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Redox-sensitive MAPK and Notch3 regulate fibroblast differentiation and activation: a dual role of ERK1/2

Myofibroblastic transformation, characterized by upregulation of α-smooth muscle actin in response to profibrotic agents such as TGF-β1, is considered as a major event leading to fibrosis. The mechanistic basis linking myofibroblast differentiation to idiopathic pulmonary fibrosis and the disease tr...

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Autores principales: Lai, Jun-Mei, Zhang, Xiong, Liu, Fang-Fang, Yang, Rui, Li, Shen-Yu, Zhu, Lan-Bing, Zou, Ming, Cheng, Wen-Hsing, Zhu, Jian-Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5190056/
https://www.ncbi.nlm.nih.gov/pubmed/27248323
http://dx.doi.org/10.18632/oncotarget.9667
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author Lai, Jun-Mei
Zhang, Xiong
Liu, Fang-Fang
Yang, Rui
Li, Shen-Yu
Zhu, Lan-Bing
Zou, Ming
Cheng, Wen-Hsing
Zhu, Jian-Hong
author_facet Lai, Jun-Mei
Zhang, Xiong
Liu, Fang-Fang
Yang, Rui
Li, Shen-Yu
Zhu, Lan-Bing
Zou, Ming
Cheng, Wen-Hsing
Zhu, Jian-Hong
author_sort Lai, Jun-Mei
collection PubMed
description Myofibroblastic transformation, characterized by upregulation of α-smooth muscle actin in response to profibrotic agents such as TGF-β1, is considered as a major event leading to fibrosis. The mechanistic basis linking myofibroblast differentiation to idiopathic pulmonary fibrosis and the disease treatment remain elusive. In this study, we studied roles of MAPK, Notch, and reactive oxygen species (ROS) during the differentiation of IMR-90 lung fibroblasts at basal level and induced by TGF-β1. Our results demonstrated that ROS-dependent activation of p38, JNK1/2 and Notch3 promoted basal and TGF-β1-induced differentiation and expression of extracellular matrix proteins. In stark contrast, ERK1/2 was suppressed by ROS and exhibited an inhibitory effect on the differentiation but showed a weak promotion on the expression of extracellular matrix proteins. TGF-β1-induced Notch3 expression depended on p38 and JNK1/2. Interestingly, Notch3 was also downstream of ERK1/2, suggesting a complex role of ERK1/2 in lung function. Our results suggest a novel ROS-mediated shift of dominance from the inhibitory ERK1/2 to the stimulatory p38, JNK1/2 and Notch3 during the pathological progression of IPF. Thus, targeting ERK1/2 signaling for activation and p38, JNK1/2 and Notch3 for inhibition may be of clinical potential against lung fibrosis.
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spelling pubmed-51900562017-01-05 Redox-sensitive MAPK and Notch3 regulate fibroblast differentiation and activation: a dual role of ERK1/2 Lai, Jun-Mei Zhang, Xiong Liu, Fang-Fang Yang, Rui Li, Shen-Yu Zhu, Lan-Bing Zou, Ming Cheng, Wen-Hsing Zhu, Jian-Hong Oncotarget Research Paper Myofibroblastic transformation, characterized by upregulation of α-smooth muscle actin in response to profibrotic agents such as TGF-β1, is considered as a major event leading to fibrosis. The mechanistic basis linking myofibroblast differentiation to idiopathic pulmonary fibrosis and the disease treatment remain elusive. In this study, we studied roles of MAPK, Notch, and reactive oxygen species (ROS) during the differentiation of IMR-90 lung fibroblasts at basal level and induced by TGF-β1. Our results demonstrated that ROS-dependent activation of p38, JNK1/2 and Notch3 promoted basal and TGF-β1-induced differentiation and expression of extracellular matrix proteins. In stark contrast, ERK1/2 was suppressed by ROS and exhibited an inhibitory effect on the differentiation but showed a weak promotion on the expression of extracellular matrix proteins. TGF-β1-induced Notch3 expression depended on p38 and JNK1/2. Interestingly, Notch3 was also downstream of ERK1/2, suggesting a complex role of ERK1/2 in lung function. Our results suggest a novel ROS-mediated shift of dominance from the inhibitory ERK1/2 to the stimulatory p38, JNK1/2 and Notch3 during the pathological progression of IPF. Thus, targeting ERK1/2 signaling for activation and p38, JNK1/2 and Notch3 for inhibition may be of clinical potential against lung fibrosis. Impact Journals LLC 2016-05-27 /pmc/articles/PMC5190056/ /pubmed/27248323 http://dx.doi.org/10.18632/oncotarget.9667 Text en Copyright: © 2016 Lai et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Lai, Jun-Mei
Zhang, Xiong
Liu, Fang-Fang
Yang, Rui
Li, Shen-Yu
Zhu, Lan-Bing
Zou, Ming
Cheng, Wen-Hsing
Zhu, Jian-Hong
Redox-sensitive MAPK and Notch3 regulate fibroblast differentiation and activation: a dual role of ERK1/2
title Redox-sensitive MAPK and Notch3 regulate fibroblast differentiation and activation: a dual role of ERK1/2
title_full Redox-sensitive MAPK and Notch3 regulate fibroblast differentiation and activation: a dual role of ERK1/2
title_fullStr Redox-sensitive MAPK and Notch3 regulate fibroblast differentiation and activation: a dual role of ERK1/2
title_full_unstemmed Redox-sensitive MAPK and Notch3 regulate fibroblast differentiation and activation: a dual role of ERK1/2
title_short Redox-sensitive MAPK and Notch3 regulate fibroblast differentiation and activation: a dual role of ERK1/2
title_sort redox-sensitive mapk and notch3 regulate fibroblast differentiation and activation: a dual role of erk1/2
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5190056/
https://www.ncbi.nlm.nih.gov/pubmed/27248323
http://dx.doi.org/10.18632/oncotarget.9667
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