Abstract
Transcriptional intermediary factor 1 γ (TIF1-γ) inhibits transforming growth factor β (TGF-β) signaling, the main pathway involved in fibrosis. We previously showed that TIF1-γ regulated anti-fibrotic processes in the liver. Here, we aimed to evaluate the therapeutic potential of TIF1-γ in pulmonary fibrosis (PF). TIF1-γ inhibited the TGF-β-induced epithelial-mesenchymal transition in alveolar type 2 cells and activation of fibroblasts in vitro. In activated macrophages, TIF1-γ reduced inflammatory cytokine secretion. In the in vivo PF mice model, TIF1-γ significantly reduced fibrosis and improved lung function. In ex vivo fibrotic precision cut lung slices from mice and patients with PF, TIF1-γ inhibited epithelial-mesenchymal transition of epithelial cells and activation of fibroblasts and reduced inflammatory cytokine secretion in macrophages. Conclusively, TIF1-γ is a promising candidate of gene therapy for PF by modulating three cell types (alveolar type 2 cells, fibroblasts, and macrophages) involved in PF pathogenesis.