Cartilage intermediate layer protein attenuates bleomycin-induced pulmonary fibrosis through the TGF-β1/Smad3 negative feedback loop

Abstract Idiopathic pulmonary fibrosis (IPF), a chronic, progressive interstitial lung disease, has multiple etiologies. It is characterized by excess myofibrocyte aggregation and extracellular matrix deposition. However, its pathomechanisms have not been conclusively elucidated. We performed a comprehensive study of mRNAs in human pulmonary fibrosis using GSE10667 microarray data from the Gene Expression Omnibus (GEO) database and identified differentially expressed mRNAs among end-stage pulmonary fibrosis (EPF), acute pulmonary fibrosis (APF) and paired non-fibrosis matched tissues. The Cartilage intermediate layer protein (CILP) mRNA was upregulated in pulmonary fibrosis and myofibroblasts upon TGF-β1 activation. However, its role in pulmonary fibrosis is unclear. Therefore, we investigated the potential effects and mechanisms of CILP on pulmonary fibrosis. In vitro, CILP attenuated TGF-β1-myofibroblast activation and inflammatory responses. Mechanistically, CILP inhibited TGF-β1-induced Smad3 activities by suppressing Smad3 phosphorylation and inhibiting its nuclear translocation by competitively binding ALK5. In vivo, CILP reduced bleomycin-induced inflammation and collagen deposition. In conclusion, CILP inhibited TGF-β1-induced inflammation and fibrosis via its negative feedback loop.