Interferon gamma induction of gastric mucous neck cell hypertrophy

Abstract

Chronic inflammation of the gastric epithelium is believed to induce mucosal changes that can eventually develop into gastric cancer. In gastrin-deficient (GÀ/À) mice exhibiting chronic inflammation in the hypochlorhydric stomach, we documented a prominent fundic mucous cell lineage sharing morphological similarity with preneoplastic changes reported in Helicobacter-infected mice. To study the identity and origin of this cell lineage, we screened for different gastric mucosal cell markers. The clusters of large, foamy cells stained for trefoil factor 2 (TFF2/SP), MUC6 and the lectin Griffonia Simplicifolia II (GSII), but not for the intestine-specific transcription factor Cdx2, suggested that they arise from gastric mucous neck cells. Ki67-labeled GSII-positive neck cells in Helicobacter felis-infected, but not GÀ/À stomachs, suggested that mucous neck cell proliferation accounted for expansion of this compartment in the H. felis model of gastritis, but not the GÀ/À model. Using RNase protection assays and quantitative PCR, we found that interferon gamma (IFNc) was the most abundant proinflammatory cytokine in the GÀ/À stomach. We also found that this Th1 cytokine can increase the abundance of mucous neck cells, since its infusion into mice recapitulated the appearance of these cells as observed in both GÀ/À and H. felis-infected mice. Using the human gastric cell line NCI-N87, we showed that IFNc induces the secretion of mucus and expression of MUC6, TFF2 and pepsinogen II, but not of pepsinogen I and intrinsic factor. In conclusion, our results demonstrate that inflammation, specifically the proinflammatory cytokine IFNc, induced expansion of the fundic mucous neck cell compartment, which likely represents both increased mucus production and cell number.

The CD4+ T Cell-Mediated IFN-γ Response to Helicobacter Infection Is Essential for Clearance and Determines Gastric Cancer Risk

“…Kang et al (54) found that the human gastric cell line NCI-N87 acquired mucous neck cell traits upon treatment with IFN-␥ such as secretion of mucus and expression of the mucin MUC6, TFF2, and pepsinogen II. Infusion of IFN-␥ into wildtype mice was further shown to induce expansion of the mucous neck cell compartment in vivo, probably by triggering the deregulated proliferation of this cell type (54).…”

Inflammation, atrophy, and gastric cancer

“…Third, deletion of the gene encoding the Th1 cytokine IFN-γ protects mice from gastric atrophy induced by infection with Helicobacter spp., whereas deletion of the gene encoding the Th2 cytokine IL-4 leads to more severe atrophic gastritis (75). Finally, infusion of IFN-γ into C57BL/6 mice can induce metaplasia and SPEM (76), whereas pretreatment of mice with IL-4 prevents the development of atrophic gastritis after infection with Helicobacter spp. (77).…”

Emergence of spasmolytic polypeptide-expressing metaplasia in Mongolian gerbils infected with Helicobacter pylori

“…39, 40 Yamaoka et al 41 investigated the chronological changes in cytokine profiles during Hp infection in gerbils and reported that mucosal IFN-g mRNA reached maximal levels at 4 weeks and remained high thereafter. Kang et al 42 reported that IFN-g induces expression of MUC6 and TFF2, and lymphocytes infiltrating into the mucosa were IFN-g positive. Shibata et al 43 reported CagA protein may be essential for the induction of IFN-g and IL-1b and infiltration of inflammatory cells.…”