| First Author | Hayashi D | Year | 2012 |
| Journal | Gastroenterology | Volume | 142 |
| Issue | 2 | Pages | 292-304 |
| PubMed ID | 22079592 | Mgi Jnum | J:292389 |
| Mgi Id | MGI:6449952 | Doi | 10.1053/j.gastro.2011.10.040 |
| Citation | Hayashi D, et al. (2012) Deficiency of claudin-18 causes paracellular H+ leakage, up-regulation of interleukin-1beta, and atrophic gastritis in mice. Gastroenterology 142(2):292-304 |
| abstractText | BACKGROUND & AIMS: Although defects in tight junction (TJ) epithelial paracellular barrier function are believed to be a primary cause of inflammation, the mechanisms responsible remain largely unknown. METHODS: We generated knockout mice of stomach-type claudin-18, a major component of TJs in the stomach. RESULTS: Cldn18(-/-) mice were afflicted with atrophic gastritis that started on postnatal day 3. This coincided with a decrease in intragastric pH due to H(+) secretion from parietal cells and concomitant up-regulation of the cytokines, interleukin-1beta, cyclooxygenase-2, and KC, resulting in spasmolytic polypeptide-expressing metaplasia (SPEM). Oral administration of hydrochloric acid on postnatal day 1 induced the expression of these cytokines in Cldn18(-/-) infant stomach, but not in Cldn18(+/+) mice. A paracellular H(+) leak in Cldn18(-/-) stomach was detected by electrophysiology and H(+) titration, and freeze-fracture electron microscopy showed structural defects in the TJs, in which the tightly packed claudin-18 (stomach-type)-based TJ strands were lost, leaving a loose meshwork of strands consisting of other claudin species. CONCLUSIONS: These findings provide evidence that claudin-18 normally forms a paracellular barrier against H(+) in the stomach and that its deficiency causes paracellular H(+) leak, a persistent up-regulation of proinflammatory cytokines, chronic recruitment of neutrophils, and the subsequent development of SPEM in atrophic gastritis. |
