School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan.
Int J Mol Sci. 2020 Nov 29;21(23):9084. doi: 10.3390/ijms21239084.
Lung epithelial cells play critical roles in idiopathic pulmonary fibrosis.
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).
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.
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.
肺上皮细胞在特发性肺纤维化中发挥着关键作用。
本研究旨在探讨转化生长因子-β（TGF-β）诱导结缔组织生长因子（CTGF）的表达是否受肺上皮细胞（A549）中细胞外信号调节激酶（ERK）/解整合素金属蛋白酶 17（ADAM17）/核糖体 S6 激酶 1（RSK1）/CCAAT/增强子结合蛋白-β（C/EBPβ）信号通路的调节。
我们的结果表明，ADAM17 小干扰 RNA（ADAM17 siRNA）、TNF-α 处理抑制剂-0（TAPI-0，ADAM17 抑制剂）、U0126（ERK 抑制剂）、RSK1 siRNA 和 C/EBPβ siRNA 可减弱 TGF-β 诱导的 CTGF 表达。U0126 减弱了 TGF-β 诱导的 ERK 磷酸化和 ADAM17 磷酸化。TAPI-0 和 U0126 抑制了 TGF-β 诱导的 RSK1 磷酸化增加。U0126、ADAM17 siRNA 和 RSK1 siRNA 减弱了 TGF-β 诱导的 C/EBPβ 磷酸化。此外，TGF-β 增加了 C/EBPβ 向 CTGF 启动子的募集。此外，TGF-β 增加了纤维连接蛋白（FN），即上皮间质转化（EMT）标志物，和 CTGF mRNA 水平，并降低了 E-钙黏蛋白 mRNA 水平。此外，TGF-β 刺激的 FN 蛋白表达减少了 ADAM17 siRNA 和 CTGF siRNA。
结果表明，TGF-β 通过 ERK/ADAM17/RSK1/C/EBPβ 信号通路诱导 CTGF 表达。此外，ADAM17 和 CTGF 参与了 TGF-β 诱导的人肺上皮细胞中 FN 的表达。
