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 antiinflammatory 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.

Etanercept Inhibits B Cell Differentiation by Regulating TNFRII/TRAF2/NF-κB Signaling Pathway in Rheumatoid Arthritis

“…Peripheral blood B cells are mainly derived from CD19 + IgM + IgD + type II transitional B cells (Loder et al, 1999). A previous study in our laboratory has shown that etanercept could reduce the percentage of CD19 + total B cells, CD19 + CD27 + memory B cells, and CD19 − CD27 + CD138 + plasma B cells in CIA mice (Shu et al, 2019). In order to investigate whether etanercept has an effect on the differentiation of B cells, we further designed a series of animal experiments.…”

Paeoniflorin attenuates gestational diabetes via Akt/mTOR pathway in a rat model

“…Many basic and preclinical studies suggested that paeoniflorin has potent anti-inflammatory, antitumor, and anti-hyperglycemia properties ( 16 – 19 ). Paeoniflorin exerts therapeutic effects on collagen-induced arthritis ( CIA ) rats via mediating Akt/mTOR signaling pathway and represses antibodies production from B cells ( 20 ). In addition, paeoniflorin imposes strong inhibition effect on mTOR-hypoxia inducible factor-1a pathway, leading to a reduction of alpha-smooth muscle actin (a-SMA) and collagen protein production and alleviation of liver fibrosis ( 21 ).…”

GRK2 Mediated Abnormal Transduction of PGE2-EP4-cAMP-CREB Signaling Induces the Imbalance of Macrophages Polarization in Collagen-Induced Arthritis Mice

“…After the onset of inflammation, the AI of the CIA mice in each group was evaluated once every 3 days as follows: 0, no signs of arthritis; 1, swelling and/or redness of the paw or one digit; 2, two joints involved; 3, more than two joints involved; and 4, severe arthritis of the entire paw and all digits. All feet were measured, the maximum score value of each mouse was 16 [21].…”

“…The ankle joints of mice were immersed in 10% formalin, then decalcified and paraffinembedded [21]. The sections (5 mm) were stained with hematoxylin and eosin.…”