Transcriptional activation of follistatin by Nrf2 protects pulmonary epithelial cells against silica nanoparticle-induced oxidative stress.

Chen Lin,Qiang Wang,Saisai Wei,Lingda Zhang,Desen Sun,Botao Liu,Zhengping Xu,Guangdi Chen,Xiangwei Gao,Tingjia Zhu,Wenpan Fang,Xinyuan Zhao

doi:10.1038/srep21133

Chen Lin, Qiang Wang + Show 10 more

Open Access

https://doi.org/10.1038/srep21133

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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.

Highlights

IntroductionIf the protection effect fails, escalation of oxidative stress results in mitochondrial perturbation and cell apoptosis[1,7,8]
These NP-responsive proteins exert antioxidant and cytoprotective effects in lungs
FST was firstly identified as a secretory protein that binds and inactivates transforming growth factor (TGF)-β family members including activin, bone morphogenetic proteins (BMPs), and myostatin

Summary

Introduction

If the protection effect fails, escalation of oxidative stress results in mitochondrial perturbation and cell apoptosis[1,7,8]. Activin induces endothelial cell oxidative stress and endothelial cell dysfunction, and these effects are mitigated by follistatin[15]. Based on the inhibitory role of FST in cellular ROS production, we proposed that FST participates in cellular response to SiO2 NP-induced oxidative stress. We evaluated the function of FST in SiO2 NP-induced lung toxicity using both in vitro and in vivo models. Our data further demonstrated that FST protected cells against apoptosis through reversing oxidative stress. These data provided evidence to support that FST is an oxidative stress responsive protein contributing to lung anti-oxidant response to SiO2 NPs

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