Department of Nephrology, The General Hospital of Jinan Military Command, Jinan, China.
Int Immunopharmacol. 2013 Nov;17(3):489-94. doi: 10.1016/j.intimp.2013.07.015. Epub 2013 Aug 11.
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) plays an important role in inflammation. However, the role of 11β-HSD1 in rheumatoid arthritis (RA) remains unknown. The purpose of this study was to evaluate the therapeutic effects of a selective 11β-HSD1 inhibitor BVT-2733 in collagen-induced arthritis (CIA) and its underlying mechanisms. CIA mice were treated with BVT-2733 (100 mg/kg, orally) or vehicle twice daily for 2 weeks. Arthritis score and joint histology were investigated. The levels of pro-inflammatory cytokines as well as anti-type II collagen antibody (anti-CII) were detected by ELISA. Western blot analysis was used to assess the activation of NF-κB and NLRP1 inflammasome in joint tissues and in human RA synovial cells. BVT-2733 treatment attenuated the arthritis severity and anti-CII level in CIA mice. BVT-2733 also decreased the levels of serum TNF-α, IL-1β, IL-6 and IL-17. BVT-2733 treatment also significantly reduced synovial inflammation and joint destruction. NF-κB activation and NLRP1 inflammasome assembly were also inhibited in arthritic joints and human RA synovial cells. In conclusion, BVT-2733 exhibits an anti-inflammatory effect on CIA. This protective effect is, at least partly, mediated by inhibition of the NF-κB and NLRP1 inflammasome signaling pathways. 11β-HSD1 inhibition may represent a potential therapeutic target for RA patients.
11β-羟类固醇脱氢酶 1（11β-HSD1）在炎症中发挥重要作用。然而，11β-HSD1 在类风湿关节炎（RA）中的作用尚不清楚。本研究旨在评估选择性 11β-HSD1 抑制剂 BVT-2733 在胶原诱导性关节炎（CIA）中的治疗效果及其潜在机制。CIA 小鼠每天两次口服 BVT-2733（100mg/kg）或载体 2 周。检测关节炎评分和关节组织学。通过 ELISA 检测促炎细胞因子和抗 II 型胶原抗体（抗-CII）的水平。Western blot 分析用于评估 NF-κB 和 NLRP1 炎性体在关节组织和人 RA 滑膜细胞中的激活。BVT-2733 治疗可减轻 CIA 小鼠的关节炎严重程度和抗 CII 水平。BVT-2733 还降低了血清 TNF-α、IL-1β、IL-6 和 IL-17 的水平。BVT-2733 治疗还显著减少了滑膜炎症和关节破坏。NF-κB 激活和 NLRP1 炎性体组装也在关节炎关节和人 RA 滑膜细胞中受到抑制。总之，BVT-2733 对 CIA 具有抗炎作用。这种保护作用至少部分是通过抑制 NF-κB 和 NLRP1 炎性体信号通路介导的。11β-HSD1 抑制可能代表 RA 患者的潜在治疗靶点。
