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.

Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells

“…5A-C). We also observed increased expression of transcription factors that function downstream of Atoh1 to orchestrate secretory cell differentiation, including Gfi1 (Shroyer et al, 2005;Bjerknes and Cheng, 2010), Spdef (Gregorieff et al, 2009;Noah et al, 2010) and Neurog3 (Jenny et al, 2002;Bjerknes and Cheng, 2006;Lopez-Diaz et al, 2006) (Fig. 5D-F).…”

“…Immunostaining was performed as described (Lopez-Diaz et al, 2006). Primary antibodies were used as described (Keeley and Samuelson, 2010;VanDussen and Samuelson, 2010) For electron microscopy, jejunum and ileum from three mice from each treatment group were evaluated.…”

Regulation of Gastric Epithelial Cell Homeostasis by Gastrin and Bone Morphogenetic Protein Signaling

“…Several studies have demonstrated that the PCs play an important role in the process of differentiation and development of other cell lineages in the gastric mucosa, as loss of mature PCs alters the normal differentiation program of the gastric epithelium and causes different types of mucosal cell remodeling (Li et al 1995(Li et al , 1996Canfield et al 1996;Lopez-Diaz et al 2006;Jain et al 2008). In our previous investigations we reported that inhibition of BMP signaling in the stomach leads to a marked decrease in the number of PCs and to the appearance of aberrant lineages that express markers of both zymogenic and mucus neck cell differentiation (Shinohara et al 2010;Takabayashi et al 2014).…”

“…Several studies have suggested that in mice, the ZCs differentiate from pluripotent stem cells through a multistep process that involves the progressive transition of mucus neck cells into fully differentiated ZCs (Nam et al 2010). It has been also shown that this process might be regulated by parietal-cell secreted factors as loss of PCs leads to alterations in the normal process of ZC maturation and differentiation (Li et al 1995(Li et al , 1996Canfield et al 1996;Lopez-Diaz et al 2006;Jain et al 2008;Shinohara et al 2010;Takabayashi et al 2014). It is therefore possible that the abnormalities in ZC differentiation that we observed in the NogTG;GasKO mice might be mostly secondary to the presence of aberrant, poorly differentiated PCs, although we cannot completely exclude that both gastrin and the BMPs might have cooperative, direct effects on the ZCs.…”

The Morphological Effects of Asthma, As Well As Conventional and Alternative Asthma Therapies on Parietal and Chief Cells in the Stomach of BALB/c Mice

“…Research, with the aid of canine and rodent models, has shown that histamine is able to induce a species specific secretion of pepsinogen by the gastric chief cells (Wiederanders et al, 1960;Lopez-Diaz et al, 2006;Tani & Tanaka, 1990). In the case of rat chief cells, Lopez-Diaz et al have shown that histamine, possibly working through the chief cells H2 receptors, induces a dose-dependent pepsinogen secretion.…”