Paeoniflorin-6′-O-benzene sulfonate alleviates collagen-induced arthritis in mice by downregulating BAFF-TRAF2-NF-κB signaling: comparison with biological agents

Abstract

Paeoniflorin-6′-O-benzene sulfonate (CP-25) is a new ester derivative of paeoniflorin with improved lipid solubility and oral bioavailability, as well as better anti-inflammatory activity than its parent compound. In this study we explored whether CP-25 exerted therapeutic effects in collagen-induced arthritis (CIA) mice through regulating B-cell activating factor (BAFF)-BAFF receptors-mediated signaling pathways. CIA mice were given CP-25 or injected with biological agents rituximab or etanercept for 40 days. In CIA mice, we found that T cells and B cells exhibited abnormal proliferation; the percentages of CD19+ total B cells, CD19+CD27+-activated B cells, CD19+BAFFR+ and CD19+TACI+ cells were significantly increased in PBMCs and spleen lymphocytes. CP-25 suppressed the indicators of arthritis, alleviated histopathology, accompanied by reduced BAFF and BAFF receptors expressions, inhibited serum immunoglobulin levels, decreased the B-cell subsets percentages, and prevented the expressions of key molecules in NF-κB signaling. Furthermore, we showed that treatment with CP-25 reduced CD19+TRAF2+ cell expressions stimulated by BAFF and decreased TRAF2 overexpression in HEK293 cells in vitro. Thus, CP-25 restored the abnormal T cells proliferation and B-cell percentages to the normal levels, and normalized the elevated levels of IgA, IgG2a and key proteins in NF-κB signaling. In comparison, rituximab and etanercept displayed stronger anti-inflammatory activities than CP-25; they suppressed the elevated inflammatory indexes to below the normal levels in CIA mice. In summary, our results provide evidence that CP-25 alleviates CIA and regulates the functions of B cells through BAFF-TRAF2-NF-κB signaling. CP-25 would be a soft immunomodulatory drug with anti-inflammatory effect.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant numbers 81330081, 81473223, and 81673444) and by the Anhui Province Postdoctoral Science Foundation (grant number 2016B134).

Author information

J-lS, X-zZ, and LH conducted the study, wrote this paper and analyzed the data. CW, X-yT, YT, Y-jW, Q-tW, FZ, J-yC, YC, H-xW, L-lZ and WW analyzed the data and wrote the paper.

Correspondence to Ling-ling Zhang or Wei Wei.

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The authors declare no competing interests.

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Keywords

  • paeoniflorin-6′-O-benzene sulfonate (CP-25)
  • collagen-induced arthritis
  • B cell
  • BAFF
  • TRAF2
  • rituximab
  • etanercept