School of Chinese Medicine
Pneumoconiosis, caused by inhalation of mineral dusts, is a major occupational disease worldwide. Currently, there are no effective drugs owing to a lack of potential therapeutic targets during either the inflammation or fibrosis molecular events in pneumoconiosis. Here, we performed microarrays to identify aberrantly expressed genes in the above molecular events in vitro and found a hub gene transforming growth factor-β-activated kinase 1 (TAK1), which was highly expressed and activated in pneumoconiosis patients as well as silica-exposed rats with experimental pneumoconiosis. Genetic modulation of TAK1 by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9, RNA interference and overexpression indicated the important role of TAK1 in both inflammation and fibrosis in experimental pneumoconiosis. To achieve pharmacological TAK1inhibition, we virtually screened out a natural product resveratrol, which targeted TAK1 at both N161 and A107 residues, and significantly inhibited TAK1 activation to attenuate inflammation and fibrosis in vitro. Consistently, in vivo prevention and intervention studies showed that resveratrol could inhibit pulmonary inflammation and fibrosis in silica-exposed rats.
TAK1, inflammation, fibrosis, pneumoconiosis
Source Publication Title
Article number: 17023 (2017)
Nature Publishing Group
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
This study was supported by the Pneumoconiosis Compensation Fund Board of Hong Kong (MK/AL/extgrant/PCFB//0325/11sh), the Hong Kong Research Grant Council Early Career Scheme (489213) and the Direct Grant for Research from the Chinese University of Hong Kong (4054138). The statistical analysis was performed by a contract service from Bioinformedicine (http://www.bioinformedicine.com/index.php).
Link to Publisher's Edition
Li, Jie, Chao Liang, Zong-Kang Zhang, Xiaohua Pan, Songlin Peng, Wing-Sze Lee, Aiping Lu, Zhixiu Lin, Ge Zhang, Wing-Nang Leung, and Bao-Ting Zhang. "TAK1 inhibition attenuates both inflammation and fibrosis in experimental pneumoconiosis." Cell Discovery 3 (2017): Article number: 17023 (2017).
Additional FilesJA-5268-29319_suppl.pdf (1602 kB)