IL-10 deficiency leads to somatic mutations in a model of IBD
IL-10 deficiency leads to somatic mutations in a model of IBD
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DOI：
10.1093/carcin/bgi327
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发表时间：
2006-05-01
期刊：
影响因子：
4.7
通讯作者：
Shimosegawa, T
中科院分区：
文献类型：
--
作者：
Sato, Y;Takahashi, S;Shimosegawa, T
患有炎症性肠病（IBD）的人患胃肠道癌的风险增加。在这里，我们测试了慢性炎症可能引发突变的可能性。为此，我们使用了 IL-10 缺陷型 (IL-10(-/-)) 小鼠，该小鼠自发产生肠道炎症，并结合转基因 gpt 基因和 red/gam 基因 (gpt(+)IL-10(-/-))，这是一个明确表征的突变报告基因座。 gpt(+)IL-10(-/-)小鼠结肠中的总突变频率比正常gpt(+)IL-10(+/+)小鼠高约5倍。在G:C到A:T转变的特定情况下，gpt(+)IL-10(-/-)小鼠的突变频率比对照小鼠高4.1倍。有趣的是，小缺失和插入的频率也显着增加（接近 10 倍）。大多数缺失或插入突变是在短串联序列的单调碱基运行或相邻重复中观察到的。相比之下，通过 red/gam 转基因中存在的 Spi 标记缺失检测到的大缺失频率在小鼠品系中是相似的。最后，作为对照，gpt(+)IL-10(-/-)小鼠和gpt(+)IL-10(+/+)小鼠之间非炎症组织（例如肝脏）的突变频率相似。我们的数据表明，结肠中的慢性炎症环境促进了突变的产生。
Individuals with inflammatory bowel disease (IBD) are at increased risk of developing gastrointestinal cancer. Here, we have tested the possibility that chronic inflammation could trigger mutations. For this, we have used IL-10-deficient (IL-10(-/-)) mice, which spontaneously develop intestinal inflammation, in combination with a transgenic gpt gene and red/gam gene (gpt(+)IL-10(-/-)), which is a well-characterized mutation reporter locus. The total mutation frequency in the colon of gpt(+)IL-10(-/-) mice was about five times higher than that in normal gpt(+)IL-10(+/+) mice. In the particular case of G:C to A:T transitions, the frequency of mutations in gpt(+)IL-10(-/-) mice was 4.1 times higher than that in control mice. Interestingly, the frequency of small deletions and insertions was also strikingly increased (similar to 10 times). The majority of the deletion or insertion mutations were observed in the monotonous base runs or adjacent repeats of short tandem sequences. In contrast, the frequency of large deletions, detected by loss of the Spi marker present in the red/gam transgene, was similar among the mouse strains. Finally, as a control, the mutation frequency in non-inflamed tissues, such as the liver, were similar between gpt(+)IL-10(-/-) mice and gpt(+)IL-10(+/+) mice. Our data demonstrate that the chronic inflammatory environment in the colon promotes the generation of mutations.