基于TLR4/MyD88/NF-κB信号轴探讨闹羊花毒素Ⅲ对类风湿关节炎的影响

刘笑蓉; 李硕夫; 刘湘丹; 王志辉; 曾娟; 周日宝

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刘笑蓉,李硕夫,刘湘丹,王志辉,曾娟,周日宝.基于TLR4/MyD88/NF-κB信号轴探讨闹羊花毒素Ⅲ对类风湿关节炎的影响[J].湖南中医药大学学报英文版,2023,43(6):992-998.[Click to copy ]

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基于TLR4/MyD88/NF-κB信号轴探讨闹羊花毒素Ⅲ对类风湿关节炎的影响

刘笑蓉,李硕夫,刘湘丹,王志辉,曾娟,周日宝

(湖南中医药大学, 湖南长沙 410208;湖南中医药大学第一附属医院, 湖南长沙 410007)

摘要:

目的本研究旨在探讨闹羊花毒素Ⅲ调控TLR4、MyD88和NF-κB的机制，以及闹羊花毒素Ⅲ对类风湿关节炎（rheumatoid arthritis, RA）的影响。方法 RA大鼠模型通过Ⅱ型胶原诱导构建。随机将Wistar大鼠分成6组（n=8）：假手术组（Sham组）、RA模型组（Model组）、阳性药物雷公藤组[TWG组，50 mg·（kg·d）^-1]、闹羊花毒素Ⅲ低剂量组[R-Ⅲ Lo组，0.06 mg·（kg·d）^-1]、中剂量[R-Ⅲ Mi组，0.12 mg·（kg·d）^-1]和高剂量组[R-Ⅲ Hi组，0.24 mg·（kg·d）^-1]。测定各组大鼠的关节炎指数（arthritis index, AI）；采用HE染色、ELISA、Western blot和RT-qPCR检测闹羊花毒素Ⅲ对TLR4/MyD88/NF-κB信号轴及RA的影响。结果与Model组比较，闹羊花毒素Ⅲ处理显著降低了RA大鼠的AI评分(P<0.05)。闹羊花毒素Ⅲ对滑膜组织的恶性增生和炎症细胞浸润有明显的抑制作用。与Model组比，闹羊花毒素Ⅲ各剂量组的TNF-α、IL-1β、IL-6、IL-17、VEGF、MMP-2、MMP-9、TLR4、MyD88、p-NF-κB/NF-κB因子的水平降低且呈浓度依赖性（P<0.05）。与TWG组比，R-Ⅲ Lo和R-Ⅲ Mi组的。TNF-α、IL-1β、IL-6、IL-17、VEGF、MMP-2、MMP-9、TLR4、MyD88、p-NF-κB/NF-κB因子的水平升高（P<0.05），而R-Ⅲ Hi组无显著差异（P>0.05）。结论闹羊花毒素Ⅲ可以通过下调TLR4、MyD88、NF-κB因子的表达水平来改善RA。本研究为利用闹羊花毒素Ⅲ治疗RA提供了一定的实验基础。

DOI：10.3969/j.issn.1674－070X.２０23.06.005

Received:November 09, 2022

基金项目:湖南省自然科学基金项目（2022JJ80086）；湖南省卫生健康委员会计划研究项目（D202302078705）；湖南省大学生创新创业训练计划项目（2022-5313）；湖南省教育厅科学研究项目（19C1384）；湖南省中医药管理局科研计划项目（2021161）；湖南中医药大学中药学一级学科开放基金项目（2020ZYX01）；湖南中医药大学青苗计划（校行人字〔2017〕25）；湖南省一流学科中药学（校行科字〔2018〕3）；2020年湖南省一流本科专业建设点（湘教通〔2020〕248号）：2020年国家级一流本科专业建设点（教高厅函〔2021〕7号）：中药学专业。

Effects of Rhodotoxin Ⅲ on rheumatoid arthritis based on TLR4/MyD88/NF-κB signal axis

LIU Xiaorong,LI Shuofu,LIU Xiangdan,WANG Zhihui,ZENG Juan,ZHOU Ribao

(Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China)

Abstract:

Objective To investigate the effects of rhodojaponin Ⅲ on rheumatoid arthritis (RA) by regulating toll-likereceptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa-B (NF-κB). Methods Type Ⅱ collagen was used to construct the RA rat model. Wistar rats were randomly divided into 6 groups, with 8 rats in each group: normal feeding group (sham group), RA model group (Model group), positive drug tripterygium wilfordii group [TWG group, 50 mg·(kg·d)^-1], low-dose Rhodojaponin Ⅲ group [R-Ⅲ Lo group, 0.06 mg·(kg·d)^-1], medium-dose group [R-Ⅲ Mi group, 0.12 mg·(kg·d)^-1], and high-dose group [Rhodojaponin Ⅲ Hi group, 0.24 mg·(kg·d)^-1]. The arthritis index (AI) of the rats was scored. Meanwhile, HE ELISA, Western blot, and real-time quantitative PCR (RT-qPCR) were used to detect the effects of Rhodojaponin Ⅲ on TLR4/MyD88/NF-κB signal axis and RA. Results Rhodojaponin Ⅲ significantly reduced the AI scores of RA rats compared with model group (P<0.05) and it effectively inhibited the development of malignant hyperplasia and inflammatory cell infiltration into synovial tissue. Meanwhile, compared with model group, the expresson levels of the tumor necrosis facor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-17 (IL-17), vascular endothelial growth factor (VEGF), matrix metallopeptidase-2 (MMP-2), matrix metallopeptidase-9 (MMP-9), TLR4, MyD88, and phosphor-nuclear factor-kappa-B (p-NF-κB)/NF-κB were reduced in R-Ⅲ Lo, Mi, and Hi groups (P<0.05). Compared with the TWG group, the levels of TNF-α, IL-1β, IL-6, IL-17, VEGF, MMP-2, MMP-9, TLR4, MyD88, p-NF-κB/NF-κB factors increased in the R-Ⅲ Lo and R-Ⅲ Mi groups (P<0.05), while no significant differences were observed in the R-Ⅲ Hi group (P>0.05). Conclusion Rhodojaponin Ⅲ can improve RA by down-regulating the expression levels of TLR4, MyD88, and NF-κB. This paper offered a solid experimental foundation for the use of Rhodojaponin Ⅲ in the treatment of RA.

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