Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma.
Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma.
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DOI：
10.1016/j.jaci.2010.08.014
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发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Conti M
中科院分区：
文献类型：
--
作者：
Jin SL;Goya S;Nakae S;Wang D;Bruss M;Hou C;Umetsu D;Conti M
环磷酸腺苷（cAMP）信号调节炎症细胞的功能，参与哮喘的发病机制，而4型cAMP特异性磷酸二酯酶（PDE 4）是这一通路的重要组成部分。PDE 4亚型PDE 4 B的诱导是单核细胞和巨噬细胞中Toll样受体信号传导所必需的，并且与T细胞中的T细胞受体/CD 3相关;然而，其在过敏性哮喘发展中的确切生理功能仍不明确。我们研究了PDE 4 B在过敏原诱导的气道高反应性（AHR）和TH 2驱动的炎症反应中的作用。野生型和PDE 4 B −/−小鼠被致敏，并用卵清蛋白激发，并测量对吸入乙酰甲胆碱的反应的AHR。通过分析气道中的白细胞浸润和细胞因子积聚来表征气道炎症。在培养的支气管淋巴结细胞中测定卵清蛋白刺激的细胞增殖和TH 2细胞因子的产生。PDE 4 B缺陷的小鼠不发展AHR。这种保护作用与嗜酸性粒细胞向肺的募集显著减少和支气管肺泡灌洗液中TH 2细胞因子水平降低相关。T细胞复制、TH 2细胞因子产生和树突状细胞迁移的缺陷在来自气道引流淋巴结的细胞中明显。相反，PDE 4 B −/−小鼠中TH 1细胞因子IFN-γ的积累不受影响。切除正磷酸酶PDE 4基因PDE 4A对气道炎症没有影响。通过解除cAMP负约束，PDE 4 B在气道炎症期间的TH 2细胞活化和树突状细胞募集中起重要作用。这些发现提供了具有PDE 4 B选择性的PDE 4抑制剂可能在哮喘治疗中有效的概念证据。
Cyclic AMP (cAMP) signaling modulates functions of inflammatory cells involved in the pathogenesis of asthma, and type 4 cAMP-specific phosphodiesterases (PDE4s) are essential components of this pathway. Induction of the PDE4 isoform PDE4B is necessary for Toll-like receptor signaling in monocytes and macrophages and is associated with T cell receptor/CD3 in T cells; however, its exact physiological function in the development of allergic asthma remains undefined. We investigated the role of PDE4B in the development of allergen-induced airway hyperresponsiveness (AHR) and TH2-driven inflammatory responses. Wild-type and PDE4B−/− mice were sensitized and challenged with ovalbumin and AHR measured in response to inhaled methacholine. Airway inflammation was characterized by analyzing leukocyte infiltration and cytokine accumulation in the airways. Ovalbumin-stimulated cell proliferation and TH2 cytokine production were determined in cultured bronchial lymph node cells. Mice deficient in PDE4B do not develop AHR. This protective effect was associated with a significant decrease in eosinophils recruitment to the lungs and decreased TH2 cytokine levels in the bronchoalveolar lavage fluid. Defects in T-cell replication, TH2 cytokine production, and dendritic cell migration were evident in cells from the airway-draining lymph nodes. Conversely, accumulation of the TH1 cytokine IFN-γ was not affected in PDE4B−/− mice. Ablation of the orthologous PDE4 gene PDE4A has no impact on airway inflammation. By relieving a cAMP-negative constraint, PDE4B plays an essential role in TH2-cell activation and dendritic cell recruitment during airway inflammation. These findings provide proof of concept that PDE4 inhibitors with PDE4B selectivity may have efficacy in asthma treatment.
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白介素5缺乏消除小鼠哮喘模型中的嗜酸性粒细胞，气道高反应性和肺损伤。
影响因子：
15.3
作者：
Foster, PS;Hogan, SP;Ramsay, AJ;Matthaei, KI;Young, IG
通讯作者：
Young, IG
影响因子：
168.9
作者：
Fabbri, Leonardo M.;Calverley, Peter M. A.;Rabe, Klaus F.
通讯作者：
Rabe, Klaus F.
影响因子：
15.3
作者：
LEBMAN, DA;COFFMAN, RL
通讯作者：
COFFMAN, RL
DOI：
10.1073/pnas.96.21.11998
发表时间：
1999-10-12
影响因子：
11.1
作者：
Jin, SLC;Richard, FJ;Conti, M
通讯作者：
Conti, M
DOI：
10.1073/pnas.122041599
发表时间：
2002-05-28
影响因子：
11.1
作者：
Jin, SLC;Conti, M
通讯作者：
Conti, M