Transgenic expression of interferon-γ in mouse stomach leads to inflammation, metaplasia, and dysplasia

Li Jyun Syu, Mohamad El-Zaatari, Kathryn A. Eaton, Zhiping Liu, Manas Tetarbe, Theresa M. Keeley, Joanna Pero, Jennifer Ferris, Dawn Wilbert, Ashley Kaatz, Xinlei Zheng, Xiotan Qiao, Marina Grachtchouk, Deborah L. Gumucio, Juanita L. Merchant, Linda C. Samuelson, Andrzej A. Dlugosz

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Gastric adenocarcinoma is one of the leading causes of cancer mortality worldwide. It arises through a stepwise process that includes prominent inflammation with expression of interferon-γ (IFN-γ) and multiple other pro-inflammatory cytokines. We engineered mice expressing IFN-γ under the control of the stomach-specific H+/K+ ATPase β promoter to test the potential role of this cytokine in gastric tumorigenesis. Stomachs of H/K-IFN-γ transgenic mice exhibited inflammation, expansion of myofibroblasts, loss of parietal and chief cells, spasmolytic polypeptide expressing metaplasia, and dysplasia. Proliferation was elevated in undifferentiated and metaplastic epithelial cells in H/K-IFN-γ transgenic mice, and there was increased apoptosis. H/K-IFN-γ mice had elevated levels of mRNA for IFN-γ target genes and the pro-inflammatory cytokines IL-6, IL-1β, and tumor necrosis factor-α. Intracellular mediators of IFN-γ and IL-6 signaling, pSTAT1 and pSTAT3, respectively, were detected in multiple cell types within stomach. H/K-IFN-γ mice developed dysplasia as early as 3 months of age, and 4 of 39 mice over 1 year of age developed antral polyps or tumors, including one adenoma and one adenocarcinoma, which expressed high levels of nuclear β-catenin. Our data identified IFN-γ as a pivotal secreted factor that orchestrates complex changes in inflammatory, epithelial, and mesenchymal cell populations to drive pre-neoplastic progression in stomach; however, additional alterations appear to be required for malignant conversion.

Original languageEnglish (US)
Pages (from-to)2114-2125
Number of pages12
JournalAmerican Journal of Pathology
Volume181
Issue number6
DOIs
StatePublished - Dec 2012
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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