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Role of T-cell Produced Interleukin-10 in the Control of Polyp Growth in the Small Intestine Versus Colon.

机译:T细胞产生的白介素10在控制小肠对结肠息肉生长中的作用。

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摘要

Interleukin (IL)-10 is elevated in colon cancer and can promote tumor growth by inhibiting anti-tumor immunity, or it can suppress progression by limiting excessive tumor-promoting inflammation. Patients with a mutation to the adenomatous polyposis coli (APC) gene develop familial adenomatous polyposis, a syndrome in which hundreds of pre-cancerous polyps form in the colon, strongly predisposing the patient to colon cancer.;Mouse models with a defective allele of APC are used to study colon cancer. Murine polyposis requires local inflammatory reactions and is associated with elevated levels of IL-10. We tested the role of CD4+ T-cell-produced IL-10 in small intestinal and colonic polyposis by rendering APCDelta468 mice defective for CD4+ T-cell-produced IL-10. Our studies have found that elevated levels of IL-10 are protective. Loss of IL-10 leads to decreased anti-tumor immunity and worse disease outcome.;We found that CD4+ T-cells are the major producers of IL-10 in the intestinal mucosa, and that the frequency of these cells is elevated in polyposis. In addition, we found that CD4+ T-cell production of IL-10 was critically required for the increase in tissue levels of IL-10 associated with polyposis.;Loss of T-cell IL-10 led to increased intra-polyp bacterial load and focal inflammation in the colon, significantly increasing polyp frequencies. Antibiotic treatment prevented this effect. In the same mice, small intestinal polyps had delayed growth compared to IL-10-proficient mice, however the polyps progressed to cancer. Small intestinal polyps differed from colonic polyps in the type of focal inflammation, and their growth was resistant to antibiotics. Furthermore, the inability of T-cells to produce IL-10 hampered T-helper-1 (TH1) commitment of CD4+ T-cells and interrupted the duration of intra-polyp cytotoxic activity.;Our findings highlight a critical role of T-cell-produced IL-10 in the regulation of inflammation and polyposis in the small intestine and colon. Colonic polyposis is driven by intra-polyp inflammatory reactions, which are tuned by microbial communities within the polyps and by infiltrating T-cells. In contrast, T-helper responses and cytotoxic activity play major roles in regulating growth of polyps and controlling their transition to cancer in the small intestine, and expression of IL-10 by T-cells critically contributes to both.
机译:白细胞介素(IL)-10在结肠癌中升高,可以通过抑制抗肿瘤免疫力促进肿瘤生长,或者可以通过限制过度的促肿瘤炎症来抑制肿瘤进展。患有腺瘤性息肉病(APC)基因突变的患者会患上家族性腺瘤性息肉病,这种综合征会在结肠中形成数百个癌前息肉,从而很容易使患者患上结肠癌。用于研究结肠癌。小鼠息肉病需要局部炎症反应,并与IL-10水平升高有关。我们通过使APCDelta468小鼠对CD4 + T细胞产生的IL-10有缺陷,测试了CD4 + T细胞产生的IL-10在小肠和结肠息肉病中的作用。我们的研究发现,升高的IL-10水平具有保护作用。 IL-10的丧失导致抗肿瘤免疫力下降和疾病后果恶化。;我们发现CD4 + T细胞是肠粘膜中IL-10的主要产生者,息肉病中这些细胞的频率升高。此外,我们发现IL-10的CD4 + T细胞产生对于息肉病相关的IL-10组织水平的增加是至关重要的。; T细胞IL-10的丢失导致息肉内细菌负荷的增加和结肠局灶性炎症,息肉频率明显增加。抗生素治疗阻止了这种作用。在同一只小鼠中,小肠息肉与IL-10熟练小鼠相比,生长延迟,但是息肉发展为癌症。小肠息肉在局部炎症方面不同于结肠息肉,它们的生长对抗生素具有抗性。此外,T细胞无法产生IL-10阻碍了CD4 + T细胞的T-helper-1(TH1)承诺,并中断了息肉内细胞毒活性的持续时间。;我们的发现凸显了T细胞的关键作用产生的IL-10可调节小肠和结肠的炎症和息肉。结肠息肉是由息肉内炎症反应驱动的,息肉内炎症反应是由息肉内的微生物群落和浸润的T细胞调节的。相比之下,T辅助反应和细胞毒性活性在调节息肉的生长和控制小肠中的癌变过程中起主要作用,而T细胞表达IL-10则对两者均起关键作用。

著录项

  • 作者

    Dennis, Kristen Lynn.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Biology Genetics.;Health Sciences Immunology.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 214 p.
  • 总页数 214
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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