The MIR155 host gene/microRNA-627/HMGB1/NF-B loop modulates fibroblast proliferation and extracellular matrix deposition

Pulmonary fibrosis (PF), which is characterized by excessive matrix formation, may ultimately lead to irreversible lung damage and thus death. Fibroblast activation has been regarded as a central event during PF pathogenesis. In our previous study, we confirmed that the miR-627/high-mobility group box protein 1 (HMGB1)/Nuclear factor kappa beta (NF-kappa B) axis modulates transforming growth factor beta 1 (TGF beta 1)-induced pulmonary fibrosis. In the present study, we investigated the upstream factors leading to miR-627 dysregulation in the process of pulmonary fibroblast activation and PF. The lncRNA MIR155 host gene (MIR155HG) was found to be abnormally upregulated in pulmonary fibrosis tissues and TGF beta 1-stimulated normal human primary lung fibroblasts (NHLFs). By directly binding to miR-627, MIR155HG inhibited miR-627 expression. MIR155HG overexpression enhanced TGF beta 1-induced increases in HMGB1 protein expression and p65 phosphorylation, NHLF proliferation, and extracellular matrix (ECM) deposition. In contrast, miR-627 overexpression attenuated the TGF beta 1-induced changes in NHLFs and significantly reversed the effects of MIR155HG overexpression. Under TGF beta 1 stimulation, miR-627 inhibition promoted, whereas JSH-23 treatment inhibited NF-kappa B activation; in NHLFs, NF-kappa B overexpression upregulated, whereas JSH-23 treatment downregulated MIR155HG expression. In tissue samples, HMGB1 protein levels and p65 phosphorylation were increased; MIR155HG was negatively correlated with miR-627 and positively correlated with HMGB1. In conclusion, we validated that the MIR155HG/miR-627/HMGB1/NF-kappa B axis formed a regulatory loop that modulates TGF beta 1-induced NHLF activation. Considering the critical role of NHLF activation in PF pathogenesis, the NF-kappa B/MIR155HG/miR-627/HMGB1 regulatory loop could exert a vital effect on PF pathogenesis. Further in vivo and clinical investigations are required to confirm this model.