Let‐7 mediated airway remodelling in chronic obstructive pulmonary disease via the regulation of IL‐6

• Published in: European journal of clinical investigation Vol. 51; no. 4; pp. e13425 - n/a
• Main Authors: Di, Tingting, Yang, Yue, Fu, Congli, Zhang, Zixiao, Qin, Chu, Sai, Xiaoyan, Liu, Jiaxin, Hu, Caixia, Zheng, Mingfeng, Wu, Yan, Bian, Tao
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-04-2021; John Wiley and Sons Inc
• Subjects: 3' Untranslated regions; airway remodelling; Cell differentiation; Chronic obstructive pulmonary disease; Cigarette smoke; Collagen (type I); COPD; Deposition; Differentiation; Embryo fibroblasts; Embryos; Enzyme-linked immunosorbent assay; Epithelial cells; Exposure; Extracellular matrix; Fibroblasts; IL‐6; let‐7; Lung diseases; Lungs; mRNA; Obstructive lung disease; Original; Phenotypes; Proteins; Western blotting; let-7; cigarette smoke; IL-6; airway remodelling; COPD
• ISSN: 0014-2972; 1365-2362
• DOI: 10.1111/eci.13425

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.