1. ¹Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
2. ²Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA

Correspondence: Dr JL Merchant, MD, PhD, 1150 West Medical Center Drive, MSRB I, Rm. 3510, Ann Arbor, MI 48109-0650, USA. E-mail: merchanj@umich.edu

Received 4 January 2005; Revised 7 January 2005; Accepted 11 January 2005; Published online 14 March 2005.

Abstract

Chronic inflammation of the gastric epithelium is believed to induce mucosal changes that can eventually develop into gastric cancer. In gastrin-deficient (G-/-) 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 G-/- stomachs, suggested that mucous neck cell proliferation accounted for expansion of this compartment in the H. felis model of gastritis, but not the G-/- model. Using RNase protection assays and quantitative PCR, we found that interferon gamma (IFN) was the most abundant proinflammatory cytokine in the G-/- 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 G-/- and H. felis-infected mice. Using the human gastric cell line NCI-N87, we showed that IFN 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 IFN, induced expansion of the fundic mucous neck cell compartment, which likely represents both increased mucus production and cell number.