Glutaredoxin 1 regulates cigarette smoke-mediated lung inflammation through differential modulation of IκB kinases in mice: impact on histone acetylation
Glutaredoxin 1 regulates cigarette smoke-mediated lung inflammation through differential modulation of IκB kinases in mice: impact on histone acetylation
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DOI：
10.1152/ajplung.00426.2009
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发表时间：
2010-08-01
影响因子：
4.9
通讯作者：
Rahman, Irfan
中科院分区：
文献类型：
--
作者：
Chung, Sangwoon;Sundar, Isaac Kirubakaran;Rahman, Irfan
钟淑琴，姚华，何勇，拉赫曼。Glutaredoxin 1通过I κ B激酶的差异调节香烟烟雾介导的小鼠肺部炎症：对组蛋白乙酰化的影响。[J] .中国生物医学工程学报，2016,31(2):444 - 444。首次发表于2010年5月14日；Doi: 10.1152/ ajplung。00426.2009.-Glutaredoxin 1 （Glrx1）是一种小的二硫醇蛋白，通过调节蛋白谷胱甘肽化调节细胞氧化还原状态和氧化还原依赖的信号通路。I κ B激酶（IKK）是nf - κ B活化的必需酶，可遭受s -谷胱甘肽化导致其活性改变。然而，Glrx1在香烟烟雾（CS）诱导的肺部炎症和染色质修饰中的作用尚不清楚。我们假设Glrx1通过s -谷胱甘肽化对小鼠肺中IKKs的差异调节来调节cs诱导的肺部炎症和染色质修饰。将Glrx1敲除型（KO）和野生型（WT）小鼠暴露于CS 3天，测定Glrx1在调节肺促炎反应中的作用。与暴露于CS的WT小鼠相比，Glrx1 KO小鼠支气管肺泡灌洗液中的中性粒细胞内流和肺部促炎细胞因子释放增加，这与RelA/p65的核易位增强及其磷酸化乙酰化有关。有趣的是，与暴露于CS的WT小鼠相比，Glrx1 KO小鼠肺中IKK α的磷酸化水平和总水平升高，但IKK β的总水平和磷酸化水平没有升高。消融Glrx1导致cs诱导的IKK β谷胱甘肽化增加，使其失活，而IKK α被激活，导致小鼠肺组蛋白H3磷酸化乙酰化增加。因此，Glrx1的靶向破坏通过组蛋白乙酰化来调节肺促炎反应，特别是在CS暴露时激活IKK α。综上所述，我们的研究表明，s -谷胱甘肽化和IKK α磷酸化在促炎基因启动子组蛋白乙酰化和NF-kappa b介导的肺部异常和持续炎症在慢性炎症性肺病的发病机制中起重要作用。
Chung S, Sundar IK, Yao H, Ho Y, Rahman I. Glutaredoxin 1 regulates cigarette smoke-mediated lung inflammation through differential modulation of I kappa B kinases in mice: impact on histone acetylation. Am J Physiol Lung Cell Mol Physiol 299: L192-L203, 2010. First published May 14, 2010; doi: 10.1152/ ajplung. 00426.2009.-Glutaredoxin 1 (Glrx1) is a small dithiol protein that regulates the cellular redox state and redox-dependent signaling pathways via modulation of protein glutathionylation. I kappa B kinase (IKK), an essential enzyme for NF-kappa B activation, can be subjected to S-glutathionylation leading to alteration of its activity. However, the role of Glrx1 in cigarette smoke (CS)-induced lung inflammation and chromatin modifications are not known. We hypothesized that Glrx1 regulates the CS-induced lung inflammation and chromatin modifications via differential regulation of IKKs by S-glutathionylation in mouse lung. Glrx1 knockout (KO) and wild-type (WT) mice were exposed to CS for 3 days and determined the role of Glrx1 in regulation of proinflammatory response in the lung. Neutrophil influx in bronchoalveolar lavage fluid and proinflammatory cytokine release in lung were increased in Glrx1 KO mice compared with WT mice exposed to CS, which was associated with augmented nuclear translocation of RelA/p65 and its phospho-acetylation. Interestingly, phosphorylated and total levels of IKK alpha, but not total and phosphorylated IKK beta levels, were increased in lungs of Glrx1 KO mice compared with WT mice exposed to CS. Ablation of Glrx1 leads to increased CS-induced IKK beta glutathionylation rendering it inactive, whereas IKK alpha was activated resulting in increased phospho-acetylation of histone H3 in mouse lung. Thus, targeted disruption of Glrx1 regulates the lung proinflammatory response via histone acetylation specifically by activation of IKK alpha in response to CS exposure. Overall, our study suggests that S-glutathionylation and phosphorylation of IKK alpha plays an important role in histone acetylation on proinflammatory gene promoters and NF-kappa B-mediated abnormal and sustained lung inflammation in pathogenesis of chronic inflammatory lung diseases.