The molecular pathogenesis of STAT3-driven gastric tumourigenesis in mice is independent of IL-17

Catherine L. Kennedy, Meri Najdovska, Gareth Wyn Jones, Louise McLeod, Norman R. Hughes, Cody Allison, Chia Huey Ooi, Patrick Tan, Richard L. Ferrero, Simon Arnett Jones, Anouk Dev, William Sievert, Prithi S. Bhathal, Brendan J. Jenkins

Research output: Contribution to journalArticle (Academic Journal)peer-review

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 (Rort, 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.
Original languageUndefined/Unknown
Pages (from-to)255-264
Number of pages10
JournalJournal of Pathology
Volume225
Issue number2
Publication statusPublished - 2011

Keywords

  • gastritis, gastric cancer, gp130, IL-6, IL-17A, STAT3

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