title: Deficiency of claudin-18 causes paracellular H+ leakage, up-regulation of interleukin-1β, and atrophic gastritis in mice.
abstract: OBJECTIVE
  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-1β, 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.
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hayashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tamura
authors.forename: Hiroo
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Shin
authors.initials: S
authors.lastname: Watanabe
authors.forename: Koya
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sentani
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tsukita
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1 / Q000378:metabolism; D057167:Claudins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005614:Freeze Fracturing; D005753:Gastric Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005757:Gastritis, Atrophic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053583:Interleukin-1beta / Q000378:metabolism*; D008679:Metaplasia; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D020556:Neutrophil Infiltration; D010295:Parietal Cells, Gastric / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure; D015854:Up-Regulation
chemical_list: D054360:Chemokine CXCL1; D057167:Claudins; C438899:Cldn18 protein, mouse; C475895:Cxcl1 protein, mouse; D053583:Interleukin-1beta; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2