摘要
背景:炎症性肠病(IBD)是一种肠道自身免疫性疾病,具有不良临床结局,目前其生物治疗的靶点主要为促炎细胞因子。白细胞介素-23(IL-23)是近期被关注的重要促炎细胞因子,临床试验显示针对IL-23亚基的单抗类药物可能使IBD患者获益。目的:应用结肠炎小鼠模型,尝试采用RNA干扰抑制IL-23表达,验证其治疗作用并探讨可能的作用机制。方法:使用三硝基苯磺酸(TNBS)灌肠建立结肠炎小鼠模型。模型动物分别经尾静脉注射IL-23p19 shRNA慢病毒和对照shRNA慢病毒,同时设立不予干预的模型对照组。2周后行疾病活动指数和结肠组织炎症活动度评分,采集血清和结肠组织检测IL-23、IL-17、肿瘤坏死因子-α(TNF-α)表达水平,并检测结肠组织Th17细胞数量。结果:IL-23 p19 RNA干扰治疗能显著降低结肠炎临床和组织学活动度(P <0. 05),有效抑制IL-23表达(P <0. 05),减少结肠组织中的Th17细胞数量(P <0. 05),进而降低血清和结肠组织IL-17、TNF-α表达水平(P <0. 05)。结论:以RNA干扰抑制IL-23表达对结肠炎小鼠模型具有治疗作用,其机制在于抑制Th17细胞及其效应细胞因子IL-17表达。
Background:Inflammatory bowel disease(IBD)is an autoimmune bowel disease with poor clinical outcome.Proinflammatory cytokines are the main targets of biological therapies.Interleukin-23(IL-23)is a key factor in IBD pathogenesis.Monoclonal antibodies against subunit of IL-23 have been reported to have therapeutic effects.Aims:To investigate the therapeutic effect of IL-23 RNA interference in mice with experimental colitis and the underlying mechanism.Methods:2,4,6-trinitrobenzenesulfonic acid(TNBS)enema was used to induce experimental colitis in mice,which were then injected with IL-23 p19 shRNA lentivirus or control shRNA lentivirus through caudal vein.Mice without lentivirus injection were served as model controls.After 2 weeks,disease activity index and histopathological inflammatory score,serum and colon tissue IL-23,IL-17 and tumor necrosis factor-α(TNF-α) expressions,as well as colon tissue Th17 cells were detected and compared.Results:IL-23 p19 shRNA therapy significantly reduced disease activity index and histopathological inflammatory score in mice with experimental colitis(P<0.05).By inhibiting IL-23 expression,IL-23 p19 shRNA suppressed further the colon tissue Th17 cells and subsequently reduced systemic and colon tissue IL-17 and TNF-αexpressions significantly(P<0.05).Conclusions:IL-23 RNA interference has therapeutic effect in mice with experimental colitis.The mechanism lies in suppression of Th17 cells and its effector cytokine IL-17.
作者
任渝棠
姜泊
林欣
REN Yutang;JIANG Bo;LIN Xin(Institue for Immunology,School of Medicine,Tsinghua University,Beijing 100084;Department of Gastroenterology,Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University,School of Clinical Medicine,Tsinghua University,Beijing)
出处
《胃肠病学》
2019年第1期10-16,共7页
Chinese Journal of Gastroenterology
基金
北京市医院管理局青年人才培养"青苗"计划(QML20160903)