Interleukin-1β Promotes Gastric Atrophy Through Suppression of Sonic Hedgehog

Background & Aims: In both human subjects and rodent models, Helicobacter infection leads to a decrease in Shh expression in the stomach. Sonic Hedgehog (Shh) is highly expressed in the gastric corpus and its loss correlates with gastric atrophy. Therefore, we tested the hypothesis that proinflammatory cytokines induce gastric atrophy by inhibiting Shh expression. Methods: Shh-LacZ reporter mice were infected with Helicobacter felis for 3 and 8 weeks. Changes in Shh expression were monitored using β-galactosidase staining and immunohistochemistry. Gastric acidity was measured after infection, and interleukin (IL)-1β was quantified by quantitative reverse-transcription polymerase chain reaction. Mice were injected with either IL-1β or omeprazole before measuring Shh mRNA expression and acid secretion. Organ cultures of gastric glands from wild-type or IL-1R1 null mice were treated with IL-1β then Shh expression was measured. Primary canine parietal or mucous cells were treated with IL-1β. Shh protein was determined by immunoblot analysis. Changes in intracellular calcium were measured by Fura-2. Results: All major cell lineages of the corpus including surface pit, mucous neck, zymogenic, and parietal cells expressed Shh. Helicobacter infection reduced gastric acidity and inhibited Shh expression in parietal cells by 3 weeks. IL-1β produced during Helicobacter infection inhibited gastric acid, intracellular calcium, and Shh expression through the IL-1 receptor. Suppression of parietal cell Shh expression by IL-1β and omeprazole was additive. IL-1β did not suppress Shh expression in primary gastric mucous cells. Conclusions: IL-1β suppresses Shh gene expression in parietal cells by inhibiting acid secretion and subsequently the release of intracellular calcium.