Parietal cell hyperstimulation and autoimmune gastritis in cholera toxin transgenic mice.

Abstract

The stimulation of gastric acid secretion from parietal cells involves both intracellular calcium and cAMP signaling. To understand the effect of increased cAMP on parietal cell function, we engineered transgenic mice expressing cholera toxin (Ctox), an irreversible stimulator of adenylate cyclase. The parietal cell-specific H(+),K(+)-ATPase beta-subunit promoter was used to drive expression of the cholera toxin A1 subunit (CtoxA1). Transgenic lines were established and tested for Ctox expression, acid content, plasma gastrin, tissue morphology, and cellular composition of the gastric mucosa. Four lines were generated, with Ctox-7 expressing approximately 50-fold higher Ctox than the other lines. Enhanced cAMP signaling in parietal cells was confirmed by observation of hyperphosphorylation of the protein kinase A-regulated proteins LASP-1 and CREB. Basal acid content was elevated and circulating gastrin was reduced in Ctox transgenic lines. Analysis of gastric morphology revealed a progressive cellular transformation in Ctox-7. Expanded patches of mucous neck cells were observed as early as 3 mo of age, and by 15 mo, extensive mucous cell metaplasia was observed in parallel with almost complete loss of parietal and chief cells. Detection of anti-parietal cell antibodies, inflammatory cell infiltrates, and increased expression of the Th1 cytokine IFN-gamma in Ctox-7 mice suggested that autoimmune destruction of the tissue caused atrophic gastritis. Thus constitutively high parietal cell cAMP results in high acid secretion and a compensatory reduction in circulating gastrin. High Ctox in parietal cells can also induce progressive changes in the cellular architecture of the gastric glands, corresponding to the development of anti-parietal cell antibodies and autoimmune gastritis.

• Authors: Lymari Lopez-Diaz, Karen L Hinkle, Renu N Jain, Yana Zavros, Cynthia S Brunkan, Theresa Keeley, Kathryn A Eaton, Juanita L Merchant, Catherine S Chew, Linda C Samuelson
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 290 Issue 5 Pg. G970-9 (May 2006) ISSN: 0193-1857 [Print] United States
• PMID: 16399875 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies
• Gastrins
• Cholera Toxin
• Cyclic AMP
• H(+)-K(+)-Exchanging ATPase

Topics

• Aging
• Animals
• Animals, Genetically Modified
• Antibodies (immunology)
• Autoimmune Diseases (metabolism)
• Cholera Toxin (genetics)
• Cyclic AMP (metabolism)
• Disease Models, Animal
• Gastric Acid (chemistry)
• Gastrins (metabolism)
• Gastritis (metabolism)
• Gastritis, Atrophic (pathology)
• H(+)-K(+)-Exchanging ATPase (genetics)
• Mice
• Mice, Inbred C57BL
• Parietal Cells, Gastric (metabolism, physiology)
• Promoter Regions, Genetic