BACKGROUND Proper blocking of toll-like receptor (TLR) activation during disease progression has been reported to have inhibitory effect on the pathogenesis of rheumatoid arthritis (RA). We tested whether the TLR4 inhibitor TAK-242 had potential as a remedy for rheumatoid arthritis. METHODS The therapeutic effect of TAK-242 was tested in vitro using the human rheumatoid fibroblast-like synoviocyte (FLS) line MH7A or primary human FLS and in an adjuvant-induced arthritis (AIA) rat model. RESULTS TAK-242 dose dependently inhibited the increased expression of IL-6, IL-8, MMP-1, and VEGF in LPS-stimulated MH7A cells. It also inhibited the expression of IL-6 and IL-8 in poly(I:C), TLR3 activator-stimulated primary FLS, but not in IL-1β-stimulated primary FLS. These findings suggest that TAK-242 blocks a specific signaling pathway to some degree. Further, TAK-242 slightly inhibited mobilization of NF-κB into nuclei. In the AIA rat model, TAK-242 significantly reversed the body weight and paw thickness of AIA rats to the normal state at a dose of 5 mg/kg, but not at 3 mg/kg, and reduced the increased serum level of IL-6 and VEGF in AIA rats. It also significantly ameliorated inflammatory symptoms of joint tissues at day 21 of treatment, according to histology and RT-PCR. CONCLUSIONS Based on the drug repositioning concept, TAK-242, which is used for the treatment of TLR4-mediated inflammatory diseases, shows potential for cost-effective development as a remedy for rheumatoid arthritis or to control the progression of RA.

中文翻译：

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Toll样受体（TLR）4抑制剂TAK-242作为一种潜在的抗类风湿关节炎药物的研究。

背景技术据报道，疾病进展过程中妥善阻断Toll样受体（TLR）的激活对类风湿关节炎（RA）的发病机理具有抑制作用。我们测试了TLR4抑制剂TAK-242是否具有作为类风湿关节炎的治疗剂的潜力。方法使用人类风湿性成纤维样滑膜细胞（FLS）MH7A或原代人FLS并在佐剂性关节炎（AIA）大鼠模型中体外测试TAK-242的治疗效果。结果TAK-242剂量依赖性抑制LPS刺激的MH7A细胞中IL-6，IL-8，MMP-1和VEGF的表达增加。它也抑制聚（I：C），TLR3激活剂刺激的原发性FLS中的IL-6和IL-8的表达，但不抑制IL-1β刺激的原发性FLS中的IL-6和IL-8的表达。这些发现表明TAK-242在某种程度上阻断了特定的信号传导途径。此外，TAK-242稍微抑制了NF-κB进入细胞核的动员。在AIA大鼠模型中，TAK-242以5 mg / kg的剂量将AIA大鼠的体重和脚掌厚度显着反转至正常状态，但未以3 mg / kg的剂量使它恢复正常状态，并降低了IL- AIA大鼠体内的6和VEGF。根据组织学和RT-PCR，在治疗的第21天，它还显着改善了关节组织的炎症症状。结论基于药物重新定位的概念，用于治疗TLR4介导的炎症性疾病的TAK-242具有潜在的成本效益，可作为类风湿性关节炎的药物或控制RA的发展。TAK-242以5 mg / kg的剂量将AIA大鼠的体重和脚掌厚度显着逆转至正常状态，但未以3 mg / kg的剂量将其恢复至正常状态，并降低了AIA大鼠的血清IL-6和VEGF升高的水平。根据组织学和RT-PCR，在治疗的第21天，它还显着改善了关节组织的炎症症状。结论基于药物重新定位的概念，用于治疗TLR4介导的炎症性疾病的TAK-242具有潜在的成本效益，可作为类风湿性关节炎的药物或控制RA的发展。TAK-242以5 mg / kg的剂量将AIA大鼠的体重和脚掌厚度显着逆转至正常状态，但未以3 mg / kg的剂量将其恢复至正常状态，并降低了AIA大鼠的血清IL-6和VEGF升高的水平。根据组织学和RT-PCR，在治疗的第21天，它还显着改善了关节组织的炎症症状。结论基于药物重新定位的概念，用于治疗TLR4介导的炎症性疾病的TAK-242具有潜在的成本效益，可作为类风湿性关节炎的药物或控制RA的发展。