Parietal cell hyperstimulation and autoimmune gastritis in cholera toxin transgenic mice
Parietal cell hyperstimulation and autoimmune gastritis in cholera toxin transgenic mice
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DOI：
10.1152/ajpgi.00461.2005
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发表时间：
2006-05-01
影响因子：
4.5
通讯作者：
Samuelson, LC
中科院分区：
文献类型：
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作者：
Lopez-Diaz, L;Hinkle, KL;Samuelson, LC
壁细胞分泌胃酸的刺激涉及细胞内钙和 cAMP 信号传导。为了了解 cAMP 增加对壁细胞功能的影响，我们设计了表达霍乱毒素 (Ctox) 的转基因小鼠，霍乱毒素是腺苷酸环化酶的不可逆刺激剂。壁细胞特异性 H+、K+-ATP 酶 β 亚基启动子用于驱动霍乱毒素 A1 亚基 (CtoxA1) 的表达。建立转基因系并测试 Ctox 表达、酸含量、血浆胃泌素、组织形态和胃粘膜细胞组成。生成了四个品系，其中 Ctox-7 的 Ctox 表达量比其他品系高 50 倍。通过观察蛋白激酶 A 调节蛋白 LASP-1 和 CREB 的过度磷酸化，证实了壁细胞中 cAMP 信号传导的增强。在 Ctox 转基因品系中，基础酸含量升高，循环胃泌素减少。胃形态学分析揭示了 Ctox-7 中进行性细胞转化。早在 3 个月大时就观察到颈部粘液细胞扩大，到 15 个月时，观察到广泛的粘液细胞化生，同时壁层和主细胞几乎完全丧失。在 Ctox-7 小鼠中检测到抗壁细胞抗体、炎症细胞浸润和 Th1 细胞因子 IFN-γ 表达增加表明组织的自身免疫破坏导致了萎缩性胃炎。因此，壁细胞cAMP的组成性高导致酸分泌高和循环胃泌素的代偿性减少。壁细胞中的高 Ctox 还会引起胃腺细胞结构的进行性变化，这与抗壁细胞抗体和自身免疫性胃炎的发展相对应。
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 similar to 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.