MicroRNA-218 acts by repressing TNFR1-mediated activation of NF-κB, which is involved in MUC5AC hyper-production and inflammation in smoking-induced bronchiolitis of COPD.

Dysregulation of microRNAs (miRNAs) has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), which is largely attributable to cigarette smoke (CS). However, little is known about the effect of miRNAs on CS-induced mucus hypersecretion and the inflammatory response in the airway epithelium, which are pathological characteristics of COPD-related chronic bronchiolitis. As determined in the present investigation, population-based data indicate that smokers with COPD had serious airflow obstruction and inflammation, whereas smokers without COPD had mild airflow obstruction and inflammation. Moreover, levels of serum miR-218 positively correlated with FEV1/FVC% and negatively correlated with levels of serum IL-6 and IL-8. In human bronchial epithelial (HBE) cells, cigarette smoke extract (CSE) decreased miR-218 levels and increased levels of MUC5AC, interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor receptor 1 (TNFR1), and p-p65. Enhancement of miR-218 levels by an miR-218 mimic blocked these CSE-induced changes. Moreover, luciferase reporter assays confirmed that miR-218 bound to the 3'UTR region of TNFR1 mRNA. Down-regulation of TNFR1 blocked the CSE-induced increases of MUC5AC, IL-6, and IL-8 and the activation of NF-κB. Furthermore, over-expression of miR-218 attenuated the CSE-induced overproduction of MUC5AC, IL-6, and IL-8, effects that were reversed by elevated expression of TNFR1. In sum, our findings provide a mechanism by which miR-218 regulates CSE-induced MUC5AC hyper-production and inflammation by targeting TNFR1-mediated activation of NF-κB, indicating that overexpression of miR-218 may be a strategy against cigarette smoking-induced bronchiolitis in COPD.