Inhibitory effect of the antimalarial agent artesunate on collagen-induced arthritis in rats through nuclear factor kappa B and mitogen-activated protein kinase signaling pathway
Inhibitory effect of the antimalarial agent artesunate on collagen-induced arthritis in rats through nuclear factor kappa B and mitogen-activated protein kinase signaling pathway
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抗疟药青蒿琥酯通过核因子κB和丝裂原激活蛋白激酶信号通路对大鼠胶原性关节炎的抑制作用
DOI：
10.1016/j.trsl.2012.06.001
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发表时间：
2013-02-01
影响因子：
7.8
通讯作者：
Shen, Xiaoyan
中科院分区：
文献类型：
--
作者：
Li, Yanmei;Wang, Shaogui;Shen, Xiaoyan
最近的证据表明，抗疟疾药物青蒿琥酯(ART)具有免疫调节特性，可能有助于治疗类风湿性关节炎(RA)。然而，ART对RA动物模型的影响尚未被描述。本研究旨在评价ART的抗炎作用，并探讨其治疗大鼠II型胶原诱导性关节炎(CIA)的可能机制。以来氟米特(Leflunomide，LEF)和ART分别以10 mg/kg/d和5 mg/kg/d的剂量灌胃治疗大鼠关节炎，共16天。观察关节炎症严重程度、促炎细胞因子和抗炎细胞因子水平。检测基质金属蛋白酶-2和基质金属蛋白酶-9的表达和活性。研究了核因子-kappaB和丝裂原活化蛋白激酶信号通路在CIA大鼠和Raw264.7细胞中的激活情况。我们的结果表明，ART治疗显著减轻炎症症状，防止软骨和骨骼破坏。ART可降低促炎细胞因子IL-1β、肿瘤坏死因子-α和IL-17α的表达。ART可有效抑制MMP9的表达和活性。ART能显著抑制CIA大鼠和脂多糖刺激的Raw264.7细胞中I kappaB的降解以及细胞外信号调节蛋白和c-jun氨基末端蛋白的激活。本研究证明ART对大鼠CIA有改善作用。其抗炎作用可能是通过抑制核因子-kappaB和丝裂原活化蛋白激酶信号通路，从而抑制促炎细胞因子的作用和基质金属蛋白酶-9的活性而实现的。这些结果表明，ART可作为RA患者的辅助治疗。(《翻译研究》2013；161：89-98)
Recent evidence indicates that the antimalarial agent artesunate (ART) has immunomodulatory properties that may be useful for treating rheumatoid arthritis (RA). However, the effects of ART on the RA animal model have not been described. The current study aimed to evaluate the antiarthritic effect of ART and explore the potential mechanism on type II collagen-induced arthritis (CIA) in rats. From the day of arthritis onset, rats were treated daily by gavage with leflunomide (Lef) or ART at a dosage of 10 mg/kg/d or 5 mg/kg/d, respectively, for 16 days. The severity of arthritis and levels of pro- and anti-inflammatory cytokines in site were measured. The expression and activity of metalloproteinase (MMP)-2 and MMP-9 were determined. The activation of nuclear factor kappa B and mitogen-activated protein kinase signaling pathways was investigated in rats with CIA and in Raw264.7 cells. Our results showed that ART treatment significantly attenuated inflammation symptoms and prevented cartilage and bone destruction. ART decreased expression of the proinflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-17 alpha. Both expression and activity of MMP-9 were efficiently inhibited by ART. ART significantly inhibited the degradation of I kappa B and activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in rats with CIA and in lipopolysaccharide-stimulated Raw264.7 cells. The present study demonstrated that ART ameliorated rat CIA. The antiarthritic effect might be achieved by inhibiting the action of proinflammatory cytokines and the activity of MMP-9 via suppression of nuclear factor kappa B and mitogen-activated protein kinase signaling pathway. These results show that ART may be used as an adjuvant therapy for patients with RA. (Translational Research 2013;161:89-98)