Paeoniflorin-6′-O-benzene sulfonate alleviates collagen-induced arthritis in mice by downregulating BAFF-TRAF2-NF-κB signaling: comparison with biological agents
Paeoniflorin-6′-O-benzene sulfonate alleviates collagen-induced arthritis in mice by downregulating BAFF-TRAF2-NF-κB signaling: comparison with biological agents
复制标题
芍药苷-6'-O-苯磺酸盐通过下调 BAFF-TRAF2-NF-kappaB 信号传导减轻小鼠胶原诱导的关节炎：与生物制剂的比较。
DOI：
10.1038/s41401-018-0169-5
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发表时间：
2019-06-01
影响因子：
8.2
通讯作者：
Wei, Wei
中科院分区：
文献类型：
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作者：
Shu, Jin-ling;Zhang, Xian-zheng;Wei, Wei
芍药苷-6'-O-苯磺酸盐（CP-25）是芍药苷的新型酯衍生物，与母体化合物相比，具有改善的脂溶性和口服生物利用度，以及更好的抗炎活性。在这项研究中，我们探讨了 CP-25 是否通过调节 B 细胞激活因子 (BAFF)-BAFF 受体介导的信号通路对胶原诱导关节炎 (CIA) 小鼠发挥治疗作用。给 CIA 小鼠注射 CP-25 或注射生物制剂利妥昔单抗或依那西普 40 天。在CIA小鼠中，我们发现T细胞和B细胞表现出异常增殖； PBMCs和脾淋巴细胞中CD19(+)总B细胞、CD19(+)CD27(+)激活B细胞、CD19(+)BAFFR(+)和CD19(+)TACI(+)细胞的百分比显着增加。 CP-25 抑制关节炎指标，减轻组织病理学，同时减少 BAFF 和 BAFF 受体表达，抑制血清免疫球蛋白水平，降低 B 细胞亚群百分比，并阻止 NF-κ B 信号传导中关键分子的表达。此外，我们发现CP-25处理可减少BAFF刺激的CD19(+) TRAF2(+)细胞表达，并减少体外HEK293细胞中TRAF2的过度表达。因此，CP-25 将异常的 T 细胞增殖和 B 细胞百分比恢复到正常水平，并使 NF-κ B 信号传导中 IgA、IgG2a 和关键蛋白的升高水平正常化。相比之下，利妥昔单抗和依那西普比 CP-25 表现出更强的抗炎活性；他们将 CIA 小鼠升高的炎症指数抑制到正常水平以下。总之，我们的结果证明 CP-25 通过 BAFF-TRAF2-NF-kappa B 信号传导减轻 CIA 并调节 B 细胞的功能。 CP-25将是一种具有抗炎作用的软免疫调节药物。
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-kappa B 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-kappa B 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-kappa B signaling. CP-25 would be a soft immunomodulatory drug with anti-inflammatory effect.