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TXNDC5 synergizes with HSC70 to exacerbate the inflammatory phenotype of synovial fibroblasts in rheumatoid arthritis through NF-κB signaling

Cellular & Molecular Immunology volume 15, pages 685–696 (2018)Cite this article

Abstract

The upregulated expression of thioredoxin domain-containing protein 5 (TXNDC5) is associated with rheumatoid arthritis in patients and model mice. However, the underlying mechanism by which TXNDC5 influences the pathological activation of rheumatoid arthritis synovial fibroblasts (RASFs) remains unknown. In this study, we show that TXNDC5 expression in RASFs and their cytokine production are significantly upregulated in response to LPS, TNF-α and IL-6, but suppressed by transfection with TXNDC5-siRNA. TXNDC5 is further validated as the direct target of NF-κB signaling. Mechanistically, TXNDC5 directly interacts with heat shock cognate 70 protein (HSC70) to sequester it in the cytoplasm, and HSC70 silencing exerts the same effects as TXNDC5 on the biological activity of RASFs (for example, decreased cell viability, invasion and cytokine production). Furthermore, HSC70 activates NF-κB signaling by destabilizing IκBβ protein in the absence of LPS or facilitating its nuclear translocation in the presence of LPS. Importantly, TXNDC5 can also regulate the activity of NF-κB signaling in a HSC70-IκBβ-dependent manner. Taken together, by linking HSC70 and NF-κB signaling, TXNDC5 plays a pro-inflammatory role in RASFs, highlighting a potential approach to treat RA by blocking the TXNDC5/HSC70 interaction.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81572254), China Postdoctoral Science Foundation (2016M600541), the Key Research and Development Project of Shandong (2016GSF201166), the Shandong Taishan Scholarship (No. tsqn20161076) and the Innovation Project of Shandong Academy of Medical Sciences.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China, Shandong

    Lin Wang

  2. Research Center for Medicinal Biotechnology, Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Shandong, Academy of Medical Sciences, Jinan, China, Shandong

    Lin Wang, Rui Zhang, Jihong Pan & Jinxiang Han

  3. Department of Pathology, Linyi People’s Hospital, Linyi, China

    Hongyan Dong

  4. Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China, Shandong

    Guanhua Song

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  1. Lin Wang
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Correspondence to Jinxiang Han.

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Wang, L., Dong, H., Song, G. et al. TXNDC5 synergizes with HSC70 to exacerbate the inflammatory phenotype of synovial fibroblasts in rheumatoid arthritis through NF-κB signaling. Cell Mol Immunol 15, 685–696 (2018). https://doi.org/10.1038/cmi.2017.20

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