Zepp Jarod A, Zhao Junjie, Liu Caini, Bulek Katazyna, Wu Ling, Chen Xing, Hao Yujun, Wang Zhenghe, Wang Xinxin, Ouyang Wenjun, Kalady Matthew F, Carman Julie, Yang Wen-Pin, Zhu Jun, Blackburn Clare, Huang Yina H, Hamilton Thomas A, Su Bing, Li Xiaoxia
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195.
J Immunol. 2017 Dec 1;199(11):3849-3857. doi: 10.4049/jimmunol.1601540. Epub 2017 Oct 25.
This study identifies a novel mechanism linking IL-17A with colon tissue repair and tumor development. Abrogation of IL-17A signaling in mice attenuated tissue repair of dextran sulfate sodium (DSS)-induced damage in colon epithelium and markedly reduced tumor development in an azoxymethane/DSS model of colitis-associated cancer. A novel IL-17A target gene, PLET1 (a progenitor cell marker involved in wound healing), was highly induced in DSS-treated colon tissues and tumors in an IL-17RC-dependent manner. PLET1 expression was induced in LGR5 colon epithelial cells after DSS treatment. LGR5PLET1 marks a highly proliferative cell population with enhanced expression of IL-17A target genes. PLET1 deficiency impaired tissue repair of DSS-induced damage in colon epithelium and reduced tumor formation in an azoxymethane/DSS model of colitis-associated cancer. Our results suggest that IL-17A-induced PLET1 expression contributes to tissue repair and colon tumorigenesis.
本研究确定了一种将白细胞介素-17A（IL-17A）与结肠组织修复及肿瘤发展联系起来的新机制。在小鼠中消除IL-17A信号可减弱葡聚糖硫酸钠（DSS）诱导的结肠上皮损伤的组织修复，并显著减少结肠炎相关癌症的氧化偶氮甲烷/DSS模型中的肿瘤发展。一个新的IL-17A靶基因PLET1（一种参与伤口愈合的祖细胞标志物）在DSS处理的结肠组织和肿瘤中以依赖IL-17RC的方式被高度诱导。DSS处理后，LGR5结肠上皮细胞中诱导了PLET1表达。LGR5+PLET1标记了一个具有增强的IL-17A靶基因表达的高增殖细胞群。PLET1缺陷损害了DSS诱导的结肠上皮损伤的组织修复，并减少了结肠炎相关癌症的氧化偶氮甲烷/DSS模型中的肿瘤形成。我们的结果表明，IL-17A诱导的PLET1表达有助于组织修复和结肠肿瘤发生。
