Research Papers:

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

Jun-Mei Lai _, Xiong Zhang, Fang-Fang Liu, Rui Yang, Shen-Yu Li, Lan-Bing Zhu, Ming Zou, Wen-Hsing Cheng and Jian-Hong Zhu

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Oncotarget. 2016; 7:43731-43745. https://doi.org/10.18632/oncotarget.9667

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Jun-Mei Lai1,2,5,*, Xiong Zhang2,*, Fang-Fang Liu1, Rui Yang1, Shen-Yu Li1, Lan-Bing Zhu2, Ming Zou2, Wen-Hsing Cheng4, Jian-Hong Zhu1,2,3

1Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China

2Department of Geriatrics and Neurology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China

3Key Laboratory of Watershed Science and Health of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China

4Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, MS, 39762, USA

5Department of Rehabilitation Medicine, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang 310014, China

*These authors have contributed equally to the work

Correspondence to:

Jian-Hong Zhu, email: [email protected].

Wen-Hsing Cheng, email: [email protected]

Keywords: differentiation, ROS, MAPK, Notch3, lung fibrosis

Received: December 26, 2015    Accepted: May 12, 2016    Published: May 27, 2016


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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