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The Role of RNase-L in Intestinal Homeostasis and Disease.

机译：RNase-L在肠道稳态和疾病中的作用。

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摘要

The Type I interferons are critical mediators of antimicrobial function and cell turnover. Increasingly, IFN has been demonstrated to have a vital role in the maintenance of intestinal homeostasis and protection from inflammatory bowel disease (IBD). RNase-L is a downstream mediator of IFN function that also induces a positive feedback mechanism through innate immune receptors to amplify IFN levels. RNase-L is widely accepted as an antiviral protein and its antibacterial functions have recently been elucidated. The goal of this work was to investigate the role of RNase-L in gastrointestinal (GI) diseases to discover new therapeutic targets with translational potential. First, the role of RNase-L in experimental colitis and colitis-associated cancer was investigated. Next, the role of IFN expression and RNase-L activity following infection with a diarrheal agent that causes mortality in infants, Enteropathogenic Escherichia coli (EPEC), was determined. Vital roles for IFN and RNase-L in intestinal inflammatory disease and infection were identified. Results demonstrated that RNase-L is protective against injury-induced colitis through regulation of the immune response including increased IFN expression, and that RNase-L inhibits tumor growth in experimental colitis-associated cancer (CAC). Antibacterial function against EPEC by IFN and RNase-L were also demonstrated. IFN signaling was found to have a critical role in intestinal epithelial cell (IEC) homeostasis and protection against EPEC infection. Furthermore, RNase-L was necessary to prevent translocation of EPEC across the IEC barrier. Supporting a protective role for IFN and RNase-L, secreted EPEC effectors inhibited IFN expression and RNase-L activity. Results indicate that IFN and RNase-L are important mediators of intestinal homeostasis with protective roles against infection and inflammatory disease.
机译：I型干扰素是抗微生物功能和细胞更新的关键介质。越来越多地证明了IFN在维持肠道动态平衡和预防炎症性肠病（IBD）中起着至关重要的作用。 RNase-L是IFN功能的下游介体，它也通过先天性免疫受体诱导正反馈机制，以放大IFN水平。 RNase-L被广泛接受为一种抗病毒蛋白，最近已阐明了其抗菌功能。这项工作的目的是调查RNase-L在胃肠道（GI）疾病中的作用，以发现具有翻译潜力的新治疗靶标。首先，研究了RNase-L在实验性结肠炎和结肠炎相关癌症中的作用。接下来，确定了引起腹泻的感染性腹泻剂感染肠炎性大肠杆菌（EPEC）后IFN表达和RNase-L活性的作用。鉴定了IFN和RNase-L在肠道炎性疾病和感染中的重要作用。结果表明，RNase-L可通过调节免疫应答（包括增加的IFN表达）来保护损伤性结肠炎，并且RNase-L抑制实验性结肠炎相关癌症（CAC）中的肿瘤生长。还证实了IFN和RNase-L对EPEC的抗菌功能。发现IFN信号传导在肠上皮细胞（IEC）稳态和防止EPEC感染中具有关键作用。此外，RNase-L是必要的，以防止EPEC跨IEC屏障移位。支持IFN和RNase-L的保护作用，分泌的EPEC效应子抑制IFN表达和RNase-L活性。结果表明，IFN和RNase-L是肠道稳态的重要介体，对感染和炎性疾病具有保护作用。

著录项

  • 作者

    Long, Tiha M.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Molecular biology.;Microbiology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 172 p.
  • 总页数 172
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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