Department of Biochemistry and Molecular Biology, The McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.
J Clin Invest. 2011 Oct;121(10):4030-42. doi: 10.1172/JCI45114. Epub 2011 Sep 1.
While there is evidence that specific T cell populations can promote the growth of established tumors, instances where T cell activity causes neoplasms to arise de novo are infrequent. Here, we employed two conditional mutagenesis systems to delete the TGF-β signaling pathway component Smad4 in T cells and observed the spontaneous development of massive polyps within the gastroduodenal regions of mice. The epithelial lesions contained increased levels of transcripts encoding IL-11, IL-6, TGF-β, IL-1β, and TNF-α, and lamina propria cells isolated from lesions contained abundant IL-17A+CD4+ T cells. Furthermore, we found that Smad4 deficiency attenuated TGF-β-mediated in vitro polarization of FoxP3+CD4+ T cells, but not IL-17A+CD4+ T cells, suggesting that the epithelial lesions may have arisen as a consequence of unchecked Th17 cell activity. Proinflammatory cytokine production likely accounted for the raised levels of IL-11, a cytokine known to promote gastric epithelial cell survival and hyperplasia. Consistent with IL-11 having a pathogenic role in this model, we found evidence of Stat3 activation in the gastric polyps. Thus, our data indicate that a chronic increase in gut Th17 cell activity can be associated with the development of premalignant lesions of the gastroduodenal region.
虽然有证据表明特定的 T 细胞群体可以促进已建立的肿瘤生长，但 T 细胞活性导致新的肿瘤发生的情况很少见。在这里，我们使用两种条件性突变系统在 T 细胞中删除 TGF-β 信号通路成分 Smad4，并观察到小鼠胃十二指肠区域内大量息肉的自发形成。上皮病变中含有高水平编码 IL-11、IL-6、TGF-β、IL-1β 和 TNF-α 的转录本，从病变中分离出的固有层细胞含有丰富的 IL-17A+CD4+T 细胞。此外，我们发现 Smad4 缺失减弱了 TGF-β 介导的体外 FoxP3+CD4+T 细胞的极化，但不能减弱 IL-17A+CD4+T 细胞的极化，这表明上皮病变可能是由于 Th17 细胞活性失控引起的。促炎细胞因子的产生可能导致 IL-11 水平升高，IL-11 是一种已知能促进胃上皮细胞存活和增生的细胞因子。与 IL-11 在该模型中具有致病性作用一致，我们发现胃息肉中存在 Stat3 激活的证据。因此，我们的数据表明，肠道 Th17 细胞活性的慢性增加可能与胃十二指肠区域的癌前病变的发展有关。
