Cell specific regulation of sonic hedgehog in adult stomach: Understanding mechanisms leading to gastric atrophy/metaplasia

Helicobacter induced gastritis of the corpus leads to atrophy, a lesion that predisposes to gastric cancer. However, the mechanism by which chronic inflammation triggers loss of the parietal cells is not understood. Atrophy is marked by loss of normal gastric glands and is accompanied by replacement with either pseudopyloric or intestinal glands. Thus, there is a shift in cellular composition of the stomach from oxyntopeptic to mucous lineages. Disturbances in gastric differentiation might play a role in the evolution of gastric atrophy.;Shh has recently been implicated as a crucial factor for gastric glandular differentiation. Several studies have shown that both in human subjects and rodent models, Helicobacter infection leads to a decrease in Shh expression. However, none of the studies to date have examined a role for specific pro-inflammatory cytokines in regulating Shh gene expression.;Polymorphisms in IL-1beta, that correlate with higher levels of the cytokine predispose Helicobacter-infected subjects to gastric atrophy. Therefore, we determined if IL-1beta induces gastric atrophy via suppressing Shh expression.;There is conflicting information about the cell types that express Shh in the stomach. Therefore using reporter mice, we first determined the patterns of Shh expression. We found that all major cell lineages of the corpus express Shh and that Hh signaling in the stomach is paracrine.;We next investigated the ability of the Helicobacter induced inflammation to regulate Shh gene expression by infecting Shh reporter mice. Helicobacter infection inhibited Shh expression in parietal cells. In addition we found that IL-1beta also inhibited Shh expression in the parietal cells. Activation of the IL-1 receptor was required to inhibit Shh expression by IL-1beta since Shh expression was not affected by the same treatment of the IL-1R1KO mouse. Suppression of Shh expression by IL-1beta was due to its ability to suppress acid secretion. The proton pump inhibitor omeprazole mimics the effects of IL-1beta by inhibiting the expression of Shh.;In summary, we have established a previously unknown role for IL-1beta in gastric patho-physiology, in inhibiting parietal cell specific Shh expression. We have further demonstrated that this effect on Shh expression was mediated via acid inhibition.