TNF-α-induced NF-κB activation promotes myofibroblast differentiation of LR-MSCs and exacerbates bleomycin-induced pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease of unknown cause. It has been reported that both lung resident mesenchymal stem cells (LR-MSCs) and tumor necrosis factor-alpha (TNF-alpha) play important roles in the development of pulmonary fibrosis. However, the underlying connections between LR-MSCs and TNF-alpha in the pathogenesis of pulmonary fibrosis are still elusive. In this study, we found that the pro-inflammatory cytokine TNF-alpha and the transcription factor nuclear factor kappa B (NF-kappa B) p65 subunit were both upregulated in bleomycin-induced fibrotic lung tissue. In addition, we discovered that TNF-alpha promotes myofibroblast differentiation of LR-MSCs through activating NF-kappa B signaling. Interestingly, we also found that TNF-a promotes the expression of beta-catenin. Moreover, we demonstrated that suppression of the NF-kappa B signaling could attenuate myofibroblast differentiation of LR-MSCs and bleomycin-induced pulmonary fibrosis which were accompanied with decreased expression of beta-catenin. Our data implicates that inhibition of the NF-kappa B signaling pathway may provide a therapeutic strategy for pulmonary fibrosis, a disease that warrants more effective treatment approaches.