Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis
Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis
复制标题
DOI：
10.3389/fimmu.2019.02632
复制
发表时间：
2019-11
影响因子：
7.3
通讯作者：
S. Mountford;A. Ringleb;R. Schwaiger;D. Mayr;S. Kobold;C. Dinarello;P. Bufler
中科院分区：
文献类型：
--
作者：
S. Mountford;A. Ringleb;R. Schwaiger;D. Mayr;S. Kobold;C. Dinarello;P. Bufler
炎症性肠病会增加患结肠癌的风险。白细胞介素（IL-）37通过减少全身和局部炎症，是先天免疫的基本抑制剂。IL-37蛋白在健康和患病的肠道和肝脏组织中表达。在这里，我们测试了人IL-37的转基因表达是否保护IL-10缺陷型（IL-10 KO）小鼠免受慢性结肠炎。将IL-37 tg小鼠与IL-10 KO小鼠杂交。纯合子IL-10 KO/IL-37 tg和IL-10 KO饮用2%葡聚糖硫酸钠（DSS）水5天以诱导轻度结肠炎。结肠癌的发生是由塞来昔布胃内给药触发的。终点是结肠炎的临床参数、LPS刺激的全血和经纯化的结肠标本中的细胞因子应答以及结肠活检的qPCR分析。通过组织学分析结肠炎症和腺瘤-癌的数量。在DSS诱导阶段，IL-10 KO和IL-10 KO/IL-37 tg小鼠由于轻度急性结肠炎而具有相似的体重减轻。从第115天开始，IL-10 KO/IL 37-tg小鼠的体重增加显著改善，尽管结肠长度相似。在离体LPS刺激后，与IL-10 KO小鼠相比，IL-10 KO/IL-37 tg的全血释放较少的IL-6、IL-17、IFNγ和TNFα，并且离体结肠培养物显示减少的IL-6产生，这两者都指示在IL-37的影响下减少的炎性病症。10只IL-10 KO小鼠中有6只发生结肠腺瘤和结肠癌。IL-10 KO/IL-37 tg小鼠结肠中仅检测到一个腺瘤而没有检测到癌。总之，IL-37转基因表达保护IL-10 KO小鼠免受结肠癌发生。目前尚不清楚IL-37是否具有直接的肿瘤抑制特性。
Inflammatory bowel disease increases the risk of developing colon cancer. Interleukin (IL-) 37 is a fundamental inhibitor of innate immunity by reducing systemic and local inflammation. IL-37 protein is expressed in healthy and diseased bowel and liver tissue. Here, we tested whether transgenic expression of human IL-37 protects IL-10 deficient (IL-10KO) mice from chronic colitis. IL-37tg mice were crossbred with IL-10KO mice. Homozygous IL-10KO/IL-37tg and IL10KO drank 2% dextran sulfate sodium (DSS) in water for 5 days to induce mild colitis. Colon carcinogenesis was triggered by intragastric administration of celecoxib. Endpoints were clinical parameters of colitis, cytokine responses in LPS-stimulated whole blood and explanted colon specimen and qPCR analysis of colon biopsies. Colon inflammation and number of adenoma—carcinoma were analyzed by histology. During the DSS-induction phase IL-10KO and IL-10KO/IL-37tg mice had a similar weight loss due to mild acute colitis. From day 115 there was a significantly improved weight gain in IL-10KO/IL37-tg mice, though colon length was similar. After ex vivo LPS stimulation whole blood of IL-10KO/IL-37tg compared to IL-10KO mice released less IL-6, IL-17, IFNγ, and TNFα and ex vivo colon cultures showed reduced IL-6 production both indicative of reduced inflammatory conditions under the influence of IL-37. Six out of 10 IL-10KO mice developed colon adenoma and carcinoma. Only one adenoma but no carcinoma was detected in colons of IL-10KO/IL-37tg mice. In conclusion, IL-37 transgene expression protects IL-10KO mice from colon carcinogenesis. It remains unclear whether IL-37 has direct tumor suppressing properties.