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TGF-β3 Induces Autophagic Activity by Increasing ROS Generation in a NOX4-Dependent Pathway

Higher concentrations of reactive oxygen species (ROS) have been associated with epithelial cell damage, cell shedding, and airway hyperresponsiveness. Previous studies have indicated that transforming growth factor-beta (TGF-β) mediates ROS production and NADPH oxidase (NOX) activity. In our previo...

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Autores principales: Zhang, Yun, Tang, Hong-Mei, Liu, Chun-Feng, Yuan, Xie-Fang, Wang, Xiao-Yun, Ma, Ning, Xu, Guo-Feng, Wang, Song-Ping, Deng, Jun, Wang, Xing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012255/
https://www.ncbi.nlm.nih.gov/pubmed/32082074
http://dx.doi.org/10.1155/2019/3153240
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author Zhang, Yun
Tang, Hong-Mei
Liu, Chun-Feng
Yuan, Xie-Fang
Wang, Xiao-Yun
Ma, Ning
Xu, Guo-Feng
Wang, Song-Ping
Deng, Jun
Wang, Xing
author_facet Zhang, Yun
Tang, Hong-Mei
Liu, Chun-Feng
Yuan, Xie-Fang
Wang, Xiao-Yun
Ma, Ning
Xu, Guo-Feng
Wang, Song-Ping
Deng, Jun
Wang, Xing
author_sort Zhang, Yun
collection PubMed
description Higher concentrations of reactive oxygen species (ROS) have been associated with epithelial cell damage, cell shedding, and airway hyperresponsiveness. Previous studies have indicated that transforming growth factor-beta (TGF-β) mediates ROS production and NADPH oxidase (NOX) activity. In our previous study, we also observed that TGF-β3 increases mucus secretion in airway epithelial cells in an autophagy-dependent fashion. Although it is well known that the relationship between ROS and autophagy is cell context-dependent, the exact mechanism of action remains unclear. The following study examined whether ROS act as upstream of autophagy activation in response to TGF-β3 induction. Using an allergic inflammation mouse model induced by house dust mite (HDM), we observed elevated lung amounts of TGF-β3 accompanied by increased ROS levels. And we found that ROS levels were elevated and NOX4 expression was increased in TGF-β3-induced epithelial cells, while the lack of NOX4 in the epithelial cells could reduce ROS generation and autophagy-dependent MUC5AC expression treated with TGF-β3. Furthermore, our studies demonstrated that the Smad2/3 pathway was involved in TGF-β3-induced ROS generation by promoting NOX4 expression. The inhibition of ROS generation by N-Acetyl-L-cysteine (NAC) resulted in a decrease in mucus expression and autophagy activity in vivo as well as in vitro. Finally, TGF-β3-neutralizing antibody significantly reduced the ROS generation, mucus expression, and autophagy activity and also decreased the phosphorylation of Smad2 and Smad3. Taken together, the obtained results revealed that persistent TGF-β3 activation increased ROS levels in a NOX4-dependent pathway and subsequently induced autophagy as well as MUC5AC expression in the epithelial cells.
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spelling pubmed-70122552020-02-20 TGF-β3 Induces Autophagic Activity by Increasing ROS Generation in a NOX4-Dependent Pathway Zhang, Yun Tang, Hong-Mei Liu, Chun-Feng Yuan, Xie-Fang Wang, Xiao-Yun Ma, Ning Xu, Guo-Feng Wang, Song-Ping Deng, Jun Wang, Xing Mediators Inflamm Research Article Higher concentrations of reactive oxygen species (ROS) have been associated with epithelial cell damage, cell shedding, and airway hyperresponsiveness. Previous studies have indicated that transforming growth factor-beta (TGF-β) mediates ROS production and NADPH oxidase (NOX) activity. In our previous study, we also observed that TGF-β3 increases mucus secretion in airway epithelial cells in an autophagy-dependent fashion. Although it is well known that the relationship between ROS and autophagy is cell context-dependent, the exact mechanism of action remains unclear. The following study examined whether ROS act as upstream of autophagy activation in response to TGF-β3 induction. Using an allergic inflammation mouse model induced by house dust mite (HDM), we observed elevated lung amounts of TGF-β3 accompanied by increased ROS levels. And we found that ROS levels were elevated and NOX4 expression was increased in TGF-β3-induced epithelial cells, while the lack of NOX4 in the epithelial cells could reduce ROS generation and autophagy-dependent MUC5AC expression treated with TGF-β3. Furthermore, our studies demonstrated that the Smad2/3 pathway was involved in TGF-β3-induced ROS generation by promoting NOX4 expression. The inhibition of ROS generation by N-Acetyl-L-cysteine (NAC) resulted in a decrease in mucus expression and autophagy activity in vivo as well as in vitro. Finally, TGF-β3-neutralizing antibody significantly reduced the ROS generation, mucus expression, and autophagy activity and also decreased the phosphorylation of Smad2 and Smad3. Taken together, the obtained results revealed that persistent TGF-β3 activation increased ROS levels in a NOX4-dependent pathway and subsequently induced autophagy as well as MUC5AC expression in the epithelial cells. Hindawi 2019-12-31 /pmc/articles/PMC7012255/ /pubmed/32082074 http://dx.doi.org/10.1155/2019/3153240 Text en Copyright © 2019 Yun Zhang et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Zhang, Yun
Tang, Hong-Mei
Liu, Chun-Feng
Yuan, Xie-Fang
Wang, Xiao-Yun
Ma, Ning
Xu, Guo-Feng
Wang, Song-Ping
Deng, Jun
Wang, Xing
TGF-β3 Induces Autophagic Activity by Increasing ROS Generation in a NOX4-Dependent Pathway
title TGF-β3 Induces Autophagic Activity by Increasing ROS Generation in a NOX4-Dependent Pathway
title_full TGF-β3 Induces Autophagic Activity by Increasing ROS Generation in a NOX4-Dependent Pathway
title_fullStr TGF-β3 Induces Autophagic Activity by Increasing ROS Generation in a NOX4-Dependent Pathway
title_full_unstemmed TGF-β3 Induces Autophagic Activity by Increasing ROS Generation in a NOX4-Dependent Pathway
title_short TGF-β3 Induces Autophagic Activity by Increasing ROS Generation in a NOX4-Dependent Pathway
title_sort tgf-β3 induces autophagic activity by increasing ros generation in a nox4-dependent pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012255/
https://www.ncbi.nlm.nih.gov/pubmed/32082074
http://dx.doi.org/10.1155/2019/3153240
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