Abstract
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.
Highlights
Idiopathic pulmonary fibrosis (IPF), a progressive and irreversible respiratory disease of unknown cause [1], is characterized by failure of alveolar re-epithelialization, persistence of myofibroblasts, deposition of extracellular matrix, and destruction of lung architecture [2]
While p38 and JNK are previously known to contribute to fibroblast differentiation, results from the current study present two novel findings: 1) the promotion of myofibroblast formation by a reactive oxygen species (ROS)-dependent and mitogen-activated protein kinase (MAPK)-regulated Notch3 signaling; 2) a dual role of ERK1/2 during lung fibrosis that inhibits fibroblast differentiation but promotes extracellular matrix formation
ERK1/2 has been shown to be activated upon Transforming growth factor β1 (TGF-β1) stimulation in other cells [18,23], here we demonstrate that ERK1/2 activation predominantly inhibits basal differentiation of IMR-90 cells in a ROS-dependent manner
Summary
Idiopathic pulmonary fibrosis (IPF), a progressive and irreversible respiratory disease of unknown cause [1], is characterized by failure of alveolar re-epithelialization, persistence of myofibroblasts, deposition of extracellular matrix, and destruction of lung architecture [2]. Epithelial cells in IPF patients undergo chronic inflammation and release cellular mediators and cytokines, which in turn induce fibroblast migration, proliferation, and differentiation towards myofibroblasts [3,4]. Accumulation and persistence of myofibroblasts play central roles in lung fibrosis through pathophysiological events including the formation of fibroblast foci, excessive matrix deposition, and decreased compliance of lung parenchyma [5,6]. Transforming growth factor β1 (TGF-β1), a potent cytokine, mediates signaling events during the pathogenesis of pulmonary fibrosis by the stimulation of fibroblast differentiation, extracellular matrix deposition, and tensile force in myofibroblasts [1,7,8]. Through interactions with Notch signaling, reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) including ERK, p38 and JNK, TGF-β1 signaling regulates various cellular processes such as vascular smooth muscle differentiation and epithelial-mesenchymal transition [9,10,11]. We have comprehensively investigated roles of ROS, MAPKs and Notch at basal and TGF-β1-ativated conditions during the differentiation processes
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