Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice
Open Access
- 3 October 2011
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 121 (10), 4030-4042
- https://doi.org/10.1172/jci45114
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.This publication has 97 references indexed in Scilit:
- Inflammation and Cancer: IL-6 and STAT3 Complete the LinkCancer Cell, 2009
- Non-Smad pathways in TGF-β signalingCell Research, 2008
- Inhibitory CD8+ T cells in autoimmune diseaseHuman Immunology, 2008
- Overexpression of Interleukin-1β Induces Gastric Inflammation and Cancer and Mobilizes Myeloid-Derived Suppressor Cells in MiceCancer Cell, 2008
- Specific Microbiota Direct the Differentiation of IL-17-Producing T-Helper Cells in the Mucosa of the Small IntestineCell Host & Microbe, 2008
- TGF-β: A Master of All T Cell TradesCell, 2008
- Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell ProgramsImmunity, 2008
- TGFβ1 and Treg cells: alliance for toleranceTrends in Molecular Medicine, 2007
- Smad-dependent and Smad-independent pathways in TGF-β family signallingNature, 2003
- Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory diseaseNature, 1992