Altered β2-adrenergic regulation of T cell activity after allergen challenge in asthma
Altered β2-adrenergic regulation of T cell activity after allergen challenge in asthma
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DOI：
10.1111/j.1365-2222.2004.02037.x
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发表时间：
2004-09-01
影响因子：
6.1
通讯作者：
Kauffman, HF
中科院分区：
文献类型：
--
作者：
Heijink, IH;van den Berge, M;Kauffman, HF
背景：哮喘气道炎症是由辅助性T淋巴细胞（Th）2募集到肺部，随后在过敏原攻击下产生th2样细胞因子而引起的。目的探讨过敏原诱导的β(2)-肾上腺素能受体（β (2)-AR）功能障碍是否与哮喘患者T（h2）细胞活性增强有关。方法研究7例哮喘患者α - cd3 / α - cd28活化外周血淋巴细胞β(2)-肾上腺素能对细胞因子mRNA表达的调控，并结合β(2)-激动剂非诺特罗对T细胞趋化和信号通路的影响。结果在过敏原刺激后，β (2)-AR对Th2细胞因子IL-4、IL-5和IL-13表达的控制完全丧失，但对Th1细胞因子ifn - γ的控制不存在。此外，我们发现β (2)-AR对T细胞迁移和信号转导途径的调节受损，即环腺苷单磷酸反应元件结合蛋白的磷酸化和丝裂原活化蛋白激酶途径的抑制。β (2)-AR控制的丧失与β -肾上腺素能受体激酶表达的增加有关，这可能与β (2)-AR脱敏有关。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细胞对非诺特罗表现出低反应性。我们的研究结果表明，过敏原诱导的β (2)-AR控制缺失，可能是由趋化因子释放介导的，在哮喘th2样活性增强中起重要作用。
Background 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.Objective To examine whether allergen-induced dysfunction of the beta(2)-adrenergic receptor (beta(2)-AR) contributes to the enhanced T(h2) cell activity in asthma.Methods beta(2)-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 beta(2)-agonist fenoterol on T cell chemotaxis and signalling pathways.Results A complete loss of beta(2)-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 beta(2)-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 beta(2)-AR control was associated with increased beta-adrenergic receptor kinase expression, which might be involved in beta(2)-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.Conclusion Our results suggest that allergen-induced loss of beta(2)-AR control, possibly mediated by chemokine release, plays an important role in enhanced Th2-like activity in asthma.