Transcriptional activation of follistatin by Nrf2 protects pulmonary epithelial cells against silica nanoparticle-induced oxidative stress.
Transcriptional activation of follistatin by Nrf2 protects pulmonary epithelial cells against silica nanoparticle-induced oxidative stress.
复制标题
Nrf2 转录激活卵泡抑素可保护肺上皮细胞免受二氧化硅纳米颗粒诱导的氧化应激。
DOI：
10.1038/srep21133
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发表时间：
2016-02-16
影响因子：
4.6
通讯作者：
Gao X
中科院分区：
文献类型：
--
作者：
Lin C;Zhao X;Sun D;Zhang L;Fang W;Zhu T;Wang Q;Liu B;Wei S;Chen G;Xu Z;Gao X
二氧化硅纳米颗粒（SiO2 NPs）在呼吸系统中引起氧化应激。与此同时，人类细胞启动适应性反应以克服SiO2 NP毒性。然而，除了一些例子之外，SiO2 NP响应蛋白的调节及其在SiO2 NP响应中的功能在很大程度上仍然未知。在这项研究中，我们证明了SiO2 NP诱导小鼠肺组织以及人肺上皮细胞（A549）中的应激反应基因卵泡抑素（FST）的表达。在SiO2 NP处理期间，FST启动子区域的Ac-H3（K9/18）和H3 K4 me 2（两个活性基因标记）的水平显著增加。FST转录的诱导是由核因子红细胞2相关因子2（Nrf 2）介导的，Nrf 2缺陷细胞中FST表达的减少以及Nrf 2与FST启动子区的直接结合证明了这一点。FST的下调促进SiO2 NP诱导的细胞凋亡在培养的细胞和小鼠肺组织。此外，敲低FST增加，而过表达FST降低NADPH氧化酶1（NOX 1）和NOX 5的表达水平以及细胞活性氧（ROS）的产生。综上所述，这些发现表明FST在SiO2 NP诱导的氧化应激中具有保护作用，并揭示了SiO2 NP与生物系统之间的相互作用。
Silica nanoparticles (SiO2 NPs) cause oxidative stress in respiratory system. Meanwhile, human cells launch adaptive responses to overcome SiO2 NP toxicity. However, besides a few examples, the regulation of SiO2 NP-responsive proteins and their functions in SiO2 NP response remain largely unknown. In this study, we demonstrated that SiO2 NP induced the expression of follistatin (FST), a stress responsive gene, in mouse lung tissue as well as in human lung epithelial cells (A549). The levels of Ac-H3(K9/18) and H3K4me2, two active gene markers, at FST promoter region were significantly increased during SiO2 NP treatment. The induction of FST transcription was mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2), as evidenced by the decreased FST expression in Nrf2-deficient cells and the direct binding of Nrf2 to FST promoter region. Down-regulation of FST promoted SiO2 NP-induced apoptosis both in cultured cells and in mouse lung tissue. Furthermore, knockdown of FST increased while overexpression of FST decreased the expression level of NADPH oxidase 1 (NOX1) and NOX5 as well as the production of cellular reactive oxygen species (ROS). Taken together, these findings demonstrated a protective role of FST in SiO2 NP-induced oxidative stress and shed light on the interaction between SiO2 NPs and biological systems.