Transgenic Expression of Interferon-γ in Mouse Stomach Leads to Inflammation, Metaplasia, and Dysplasia

Department of Dermatology, School of Medicine, University of Michigan, Ann Arbor, Michigan.
American Journal Of Pathology (Impact Factor: 4.59). 10/2012; 61(6). DOI: 10.1016/j.ajpath.2012.08.017
Source: PubMed


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 four 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.

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    • "A recent experiment employed a murine model that directly implicates IFN-γ in this course of preneoplastic change. The transgenic mice, which were engineered to overexpress IFN-γ from a stomach-specific, H/K ATPase β promoter, exhibited a prominent inflammatory infiltrate along with accelerated histological changes characteristic of a premalignant phenotype: metaplasia, loss of parietal and chief cells, gastric gland atrophy, and dysplasia beginning as early as 3 months of age (16). "
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    • "A, Hematoxylin-eosin (HE)–stained gastric sections from a mouse 3 weeks after dosing with SS1s1i1 in Brucella broth showing inflammatory infiltrate (asterisk), loss of specialized gland cells, and marked expansion of cells with foamy cytoplasm indicative of mucinous metaplasia (arrows). B, Periodic acid–Schiff (PAS)/Alcian blue staining on gastric sections from SS1s1i1-dosed mice after 3 weeks of infection confirmed the replacement of specialized gland cells with mucin-containing cells (blue-staining acid mucin and purple-staining neutral mucin), consistent with SPEM [36]. C, Sections from a mouse dosed with Brucella broth only. "
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    • "Expression of IFN-γ inhibited Th1 and Th17 immune responses through Fas induction and apoptosis of CD4 T cells, and evoked autophagy in gastric epithelial cells by increasing Beclin-1. These results were far different than the results observed in the above-described IFN-γ transgenic mice that spontaneously develop spasmolytic polypeptide expressing metaplasia and dysplasia.45 This discrepancy might be explained by differences in the amount of IFN-γ produced and the cytokine milieu in the mutant mouse lines. "
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