title: Transcriptional activation of follistatin by Nrf2 protects pulmonary epithelial cells against silica nanoparticle-induced oxidative stress.
abstract: 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.
authors.affiliation: Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Lin
authors.affiliation: Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China.|Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Desen
authors.initials: D
authors.lastname: Sun
authors.affiliation: Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Lingda
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Wenpan
authors.initials: W
authors.lastname: Fang
authors.affiliation: Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Tingjia
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: University of Massachusetts Medical School, Program in Molecular Medicine, Worcester, MA, 01605, USA.
authors.forename: Botao
authors.initials: B
authors.lastname: Liu
authors.affiliation: Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Saisai
authors.initials: S
authors.lastname: Wei
authors.affiliation: Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China.|Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Chen
authors.affiliation: Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.|Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China.|Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Gao
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D038681:Follistatin / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D000074624:NADPH Oxidase 1; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D053758:Nanoparticles / Q000009:adverse effects; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012822:Silicon Dioxide / Q000009:adverse effects; D015533:Transcriptional Activation
chemical_list: D038681:Follistatin; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D012822:Silicon Dioxide; D000074624:NADPH Oxidase 1; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C431571:NOX5 protein, human