1. Let-7 mediated airway remodelling in chronic obstructive pulmonary disease via the regulation of IL-6.
- Author
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Di T, Yang Y, Fu C, Zhang Z, Qin C, Sai X, Liu J, Hu C, Zheng M, Wu Y, and Bian T
- Subjects
- Actins metabolism, Adult, Aged, Animals, Cadherins metabolism, Cell Differentiation genetics, Cigarette Smoking, Collagen Type I metabolism, Extracellular Matrix metabolism, Female, Humans, In Vitro Techniques, Male, Mice, Middle Aged, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Disease, Chronic Obstructive pathology, RNA, Messenger metabolism, Respiratory Mucosa cytology, Respiratory Mucosa metabolism, Smoke, Tobacco Products, Airway Remodeling genetics, Epithelial Cells metabolism, Interleukin-6 metabolism, Lung metabolism, MicroRNAs genetics, Myofibroblasts metabolism, Pulmonary Disease, Chronic Obstructive genetics
- Abstract
Background: Myofibroblast differentiation and extracellular matrix (ECM) deposition are observed in chronic obstructive pulmonary disease (COPD). However, the mechanisms of regulation of myofibroblast differentiation remain unclear., Materials and Methods: We detected let-7 levels in peripheral lung tissues, serum and primary bronchial epithelial cells of COPD patients and cigarette smoke (CS)-exposed mice. IL-6 mRNA was explored in lung tissues of COPD patients and CS-exposed mice. IL-6 protein was detected in cell supernatant from primary epithelial cells by ELISA. We confirmed the regulatory effect of let-7 on IL-6 by luciferase reporter assay. Western blotting assay was used to determine the expression of α-SMA, E-cadherin and collagen I. In vitro, cell study was performed to demonstrate the role of let-7 in myofibroblast differentiation and ECM deposition., Results: Low expression of let-7 was observed in COPD patients, CS-exposed mice and CS extract (CSE)-treated human bronchial epithelial (HBE) cells. Increased IL-6 was found in COPD patients, CS-exposed mice and CSE-treated HBE cells. Let-7 targets and silences IL-6 protein coding genes through binding to 3' untranslated region (UTR) of IL-6. Normal or CSE-treated HBE cells were co-cultured with human embryonic lung fibroblasts (MRC-5 cells). Reduction of let-7 in HBE cells caused myofibroblast differentiation and ECM deposition, while increase of let-7 mimics decreased myofibroblast differentiation phenotype and ECM deposition., Conclusion: We demonstrate that CS reduced let-7 expression in COPD and, further, identify let-7 as a regulator of myofibroblast differentiation through the regulation of IL-6, which has potential value for diagnosis and treatment of COPD., (© 2020 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)
- Published
- 2021
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