Abstract
Background: Lung epithelial cells play critical roles in idiopathic pulmonary fibrosis. Methods: In the present study, we investigated whether transforming growth factor-β (TGF-β)-induced expression of connective tissue growth factor (CTGF) was regulated by the extracellular signal-regulated kinase (ERK)/a disintegrin and metalloproteinase 17 (ADAM17)/ribosomal S6 kinases 1 (RSK1)/CCAAT/enhancer-binding protein β (C/EBPβ) signaling pathway in human lung epithelial cells (A549). Results: Our results revealed that TGF-β-induced CTGF expression was weakened by ADAM17 small interfering RNA (ADAM17 siRNA), TNF-α processing inhibitor-0 (TAPI-0, an ADAM17 inhibitor), U0126 (an ERK inhibitor), RSK1 siRNA, and C/EBPβ siRNA. TGF-β-induced ERK phosphorylation as well as ADAM17 phosphorylation was attenuated by U0126. The TGF-β-induced increase in RSK1 phosphorylation was inhibited by TAPI-0 and U0126. TGF-β-induced C/EBPβ phosphorylation was weakened by U0126, ADAM17 siRNA, and RSK1 siRNA. In addition, TGF-β increased the recruitment of C/EBPβ to the CTGF promoter. Furthermore, TGF-β enhanced fibronectin (FN), an epithelial–mesenchymal transition (EMT) marker, and CTGF mRNA levels and reduced E-cadherin mRNA levels. Moreover, TGF-β-stimulated FN protein expression was reduced by ADAM17 siRNA and CTGF siRNA. Conclusion: The results suggested that TGF-β induces CTGF expression through the ERK/ADAM17/RSK1/C/EBPβ signaling pathway. Moreover, ADAM17 and CTGF participate in TGF-β-induced FN expression in human lung epithelial cells.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a type of an interstitial lung disease that is prevalent in elder smokers
We investigated whether transforming growth factor-β (TGF-β) increases connective tissue growth factor (CTGF) expression in human lung epithelial cells (A549)
When A549 cells were treated with TGF-β (10 ng/mL) for 0–8 h, CTGF expression significantly increased at 6 h, with a maximal effect at 8 h (Figure 1A)
Summary
Idiopathic pulmonary fibrosis (IPF) is a type of an interstitial lung disease that is prevalent in elder smokers. Connective tissue growth factor (CTGF) is an immediate early protein mediated by TGF-β, and it regulates the growth of fibroblasts and the secretion of ECM [9,10,11]. The relationship between ADAM17 and CTGF in TGF-β-induced EMT process in human lung epithelial cells remains unclear. Weng et al found that MEK inhibitor significantly attenuated CTGF expression in TGF-β-induced renal fibrosis in mice [18], but information on the responsibilities of RSK1 and C/EBPβ in TGF-β-induced CTGF expression in human lung epithelial cells remains limited. Data showed that TGF-β might activate ERK, ADAM17, and RSK1 signaling pathways, which initiate C/EBPβ phosphorylation and the binding of C/EBPβ to the CTGF promoter region and lead to CTGF expression. CTGF participates in TGF-induced FN expression in human lung epithelial cells
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