title: Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice.
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: Department of Biochemistry and Molecular Biology, The McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.
authors: Jennifer Nancy
authors: JN
authors: Hahn
authors: Vincent George
authors: VG
authors: Falck
authors: Frank Robert
authors: FR
authors: Jirik
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005770:Gastrointestinal Neoplasms / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D017370:Interleukin-11 / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007417:Intestinal Polyps / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051901:Smad4 Protein / Q000172:deficiency* / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D017370:Interleukin-11; D053583:Interleukin-1beta; D015850:Interleukin-6; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha