Sirtuin 6 attenuates epithelial–mesenchymal transition by suppressing the TGF-β1/Smad3 pathway and c-Jun in asthma models

• Published in: International immunopharmacology 2020-05, Vol.82, p.106333-106333, Article 106333
• Main Authors: Liu, Fen, Shang, Yun-Xiao
• Format: Article
• Language: English
• Subjects: Acetylation; Actin; Airway remodeling; Allergic diseases; Alveoli; Asthma; Bronchus; c-Jun protein; Cell adhesion & migration; Cell migration; Cell proliferation; E-cadherin; Epithelial cells; Epithelial–mesenchymal transition; Fibrosis; Growth factors; Histone deacetylase; Histones; Mesenchyme; Metalloproteinase; Muscles; N-Cadherin; Ovalbumin; Plasmids; Polymerase chain reaction; Respiratory tract diseases; Sirtuin 6; Smad3 protein; Smooth muscle; Transcription factors; Transforming growth factor-b1; Western blotting
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2020.106333

•SIRT6 plays a key role in airway remodeling in asthma.•SIRT6 was upregulated both in a rat model of airway remodeling and cells in response to TGF-β1.•SIRT6 overexpression attenuated the effects of TGF-β1 in 16HBE cells.•SIRT6 suppressed the TGF-β1/Smad3 pathway and c-Jun. Allergic asthma is a chronic inflammatory airway disease involving airway remodeling. The histone deacetylase sirtuin6 (SIRT6) has protective effects in cardiac and liver fibrosis; however, its role in airway remodeling is unclear. In this study, we investigated the expression of SIRT6 in a rat model of airway remodeling and observed its effects on the epithelial–mesenchymal transition (EMT) in human bronchial epithelial 16HBE cells. Sprague–Dawley rats were sensitized and challenged with ovalbumin to induce airway remodeling or with phosphate-buffered saline as a control for different periods. Morphological changes, cell counts in the bronchoalveolar lavage fluid, and SIRT6 expression were assessed. 16HBE cells were transfected with plasmids to silence or overexpress SIRT6. Western blotting, quantitative polymerase chain reaction, Transwell assays, and cell proliferation assays were performed to examine the transforming growth factor (TGF)-β1-induced changes in EMT indicators and EMT-related cell behaviors. SIRT6 expression was upregulated in bronchial epithelial cells from rats with airway remodeling and in TGF-β1-treated 16HBE cells. SIRT6 overexpression affected TGF-β1-induced changes in EMT markers and EMT-like cell behaviors. In particular, SIRT6 overexpression alleviated the reduction in E-cadherin and the increases in N-cadherin, vimentin, alpha-smooth muscle actin, and metalloproteinase-9 levels in TGF-β1-treated 16HBE cells. Forced expression of SIRT6 also decreased the rates of cell migration and proliferation, reduced activation of phosphorylated Smad3 induced by TGF-β1 treatment, suppressed the acetylation level at histone H3K9, and inhibited the transcriptional activity of the c-Jun promotor. These results suggested that SIRT6 expression is upregulated during airway remodeling and modulates EMT in bronchial epithelial cells targeting Smad3 and c-Jun, highlighting a new therapeutic candidate for improving airway remodeling in asthma.