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Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice
Jennifer Nancy Hahn, … , Vincent George Falck, Frank Robert Jirik
Jennifer Nancy Hahn, … , Vincent George Falck, Frank Robert Jirik
Published September 1, 2011
Citation Information: J Clin Invest. 2011;121(10):4030-4042. https://doi.org/10.1172/JCI45114.
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Research Article Gastroenterology

Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice

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Abstract

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.

Authors

Jennifer Nancy Hahn, Vincent George Falck, Frank Robert Jirik

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Figure 1

Hyperplastic gastric polyps in GB-Cre;Smad4fl/fl mice.

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Hyperplastic gastric polyps in GB-Cre;Smad4fl/fl mice.
   
(A) The upper...
(A) The upper digestive tract of 12- to 18-month-old Smad4fl/fl (WT) and GB-Cre;Smad4fl/fl (GB-Cre) mice, with the latter showing swelling at the gastroduodenal junction (arrows). Scale bar: 0.5 cm. (B) A representative GB-Cre antro-pyloric polyp (dash-lined box) and WT antro-pyloric region. Scale bars: 0.25 cm. (C–E) Antro-pyloric region of a WT mouse showing H&E staining and anti-TFF1 antibody reactivity (scale bars: 1,000 μm, 125 μm, and 500 μm, respectively). The pyloric junction (indicated by a dash-lined box in C), as well as a higher-magnification view of the antro-pyloric mucosa (D). Anti-TFF1 staining was limited to the gastric mucosa (E; arrow). (F–K) GB-Cre gastric lesion sections stained with H&E, anti-TFF1 antibody, or anti-PCNA antibody (scale bars: 1,000 μm [F], 250 μm [G], 500 μm [H], 40 μm [I–K]). A GB-Cre gastric polyp (F), with glands demonstrating elongation, branching, and dilation (G), as well as “side buds” (I; asterisks) containing abundant anti-PCNA antibody–reactive cells (J; black arrow indicates non-proliferating elongated gland; red arrows indicate proliferative side buds). Low-grade epithelial dysplasia was evident (K; arrows), as well as diffuse anti-TFF1 antibody staining of the polyp mucosa (H). Images are representative of 4–6 mice per group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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