Cell Specific Regulation of Sonic Hedgehog in Adult Stomach:Understanding Mechanisms Leading to Gastric Atrophy/Metaplasia. Mechanisms Leading to Gastric Atrophy/Metaplasia.

[摘要] Helicobacter induced gastritis of the corpus results in loss of parietal cell function, loss of the oxyntic gland (atrophy), changes that predispose to gastric cancer.The molecular details of how chronic inflammation in the corpus leads to atrophy is not well understood.Recently, Shh has been implicated as a crucial factor in gastric gland organogenesis and differentiation.Several studies have shown in both human subjects and rodent models that 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 the regulation of Shh expression.Polymorphisms in the promoter of the pro-inflammatory cytokine IL-1betathat increase gene expression correlate with gastric atrophy and cancer in Helicobacter-infected subjects.Recently, gastric transgenic overexpression of human IL-1beta in mice was shown to induce dysplasia and gastric cancer.Apart from its role in inflammation, IL-1beta inhibits gastric acid secretion and hence in this way might hasten atrophy.Prior studies have suggested a role for gastric acid in regulating Shh expression.Therefore, I tested whether IL-1beta induces gastric atrophy through its ability to inhibit Shh gene expression. There is conflicting information about the cell types that express Shh in the stomach. Therefore using reporter mice, I first determined the patterns of Shh expression. I found that all major cell lineages of the corpus express Shh and that Hh signaling in the stomach is paracrine.Next, I investigated the ability of Helicobacter-induced inflammation to regulate Shh gene expression by infecting ShhLacZ reporter mice.Helicobacter infection inhibited Shh expression in parietal cells.In addition I found that IL-1 also inhibited Shh expression in the parietal cells.Activation of the IL-1receptor was required to inhibit Shh expression by IL-1beta. As previously reported, I found that IL-1beta inhibited acid secretion.Further I demonstrated that IL-1beta inhibits Shh gene expression by both acid dependent and independent mechanisms.In summary, I have established a previously unknown role for IL-1beta in gastric pathophysiology, that is, its ability to suppress Shh gene expression, a factor essential to the functional maturity of the parietal cell.

[发布机构] University of Michigan

[效力级别] Health Sciences

[关键词] Helicobacter Induced IL-1b Regulation of Sonic Hedgehog;Health Sciences;Science;Cell and Developmental Biology