title: Redox-sensitive MAPK and Notch3 regulate fibroblast differentiation and activation: a dual role of ERK1/2.
abstract: Myofibroblastic transformation, characterized by upregulation of α-smooth muscle actin in response to proï¬brotic agents such as TGF-β1, is considered as a major event leading to ï¬brosis. The mechanistic basis linking myoï¬broblast differentiation to idiopathic pulmonary ï¬brosis 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.
authors.affiliation: Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.|Department of Geriatrics and Neurology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.|Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, China.
authors.forename: Jun-Mei
authors.initials: JM
authors.lastname: Lai
authors.affiliation: Department of Geriatrics and Neurology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Liu
authors.affiliation: Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Shen-Yu
authors.initials: SY
authors.lastname: Li
authors.affiliation: Department of Geriatrics and Neurology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Lan-Bing
authors.initials: LB
authors.lastname: Zhu
authors.affiliation: Department of Geriatrics and Neurology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zou
authors.affiliation: Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, MS, 39762, USA.
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Cheng
authors.affiliation: Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.|Department of Geriatrics and Neurology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.|Key Laboratory of Watershed Science and Health of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D000071656:Receptor, Notch3 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000071656:Receptor, Notch3; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: MAPK; Notch3; ROS; differentiation; lung fibrosis