Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China; Translational Gastroenterology Research Unit, GIGA-R, University of Liège, Belgium.
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China; Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, Hubei, PR China.
Int Immunopharmacol. 2019 May;70:88-100. doi: 10.1016/j.intimp.2019.02.022. Epub 2019 Feb 20.
AZD8055, a new immunosuppressive reagent, a dual TORC1/2 inhibitor, had been used successfully in animal models for heart transplantation. The aim of this study was to evaluate the effects and mechanisms of AZD8055 on chronic intestinal inflammation.
Dextran sulfate sodium (DSS) - induced chronic colitis was used to investigate the effects of AZD8055 on the development of colitis. Colitis activity was monitored by body weight assessment, colon length, histology and cytokine profile analysis.
AZD8055 treatment significantly alleviated the severity of colitis, as assessed by colonic length and colonic damage. In addition, AZD8055 treatment decreased the colonic CD4+ T cell numbers and reduced both Th1 and Th17 cell activation and cytokine production. The percentages of Treg cells in the colon were also expanded by AZD8055 treatment. Furthermore, AZD8055 effectively inhibited mTOR downstream proteins and signal transducer and activator of transcription related proteins in CD4+ T cells of intestinal lamina propria.
These findings increased our understanding of DSS-induced colitis and shed new lights on mechanisms of digestive tract chronic inflammation. Dual TORC1/2 inhibition showed potent anti-inflammatory and immune regulation effects by targeting critical signaling pathways. The results supported the strategy of using dual mTOR inhibitor to treat inflammatory bowel disease.
AZD8055 是一种新型免疫抑制剂，是一种双重 TORC1/2 抑制剂，已成功应用于心脏移植的动物模型中。本研究旨在评估 AZD8055 对慢性肠道炎症的作用和机制。
使用葡聚糖硫酸钠（DSS）诱导的慢性结肠炎来研究 AZD8055 对结肠炎发展的影响。通过体重评估、结肠长度、组织学和细胞因子谱分析来监测结肠炎的活动。
AZD8055 治疗显著减轻了结肠炎的严重程度，表现在结肠长度和结肠损伤方面。此外，AZD8055 治疗减少了结肠 CD4+T 细胞数量，并降低了 Th1 和 Th17 细胞的激活和细胞因子的产生。AZD8055 治疗还扩增了结肠中的 Treg 细胞比例。此外，AZD8055 还能有效地抑制 mTOR 下游蛋白和信号转导和转录激活剂相关蛋白在肠道固有层 CD4+T 细胞中的活性。
这些发现加深了我们对 DSS 诱导的结肠炎的认识，并为消化道慢性炎症的机制提供了新的见解。双重 TORC1/2 抑制通过靶向关键信号通路显示出强大的抗炎和免疫调节作用。这些结果支持使用双重 mTOR 抑制剂治疗炎症性肠病的策略。
