Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia.
Int Immunopharmacol. 2020 Jul;84:106494. doi: 10.1016/j.intimp.2020.106494. Epub 2020 Apr 15.
Rheumatoid arthritis (RA) is an autoimmune disease classified by uncontrolled joint inflammation leading to the destruction of both cartilage and joints. Despite progress made in RA treatment in the past decade, new drugs with high efficacy and fewer long-term adverse effects are still needed; thus, safe anti-inflammatory therapies for RA are urgently needed. Previous results demonstrated that the CXCR3 antagonist is an extremely attractive therapeutic target for the treatment of several autoimmune diseases, suggesting that it might have an inhibitory effect on RA. In this study, we investigated the effect of AMG487, a selective CXCR3 antagonist, on collagen-induced arthritis (CIA) in mice and evaluated its potential therapeutic mechanism.Following induction of CIA, mice were treated with AMG487 (5 mg/kg, intraperitoneally), to investigate their protective effects against CIA. CD4, CD25, CCR6, IL-9, NF-κB, IL-6, IL-17A, IL-21, STAT6 and Foxp3 expressing GITR and CD45 cells were measured in the spleen using flow cytometry to assess anti-inflammatory effects of AMG487. The mRNA and protein expression of GITR, CCR6, IL-9, and IL-21 were measured using quantitative real-time PCR and western blot analysis in knee tissue. AMG487 significantly alleviated joint inflammation by decreasing GITRCD25, GITRCD45, GITRIL-9, GITRNF-κB CD45CD4, CD45CCR6, CD45IL-6 cells, CD45IL-17A, and CD45IL-21, and increasing GITRFoxp3 and GITRSTAT6 cells. There was a significant decrease in mRNA and protein expression of GITR, CD4, CCR6, IL-6, IL-9, and IL-21 in knee tissue of CIA mice. This study demonstrates that AMG487 has a potential therapeutic effect on RA and could explore novel anti-inflammatory therapies for its treatment.
类风湿关节炎（RA）是一种自身免疫性疾病，其特征为不受控制的关节炎症导致软骨和关节均遭到破坏。尽管在过去十年中，RA 的治疗取得了进展，但仍需要具有高效性和较少长期不良反应的新药；因此，迫切需要安全的 RA 抗炎疗法。先前的结果表明，CXCR3 拮抗剂是治疗几种自身免疫性疾病的极具吸引力的治疗靶标，这表明它可能对 RA 具有抑制作用。在这项研究中，我们研究了选择性 CXCR3 拮抗剂 AMG487 对胶原诱导性关节炎（CIA）小鼠的作用，并评估了其潜在的治疗机制。在 CIA 诱导后，用 AMG487（5mg/kg，腹腔内）处理小鼠，以研究其对 CIA 的保护作用。用流式细胞术测量脾脏中 CD4、CD25、CCR6、IL-9、NF-κB、IL-6、IL-17A、IL-21、STAT6 和 Foxp3 表达的 GITR 和 CD45 细胞，以评估 AMG487 的抗炎作用。用定量实时 PCR 和 Western blot 分析测量膝关节组织中 GITR、CCR6、IL-9 和 IL-21 的 mRNA 和蛋白表达。AMG487 通过减少 GITRCD25、GITRCD45、GITRIL-9、GITRNF-κB CD45CD4、CD45CCR6、CD45IL-6 细胞、CD45IL-17A 和 CD45IL-21，并增加 GITRFoxp3 和 GITRSTAT6 细胞，显著缓解了关节炎症。CIA 小鼠膝关节组织中 GITR、CD4、CCR6、IL-6、IL-9 和 IL-21 的 mRNA 和蛋白表达均显著降低。本研究表明 AMG487 对 RA 具有潜在的治疗作用，并可为其治疗探索新的抗炎疗法。
