Abstract
Epithelial–mesenchymal transition (EMT) is implicated in bronchial remodeling and loss of lung function in chronic inflammatory airway diseases. Previous studies showed the involvement of the high mobility group box 1 (HMGB1) protein in the pathology of chronic pulmonary inflammatory diseases. However, the role of HMGB1 in EMT of human airway epithelial cells is still unclear. In this study, we used RNA sequencing to show that HMGB1 treatment regulated EMT-related gene expression in human primary-airway epithelial cells. The top five upregulated genes were SNAI2, FGFBP1, VIM, SPARC (osteonectin), and SERPINE1, while the downregulated genes included OCLN, TJP1 (ZO-1), FZD7, CDH1 (E-cadherin), and LAMA5. We found that HMGB1 induced downregulation of E-cadherin and ZO-1, and upregulation of vimentin mRNA transcription and protein translation in a dose-dependent manner. Additionally, we observed that HMGB1 induced AKT phosphorylation, resulting in GSK3β inactivation, cytoplasmic accumulation, and nuclear translocation of β-catenin to induce EMT in human airway epithelial cells. Treatment with PI3K inhibitor (LY294006) and β-catenin shRNA reversed HMGB1-induced EMT. Moreover, HMGB1 induced expression of receptor for advanced glycation products (RAGE), but not that of Toll-like receptor (TLR) 2 or TLR4, and RAGE shRNA inhibited HMGB1-induced EMT in human airway epithelial cells. In conclusion, we found that HMGB1 induced EMT through RAGE and the PI3K/AKT/GSK3β/β-catenin signaling pathway.
Highlights
Tissue and contributes to reduced response to steroid treatment in severe asthma or chronic obstructive pulmonary disease (COPD) patients and unwanted side effects resulting from prolonged high-dose steroid therapy[13,14]
This study demonstrated that high mobility group box 1 (HMGB1) induced Epithelial mesenchymal transition (EMT), as well as cell migration, in human airway epithelial cells
Pro-inflammatory cytokines enhance TGF-β 1-induced EMT, few reports indicate that pro-inflammatory cytokines are capable of inducing EMT in the absence of TGF-β 1 involvement[36]
Summary
Tissue and contributes to reduced response to steroid treatment in severe asthma or COPD patients and unwanted side effects resulting from prolonged high-dose steroid therapy[13,14]. Previous studies have showed that HMGB1 participates in the pathology of chronic pulmonary inflammatory diseases, such as asthma[19] and COPD20 and that HMGB1 levels were positively associated with the severity of those diseases,. We previously reported HMGB1 involvement in allergen-induced airway remodeling in a chronic asthma mouse model[21], and its induction of myofibroblast differentiation in primary human-lung fibroblasts[22]. Given the importance of HMGB1 in airway remodeling during chronic airway inflammatory diseases, we hypothesized that HMGB1 may directly influence airway epithelial cells by inducing EMT. In this study, we cultured human airway epithelial cells to determine the effect of HMGB1 on EMT and the mechanisms involved. We found that HMGB1 induced mesenchymal transition in airway epithelial cells through the receptor for advanced glycation products (RAGE) and the β -catenin signaling pathway
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