Transcriptional intermediary factor 1 gamma prevents lung inflammation and fibrosis via alveolar type 2 cells, fibroblasts, and macrophages.

Transcriptional intermediary factor 1 gamma (TIF1γ) inhibits transforming growth factor-beta (TGFβ) signaling, the main pathway involved in fibrosis. We previously showed that TIF1γ regulated anti fibrotic processes in the liver. Herein, we aimed to evaluate the therapeutic potential of TIF1γ in pulmonary fibrosis (PF). TIF1γ inhibited the TGFβ-induced epithelial-mesenchymal transition in alveolar type 2 cells and activation of fibroblasts in vitro. In activated macrophages, TIF1γ reduced inflammatory cytokine secretion. In the in vivo PF mice model, TIF1γ significantly reduced fibrosis and improved lung function. In ex vivo fibrotic precision cut lung slices from mice and patients with PF, TIF1γ inhibited epithelial-mesenchymal transition of epithelial cells and activation of fibroblasts and reduced inflammatory cytokine secretion in macrophages. Conclusively, TIF1γ 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.