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CXCL16 upregulates RANKL expression in rheumatoid arthritis synovial fibroblasts through the JAK2/STAT3 and p38/MAPK signaling pathway

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Abstract

Objective

To explore the influence of chemokine, CXCL16, on the expression of the receptor activator nuclear factor κB ligand (RANKL) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLS).

Methods

The expression of CXCL16/CXCR6 and RANKL in RA or osteoarthritis (OA) patient synovia was examined by Western blot and immunohistochemistry. The serum concentration of CXCL16 and RANKL was measured by enzyme-linked immunosorbent assay (ELISA). RA-FLS were treated with recombinant CXCL16, and RANKL mRNA and protein were measured using PCR, Western blot and ELISA.

Results

The synovial expression of CXCL16, CXCR6, and RANKL was higher in RA patients than in patients with OA. The serum CXCL16 and RANKL levels were higher in RA patients compared with OA patients and healthy controls. CXCL16 correlated with erythrocyte sedimentation rate, C reactive protein, disease activity, serum rheumatoid factor, and RANKL. RA-FLS treated with CXCL16 showed markedly increased expression of RANKL. When STAT3 or p38 activation was blocked by an inhibitor, CXCL16 failed to upregulate RANKL expression. In contrast, inhibiting the Akt or Erk pathway did not achieve the same effect.

Conclusions

CXCL16 upregulates RANKL expression in RA-FLS and these effects are mainly mediated by the JAK2/STAT3 and p38/MAPK signaling pathways.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (No. 81273293, No. 81471599, No. 81501387).

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    Authors and Affiliations

    1. Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China

      Chang-hong Li, Jin-xia Zhao, Lin Sun, Zhong-qiang Yao, Xiao-li Deng, Rui Liu, Lin Yang, Rui Xing & Xiang-yuan Liu

    2. Department of Clinical Nutrition, First Hospital of Tsinghua Univiersity, Beijing, 100016, People’s Republic of China

      Lin-lin Xu

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    Authors’ Contribution

    CL, LX, and XL designed the research. CL and LX performed the research and analyzed the data. CL, LX, and XL wrote the manuscript. JZ, LS, ZY, XD, RL, LY, and RX helped with sample collection and data analysis.

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    Responsible Editor: Jason J. McDougall.

    Chang-hong Li and Lin-lin Xu equally contributed to this work.

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    Li, Ch., Xu, Ll., Zhao, Jx. et al. CXCL16 upregulates RANKL expression in rheumatoid arthritis synovial fibroblasts through the JAK2/STAT3 and p38/MAPK signaling pathway. Inflamm. Res. 65, 193–202 (2016). https://doi.org/10.1007/s00011-015-0905-y

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    • DOI: https://doi.org/10.1007/s00011-015-0905-y

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