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首页> 外文期刊>Digestive Diseases and Sciences >Dysregulated Up-Frameshift Protein 1 Promotes Ulcerative Colitis Pathogenesis Through the TNFR1-NF-B/MAPKs Pathway
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Dysregulated Up-Frameshift Protein 1 Promotes Ulcerative Colitis Pathogenesis Through the TNFR1-NF-B/MAPKs Pathway

机译：功能化的上帧蛋白1通过TNFR1-NF-B / MAPKS途径促进溃疡性结肠炎发病机制

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摘要

BackgroundUlcerative colitis (UC) is an idiopathic colonic mucosal disease, and its pathogenesis has not been fully understood. Up-frameshift protein 1 (UPF1) is a potential molecule for UC predicted by a computational approach.AimThe present study aimed to validate the underlying mechanism of UPF1 in UC.MethodsUPF1 expression was detected by qRT-PCR, western blotting, and immunohistochemistry in dextran sulfate sodium-induced colitis in mice. To simulate the intestinal inflammation microenvironment, NCM460 human colonic epithelial cells were exposed to a mixture of inflammatory mediators. The potential mechanism involving TNFR1-NF-B/MAPKs pathway activation was addressed by western blotting, reporter gene assays, and siRNA (siUPF1) or UPF1-expressing plasmid pENTER-transfected cells.ResultsUPF1 was downregulated in colonic epithelial cells of colitic mice, and in vitro, contrary to the mRNA levels of the associated cytokines enhanced in the UPF1 dysregulation group within stimulatory factors, most relevant cytokines were significantly decreased in UPF1 overexpression group. Mechanistically, the increased expression of tumor necrosis factor receptor 1 (TNFR1) was found in NCM460 cells pre-treated with siUPF1, with the activation of IKK/NF-B and MAPKs pathways, including JNK/AP-1 and P38, but not the ERK1/2 pathway. Moreover, the repression of TNFR1 required the interaction of UPF1 with the promoter.ConclusionUPF1, which negatively regulated the transcription of TNFR1, is a novel factor regulating intestinal inflammation. The downregulation of UPF1 activated the TNFR1-dependent NF-B/MAPKs pathway, and promoting inflammatory responses in colon might act as a causal role in UC.
机译：背景结肠炎（UC）是特发性结肠粘膜疾病，其发病机制尚未得到完全理解。上越帧蛋白质1（UPF1）是通过计算方法预测的UC的潜在分子。目前的研究旨在通过QRT-PCR，Western印迹和葡聚糖中的QRT-PCR，Western印迹和免疫组化检测UCF1中的UPF1的潜在机制硫酸钠诱导的小鼠结肠炎。为了模拟肠炎微环境，将NCM460人结肠上皮细胞暴露于炎症介质的混合物中。通过蛋白质印迹，报告基因测定和siRNA（SIUPF1）或UPF1表达质粒戊转染细胞进行解决涉及TNFR1-NF-B / MAPKS途径激活的潜在机制。胚胎小鼠的结肠上皮细胞中，培养量upf1是下调的，体外，与刺激因子中UPF1诱导组中增强的相关细胞因子的mRNA水平相反，大多数相关的细胞因子在UPF1过表达组中显着降低。机械地，在用Siupf1预处理的NCM460细胞中发现肿瘤坏死因子受体1（TNFr1）的增加，其激活IKK / NF-B和MAPKS途径，包括JNK / AP-1和P38，但不是ERK1 / 2路径。此外，TNFR1的抑制需要UPF1与启动子的相互作用。结论upF1，其负调节TNFR1的转录，是一种调节肠炎的新型因子。 UPF1的下调活化了TNFR1依赖性NF-B / MAPKS途径，促进结肠中的炎症反应可能在UC中作用。

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  • 来源
    《Digestive Diseases and Sciences》 |2018年第10期|共11页
  • 作者

    Zhu Huatuo; Huang Shujun; Yue Min; Chen Wenguo; Lu Chao; Lou Xinhe; Li Chunxiao; Shan Guodong; Chen Hongtan; Xu Xiaowei; Xu Guoqiang; Chen Lihua;

  • 作者单位

    Zhejiang Univ Affiliated Hosp 1 Coll Med Dept Gastroenterol 79 Qingchun Rd Hangzhou 310003;

    Zhejiang Univ Affiliated Hosp 1 Coll Med Dept Gastroenterol 79 Qingchun Rd Hangzhou 310003;

    Zhejiang Univ Affiliated Hosp 1 Coll Med Dept Gastroenterol 79 Qingchun Rd Hangzhou 310003;

    Zhejiang Univ Affiliated Hosp 1 Coll Med Dept Gastroenterol 79 Qingchun Rd Hangzhou 310003;

    Zhejiang Univ Affiliated Hosp 1 Coll Med Dept Gastroenterol 79 Qingchun Rd Hangzhou 310003;

    Zhejiang Univ Affiliated Hosp 1 Coll Med Dept Gastroenterol 79 Qingchun Rd Hangzhou 310003;

    Zhejiang Univ Affiliated Hosp 1 Coll Med Dept Gastroenterol 79 Qingchun Rd Hangzhou 310003;

    Zhejiang Univ Affiliated Hosp 1 Coll Med Dept Gastroenterol 79 Qingchun Rd Hangzhou 310003;

    Zhejiang Univ Affiliated Hosp 1 Coll Med Dept Gastroenterol 79 Qingchun Rd Hangzhou 310003;

    Zhejiang Univ Affiliated Hosp 1 Coll Med Dept Gastroenterol 79 Qingchun Rd Hangzhou 310003;

    Zhejiang Univ Affiliated Hosp 1 Coll Med Dept Gastroenterol 79 Qingchun Rd Hangzhou 310003;

    Zhejiang Univ Affiliated Hosp 1 Coll Med Dept Gastroenterol 79 Qingchun Rd Hangzhou 310003;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 消化系及腹部疾病;
  • 关键词

    Ulcerative colitis (UC); Up-frameshift mutant 1 (UPF1); Tumor necrosis factor receptor 1 (TNFR1); NF-B; MAPKs pathway;

    机译：溃疡性结肠炎（UC）;上帧突变体1（UPF1）;肿瘤坏死因子受体1（TNFR1）;NF-B;MAPKS途径;

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