Exploring a novel triptolide derivative possess anti-colitis effect via regulating T cell differentiation
Exploring a novel triptolide derivative possess anti-colitis effect via regulating T cell differentiation
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DOI：
10.1016/j.intimp.2021.107472
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发表时间：
2021-02-18
影响因子：
5.6
通讯作者：
Zhang, Tiantai
中科院分区：
文献类型：
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作者：
Fu, Junmin;Zang, Yingda;Zhang, Tiantai
炎症性肠病（IBD）通常以胃肠道慢性炎症性疾病为特征，称为溃疡性结肠炎（UC）或克罗恩病（CD）。尽管IBD的潜在作用机制尚不清楚，并且由于缺乏令人满意的治疗方法，但越来越多的证据表明，激活JAK-STAT信号通路的促炎细胞因子可调节幼稚T细胞向辅助性T细胞（Th）1和Th17细胞亚群的分化，并有助于IBD的发展。 ZT01是新获得的雷公藤甲素衍生物，具有强抗炎作用、低毒性。在这项研究中，我们评估了 ZT01 对 DSS 诱导的结肠炎的作用，并研究了其潜在的作用机制。使用DSS诱导的急性或慢性结肠炎小鼠评估ZT01治疗的疗效，培养T细胞并通过流式细胞术分析Th1和Th17细胞的分化。此外，还测量了肠上皮屏障功能、巨噬细胞极化、JAK-STAT信号通路的激活以及细胞因子和转录因子的表达，以评估ZT01的可能机制。我们发现ZT01对DSS诱导的结肠炎有明显的有益作用，可以改善血性腹泻、体重减轻和结肠缩短的症状，从而保留小鼠结肠的上皮屏障功能。此外，ZT01 通过调节 JAK-STAT 信号通路显着抑制 T 细胞分化为 Th1 和/或 Th17 细胞亚群以及巨噬细胞极化为炎症表型。因此，我们的研究结果表明，ZT01 可能是一种潜在的候选药物，值得进一步研究作为 IBD 患者的治疗方法。
Inflammatory bowel disease (IBD) is generally characterized by chronic inflammatory disorders of the gastrointestinal tract that are known as ulcerative colitis (UC) or Crohn?s disease (CD). Although the underlying mechanism of action of IBD is unclear and because of the lack of satisfactory treatment, increasing evidence has indicated that pro-inflammatory cytokines that activate JAK-STAT signaling pathway regulate the differentiation of na?ve T cells towards T helper (Th)1 and Th17 cell subsets and contribute to the development of IBD. ZT01 is a newly obtained triptolide derivative with strong anti-inflammatory effects and low toxicity. In this study, we evaluated the effects of ZT01 on DSS-induced colitis and investigated the underlying mechanism of action involved. Mice with DSS-induced acute or chronic colitis were used to assess the efficacy of ZT01 treatment, and T cells were cultured to analyze the differentiation of Th1 and Th17 cell by flow cytometry. In addition, intestinal epithelial barrier function, macrophage polarization, activation of the JAK-STAT signaling pathway, and the expression of cytokines and transcription factors were measured to assess the possible mechanisms of ZT01. We found that ZT01 had an obviously beneficial effect on DSS-induced colitis by improving the symptoms of bloody diarrhea, weight loss, and a shortened colon, thereby preserving the epithelial barrier function in the mouse colon. Furthermore, ZT01 significantly inhibited T cell differentiation into Th1 and/or Th17 cell subsets and macrophage polarization towards into an inflammatory phenotype via regulating the JAK-STAT signaling pathway. Thus, our findings suggested that ZT01 might be a potential pharmaceutical candidate that deserves to be further investigated as a treatment for IBD patients.