Interleukin-23 is sufficient to induce rapid de novo legut tumorigenesis, independent of carcinogens, through activation of innate lymphoid cells
Interleukin-23 is sufficient to induce rapid de novo legut tumorigenesis, independent of carcinogens, through activation of innate lymphoid cells
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DOI：
10.1038/mi.2013.101
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发表时间：
2014-07-01
影响因子：
8
通讯作者：
LaFace, D.
中科院分区：
文献类型：
--
作者：
Chan, I. H.;Jain, R.;LaFace, D.
慢性炎症与罹患胃肠道癌症的风险增加有关。白介素 23 (IL-23) 受体信号传导与炎症性肠病发病机制以及促进肿瘤生长相关。然而，人们对 IL-23 介导的肠道肿瘤发生中的因果关系的相对潜力知之甚少。我们报告说，IL-23 转基因表达足以诱导肠腺瘤快速（3-4 周）从头发展，发病率为 100%。肿瘤发生的起始与外源性致癌物、螺杆菌定植或预先存在的肿瘤抑制基因突变无关。肿瘤发生是由 Thy1(+)IL-23R(+) 先天淋巴细胞 (ILC3) 介导的，部分是通过 IL-17 反应介导的，因为在 RAG(-/-) x IL-17(-/-) 双敲除小鼠中肿瘤发展受到抑制。值得注意的是，IL-23 常驻 ILC 引发的肿瘤发生始终发生在招募明显的炎症浸润之前。我们的结果揭示了 IL-23 介导的肠道肿瘤发生起始的明确作用，并暗示在没有明显的细胞浸润招募的情况下 IL-23R+ILC3 的关键作用。
Chronic inflammation has been associated with increased risk for developing gastrointestinal cancer. Interleukin-23 (IL-23) receptor signaling has been correlated with inflammatory bowel disease pathogenesis, as well as promotion of tumor growth. However, little is known about the relative potential for IL-23-directed causality in gut tumorigenesis. We report that IL-23 transgene expression was sufficient to induce rapid (3-4 weeks) de novo development of intestinal adenomas with 100% incidence. Initiation of tumorigenesis was independent of exogenous carcinogens, Helicobacter colonization, or pre-existing tumor-suppressor gene mutations. Tumorigenesis was mediated by Thy1(+)IL-23R(+) innate lymphoid cells (ILC3), in part, through IL-17 responses as tumor development was inhibited in RAG(-/-) x IL-17(-/-) double knockout mice. Remarkably, IL-23 initiation of tumorigenesis by resident ILCs consistently occurred before recruitment of conspicuous inflammatory infiltrates. Our results reveal an explicit role for IL-23-mediated initiation of gut tumorigenesis and implicate a key role for IL-23R+ILC3 in the absence of overt cellular infiltrate recruitment.