Unspliced X-box-binding protein 1 Protects Against Fibroblast Differentiation via Activating Nrf2 Signal during Pulmonary Fibrosis

Abstract

Background: Pulmonary fibrosis is characterized by the excessive accumulation of extracellular matrix synthesized from activated fibroblasts. X box binding protein 1(XBP-1) is a transcription factor regulating various cellular functions, including unfold protein responses.While few studies aimed to investigate the function of unspliced XBP1 in fibroblast differentiation. Here we explore the role of uXBP1 in fibroblast differentiation during pulmonary fibrosis.

Method: Levels of uXBP-1 mRNA and protein were measured in lungs of bleomycin exposed rats and transforming growth factor β 1 treated human lung fibroblasts detected by PCR, Western blot, and immunostaining. Transfection of uXBP-1 siRNA and overexpression plasmids were performed in human lung fibroblasts treated with TGFβ1 in the present of nuclear factor erythroid 2 related factor 2 activator sulforaphane.

Results: We discovered that uXBP-1 levels were reduced in lungs from bleomycin exposed rats and TGFβ1 treated human lung fibroblasts. Knockdown of uXBP-1 by siRNA augmented α-SMA levels and collagen I synthesis, and these effects were ameliorated by uXBP-1 overexpression in TGFβ1 treated lung fibroblasts. Interestingly, uXBP-1 enhanced Nrf2 expression in lung fibroblasts treated with TGFβ1. Sulforaphane significantly lowered uXBP1 knockdown induced fibroblast differentiation.

Conclusion: In conclusion, uXBP-1 reduction induced by bleomycin and TGFβ1 induced fibroblast differentiation and Pulmonary fibrosis by activating Nrf2 signal.

Acknowledgements: This work was supported by the National Natural Science Foundation of China (No. 81274172,81473267, 81503330 and 81503129).

*Address for correspondence: Prof. Jian Gao, PhD., 218 Jixi Road, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.

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