Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by fibroblast activation, excessive deposition of extracellular matrix, and progressive scarring; the pathogenesis remains elusive. The present study explored the role of Tribbles pseudokinase 3 (TRIB3), a well-known stress and metabolic sensor, in IPF.TRIB3is down-regulated in the lungs of IPF patients in comparison to control subjects. Deficiency ofTRIB3markedly inhibited A549 epithelial cells’ proliferation and migration, significantly reducing wound healing. Conversely, overexpression ofTRIB3promoted A549 cell proliferation and transmigration while it inhibited its apoptosis. Meanwhile, overexpressedTRIB3inhibited fibroblast activation and decreased ECM synthesis and deposition in MRC5 cells.TRIB3attenuated pulmonary fibrosis by negative regulation of ATF4, whileTRIB3expression markedly inhibitedATF4promoter-driven transcription activity and down-regulatedATF4expression. A co-culture system showed thatTRIB3is important to maintain the normal epithelial–mesenchymal crosstalk and regulate fibroblast activation. Taken together, our data suggested that an axis ofTRIB3–ATF4is a key mediator in IPF which might be a potential target for fibroproliferative lung disease treatment.Keywords:idiopathic pulmonary fibrosis;TRIB3;ATF4;epithelial cell;fibroblast activation