Article

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

Authors: Jin-ling Shu1, Xian-zheng Zhang1, Le Han1, Feng Zhang1, Yu-jing Wu1, Xiao-yu Tang1, Chen Wang1, Yu Tai1, Qing-tong Wang1, Jing-yu Chen1, Yan Chang1, Hua-xun Wu1, Ling-ling Zhang1, Wei Wei1
1 Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anti-Inflammatory Immune Drugs Collaborative Innovation Center, Hefei 230032, China
Correspondence to: Ling-ling Zhang: ll-zhang@hotmail.com, Wei Wei: wwei@ahmu.edu.cn,
DOI: 10.1038/s41401-018-0169-5
Received: 12 March 2018
Accepted: 6 September 2018
Advance online: 16 November 2018

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

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