The molecular pathogenesis of STAT3‐driven gastric tumourigenesis in mice is independent of IL‐17
- 10 May 2011
- journal article
- research article
- Published by Wiley in The Journal of Pathology
- Vol. 225 (2), 255-264
- https://doi.org/10.1002/path.2933
Abstract
Chronic activation of the gastric mucosal adaptive immune response is a characteristic trait of gastric cancer. It has recently emerged that a new class of T helper (Th) cells, defined by their ability to produce interleukin (IL)-17A (Th17), is associated with a host of inflammatory responses, including gastritis. However, the role of these Th17 cells in the pathogenesis of gastric cancer is less clear. To formally address this, we employed gp130F/F mice, which spontaneously develop gastric inflammation-associated tumours akin to human intestinal-type gastric cancer. At the molecular level, these tumours demonstrate hyper-activation of the latent transcription factor signal transducer and activator of transcription (STAT)3 via the IL-6 cytokine family member, IL-11. In gp130F/F mice, the generation of Th17 cells, as well as the gastric expression of IL-17a and other Th17-related factors (Rorγt, IL-23), were augmented compared to wild-type gp130+/+ mice. Consistent with a role for IL-6 and STAT3 in regulating IL-17A, increased Th17 generation and gastric expression of Th17-related factors in gp130F/F mice were reduced to wild-type levels in gp130F/F:Stat3−/+ mice displaying normalized STAT3 activity, and also in gp130F/F:IL-6−/− mice. Importantly, genetic ablation of IL-17A in gp130F/F:IL-17a−/− mice did not suppress the initiation and growth of gastric tumours. Furthermore, IL-17A and RORC gene expression was strongly increased in human gastric biopsies from patients with gastritis, but not gastric cancer. Collectively, our data suggest that increased expression of Th17-related factors does not correlate with the molecular pathogenesis of gastric tumourigenesis.# Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.Keywords
Funding Information
- NHMRC
- Association for International Cancer Research
- Cancer Council of Victoria
This publication has 50 references indexed in Scilit:
- Up for Mischief? IL-17/Th17 in the tumour microenvironmentOncogene, 2010
- IL‐6: Regulator of Treg/Th17 balanceEuropean Journal of Immunology, 2010
- The IL-17 Family Cytokines in Immunity and DiseaseJournal of Clinical Immunology, 2010
- Precarious Balance: Th17 Cells in Host DefenseInfection and Immunity, 2010
- IL-17 and Th17 CellsAnnual Review of Immunology, 2009
- The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17–producing effector T helper cells in vivoNature Immunology, 2009
- Cutting Edge: IL-21 Is Not Essential for Th17 Differentiation or Experimental Autoimmune EncephalomyelitisPublished by The American Association of Immunologists ,2008
- IL-21 initiates an alternative pathway to induce proinflammatory TH17 cellsNature, 2007
- Inflammation, atrophy, and gastric cancerJCI Insight, 2006
- Gastic cancerThe Lancet, 2003