Oxidative stress modulates theophylline effects on steroid responsiveness
Oxidative stress modulates theophylline effects on steroid responsiveness
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DOI：
10.1016/j.bbrc.2008.10.065
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发表时间：
2008-12-19
影响因子：
3.1
通讯作者：
Kirkham, Paul A.
中科院分区：
文献类型：
--
作者：
Marwick, John A.;Wallis, Gillian;Kirkham, Paul A.
氧化应激是许多慢性炎症性疾病如严重哮喘和慢性阻塞性肺病（COPD）的核心因素。氧化应激降低了皮质类固醇的抗炎作用，因此可能导致这些疾病中皮质类固醇的相对不敏感性。低浓度的茶碱可以恢复皮质类固醇在氧化剂暴露的细胞中的抗炎作用，但其机制尚不清楚。在这里，我们证明了低浓度的茶碱恢复皮质类固醇抑制促炎介质释放和组蛋白乙酰化在氧化剂暴露的细胞。整体基因表达分析表明，茶碱调节不同的途径在幼稚和氧化剂暴露的细胞和逆转氧化剂介导的调制的途径。此外，定量化学蛋白质组学显示，茶碱在幼稚细胞中具有很少的高亲和力靶点，但在氧化应激细胞中具有升高的亲和力。总之，氧化应激改变茶碱结合谱和基因表达，这可能导致皮质类固醇功能的恢复。(C)2008年爱思唯尔公司All rights reserved.
Oxidative stress is a central factor in many chronic inflammatory diseases such as severe asthma and chronic obstructive pulmonary disease (COPD). Oxidative stress reduces the anti-inflammatory corticosteroid action and may therefore contribute to the relative corticosteroid insensitivity seen in these diseases. Low concentrations of theophylline can restore the anti-inflammatory action of corticosteroids in oxidant exposed cells, however the mechanism remains unknown. Here, we demonstrate that a low concentration of theophylline restores corticosteroid repression of pro-inflammatory mediator release and histone acetylation in oxidant exposed cells. Global gene expression analysis shows that theophylline regulates distinct pathways in naive and oxidant exposed cells and reverses oxidant mediated modulated of pathways. Furthermore, quantitative chemoproteomics revealed that theophylline has few high affinity targets in naive cells but an elevated affinity in oxidant stressed cells. In conclusion, oxidative stress alters theophylline binding profile and gene expression which may result in restoration of corticosteroid function. (C) 2008 Elsevier Inc. All rights reserved.