokines IL-4, IL-5 and IL-13, but not of the Th1 cytokine IFN-gamma, was observed after allergen challenge. Furthermore, we found impaired beta2-AR regulation of T cell migration as well as signal transduction pathways, i.e. the phosphorylation of cyclic adenosine monophosphate-responsive element binding protein and the inhibition of the mitogen-activated protein kinase pathway. The loss of beta2-AR control was associated with increased beta-adrenergic receptor kinase expression, which might be involved in beta2-AR desensitization. In addition, we demonstrate for the first time that T cells exposed to the chemokine thymus and activation-regulated chemokine show hyporesponsiveness to fenoterol.
Our results suggest that allergen-induced loss of beta2-AR control, possibly mediated by chemokine release, plays an important role in enhanced Th2-like activity in asthma.
哮喘中的气道炎症是由T辅助（Th）2淋巴细胞募集到肺部并在过敏原激发后产生Th2样细胞因子所调控的。
研究过敏原诱导的β2肾上腺素能受体（β2-AR）功能障碍是否导致哮喘中Th2细胞活性增强。
在7名哮喘患者的过敏原激发前和激发后6小时，研究α-CD3/α-CD28激活的外周血淋巴细胞中β2肾上腺素能对细胞因子mRNA表达的调节作用，并研究β2激动剂非诺特罗对T细胞趋化性和信号通路的影响。
过敏原激发后，观察到β2-AR对Th2细胞因子白细胞介素-4、白细胞介素-5和白细胞介素-13表达的控制完全丧失，但对Th1细胞因子干扰素-γ的控制未丧失。此外，我们发现β2-AR对T细胞迁移以及信号转导通路的调节受损，即环磷酸腺苷反应元件结合蛋白的磷酸化和丝裂原活化蛋白激酶通路的抑制。β2-AR控制的丧失与β肾上腺素能受体激酶表达增加有关，这可能参与β2-AR脱敏。此外，我们首次证明，暴露于趋化因子胸腺和激活调节趋化因子的T细胞对非诺特罗反应低下。
我们的结果表明，过敏原诱导的β2-AR控制丧失，可能由趋化因子释放介导，在哮喘中增强的Th2样活性中起重要作用。
