CP-25 reverses prostaglandin E4 receptor desensitization-induced fibroblast-like synoviocyte dysfunction via the G protein-coupled receptor kinase 2 in autoimmune arthritis.,Acta Pharmacologica Sinica

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CP-25 reverses prostaglandin E4 receptor desensitization-induced fibroblast-like synoviocyte dysfunction via the G protein-coupled receptor kinase 2 in autoimmune arthritis.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2019-01-14 , DOI: 10.1038/s41401-018-0196-2
Xiao-Yi Jia _{1,

2} , Yan Chang ₁ , Fang Wei ₁ , Xing Dai ₁ , Yu-Jing Wu ₁ , Xiao-Jing Sun ₁ , Shu Xu ₁ , Hua-Xun Wu ₁ , Chun Wang ₁ , Xue-Zhi Yang ₁ , Wei Wei ₁

Affiliation

Paeoniflorin-6'-O-benzene sulfonate (CP-25) is a novel compound derived from paeoniflorin that has been demonstrated to have therapeutic effects in a rat model of rheumatoid arthritis (RA). However, the underlying mechanism has not been elucidated to date. We explored this mechanism in the present study by treating rats with adjuvant arthritis (AA) with CP-25. We found that the membrane EP4 protein level was downregulated; whereas, GRK2 was upregulated, in fibroblast-like synoviocyte (FLS)s of AA rats. Prostaglandin (PGE)2 stimulated FLS proliferation and enhanced the membrane EP4 receptor protein level; the latter was reversed by the administration of an EP4 receptor agonist, whereas the membrane GRK2 protein level gradually increased. The changes in the EP4 receptor and GRK2 expression were enhanced by TNF-α, and the former was accompanied by an alteration in the cyclic (c)AMP level. The EP4 receptor agonist stimulation increased the association between GRK2 and the EP4 receptor. GRK2 knockdown abrogated the abnormalities in FLS proliferation. The CP-25 treatment (100 mg/kg) suppressed joint inflammation with an efficacy that was similar to that of methotrexate. This finding was associated with EP4 upregulation and GRK2 downregulation in FLSs. Thus, GRK2 plays an important role in the abnormal FLS proliferation observed in AA possibly by promoting EP4 receptor desensitization and decreasing the cAMP level. Our results demonstrate that CP-25 has therapeutic potential for the treatment of human RA via GRK2 regulation.

中文翻译：

CP-25 通过自身免疫性关节炎中的 G 蛋白偶联受体激酶 2 逆转前列腺素 E4 受体脱敏诱导的成纤维细胞样滑膜细胞功能障碍。

Paeoniflorin-6'-O-benzo sulfonate (CP-25) 是一种源自芍药苷的新型化合物，已被证明在类风湿性关节炎 (RA) 大鼠模型中具有治疗作用。然而，迄今为止尚未阐明潜在的机制。我们在本研究中通过用 CP-25 治疗患有佐剂性关节炎 (AA) 的大鼠来探索这种机制。我们发现膜 EP4 蛋白水平下调；而在 AA 大鼠的成纤维细胞样滑膜细胞 (FLS) 中，GRK2 上调。前列腺素 (PGE)2 刺激 FLS 增殖并提高膜 EP4 受体蛋白水平；后者通过施用 EP4 受体激动剂被逆转，而膜 GRK2 蛋白水平逐渐增加。TNF-α增强了EP4受体和GRK2表达的变化，前者伴随着循环（c）AMP水平的改变。EP4受体激动剂刺激增加了GRK2和EP4受体之间的关联。GRK2 敲低消除了 FLS 增殖的异常。CP-25 治疗（100 mg/kg）以与甲氨蝶呤相似的功效抑制关节炎症。这一发现与 FLS 中 EP4 上调和 GRK2 下调有关。因此，GRK2可能通过促进EP4受体脱敏和降低cAMP水平在AA中观察到的异常FLS增殖中起重要作用。我们的研究结果表明，CP-25 具有通过 GRK2 调节治疗人类 RA 的治疗潜力。EP4受体激动剂刺激增加了GRK2和EP4受体之间的关联。GRK2 敲低消除了 FLS 增殖的异常。CP-25 治疗（100 mg/kg）以与甲氨蝶呤相似的功效抑制关节炎症。这一发现与 FLS 中 EP4 上调和 GRK2 下调有关。因此，GRK2可能通过促进EP4受体脱敏和降低cAMP水平在AA中观察到的异常FLS增殖中起重要作用。我们的研究结果表明，CP-25 具有通过 GRK2 调节治疗人类 RA 的治疗潜力。EP4受体激动剂刺激增加了GRK2和EP4受体之间的关联。GRK2 敲低消除了 FLS 增殖的异常。CP-25 治疗（100 mg/kg）以与甲氨蝶呤相似的功效抑制关节炎症。这一发现与 FLS 中 EP4 上调和 GRK2 下调有关。因此，GRK2可能通过促进EP4受体脱敏和降低cAMP水平在AA中观察到的异常FLS增殖中起重要作用。我们的研究结果表明，CP-25 具有通过 GRK2 调节治疗人类 RA 的治疗潜力。这一发现与 FLS 中 EP4 上调和 GRK2 下调有关。因此，GRK2可能通过促进EP4受体脱敏和降低cAMP水平在AA中观察到的异常FLS增殖中起重要作用。我们的研究结果表明，CP-25 具有通过 GRK2 调节治疗人类 RA 的治疗潜力。这一发现与 FLS 中 EP4 上调和 GRK2 下调有关。因此，GRK2可能通过促进EP4受体脱敏和降低cAMP水平在AA中观察到的异常FLS增殖中起重要作用。我们的研究结果表明，CP-25 具有通过 GRK2 调节治疗人类 RA 的治疗潜力。

更新日期：2019-05-16

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