Interleukin-1beta promotes gastric atrophy through suppression of Sonic Hedgehog.
OBJECTIVE
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 beta-galactosidase staining and immunohistochemistry. Gastric acidity was measured after infection, and interleukin (IL)-1beta was quantified by quantitative reverse-transcription polymerase chain reaction. Mice were injected with either IL-1beta 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-1beta then Shh expression was measured. Primary canine parietal or mucous cells were treated with IL-1beta. 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-1beta 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-1beta and omeprazole was additive. IL-1beta did not suppress Shh expression in primary gastric mucous cells.


CONCLUSIONS
IL-1beta suppresses Shh gene expression in parietal cells by inhibiting acid secretion and subsequently the release of intracellular calcium.
Waghray
Meghna
M
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Zavros
Yana
Y
Saqui-Salces
Milena
M
El-Zaatari
Mohamad
M
Alamelumangapuram
C Bharath
CB
Todisco
Andrea
A
Eaton
Kathryn A
KA
Merchant
Juanita L
JL
D000818:Animals; D001284:Atrophy; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D016481:Helicobacter Infections / Q000378:metabolism; D016480:Helicobacter pylori; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009853:Omeprazole / Q000494:pharmacology; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D053823:Hedgehog Proteins; D053583:Interleukin-1beta; D009853:Omeprazole; D002118:Calcium