TAK1 inhibition attenuates both inflammation and fibrosis in experimental pneumoconiosis

Jie Li, Chao LIANG, Zong Kang Zhang, Xiaohua Pan, Songlin Peng, Wing Sze Lee, Aiping LYU, Zhixiu Lin, Ge ZHANG*, Wing Nang Leung, Bao Ting Zhang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

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 TAK1 inhibition, 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.

Original languageEnglish
Article number17023
JournalCell Discovery
Volume3
DOIs
Publication statusPublished - 11 Jul 2017

Scopus Subject Areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

User-Defined Keywords

  • fibrosis
  • inflammation
  • pneumoconiosis
  • TAK1

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