title: Helicobacter pylori represses proton pump expression and inhibits acid secretion in human gastric mucosa.
abstract: OBJECTIVE
  Helicobacter pylori infection of gastric mucosa causes gastritis and transient hypochlorhydria, which may provoke emergence of a mucosal precancer phenotype; H pylori strains containing a cag pathogenicity island (PAI) augment cancer risk. Acid secretion is mediated by the catalytic alpha subunit of parietal cell H,K-ATPase (HKalpha). In AGS gastric epithelial cells, H pylori induces nuclear factor-kappaB (NF-kappaB) binding to and repression of transfected HKalpha promoter activity. This study sought to identify bacterial genes involved in HKalpha repression and to assess their impact on acid secretion.
  
  
  RESULTS
  AGS cells transfected with an HKalpha promoter construct or human gastric body biopsies were infected with wild-type (wt) or isogenic mutant (IM) H pylori strains. AGS cell HKalpha promoter activity, and biopsy HKalpha mRNA, protein and H(+) secretory activity were measured by luminometry, reverse transcription-PCR, immunoblotting and extracellular acidification, respectively. Wt H pylori and DeltavacA, DeltaureA, Deltaslt and DeltaflaA IM strains repressed HKalpha promoter activity by approximately 50%, a DeltacagA IM strain repressed HKalpha by approximately 33%, and DeltacagE, DeltacagM and DeltacagL IM strains elicited no HKalpha repression. Wt H pylori-infected biopsies had markedly reduced HKalpha mRNA and protein compared with IM strain infections or mock-infected controls. Histamine-stimulated, SCH28080-sensitive biopsy acid secretion was significantly inhibited by wt but not by DeltacagL IM H pylori infection compared with vehicle-only controls.
  
  
  CONCLUSIONS
  It is concluded that H pylori cag PAI gene products CagE, CagM, CagL and, possibly, CagA are mechanistically involved in repression of HKalpha transcription. Further, acute H pylori infection of human gastric mucosa downregulates parietal cell H,K-ATPase expression, significantly inhibiting acid secretion.
authors.affiliation: Medical University of South Carolina, 96 Jonathan Lucas St., Charleston, SC 29425, USA.
authors.forename: Arindam
authors.initials: A
authors.lastname: Saha
authors.forename: Charles E
authors.initials: CE
authors.lastname: Hammond
authors.forename: Craig
authors.initials: C
authors.lastname: Beeson
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Smolka
mesh_terms: D000328:Adult; D000942:Antigens, Bacterial / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism* / Q000382:microbiology; D005798:Genes, Bacterial; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism; D016481:Helicobacter Infections / Q000378:metabolism* / Q000382:microbiology; D016480:Helicobacter pylori / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D017494:Proton Pumps / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D046509:Tissue Culture Techniques; D014407:Tumor Cells, Cultured; D014774:Virulence / Q000235:genetics; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D017494:Proton Pumps; D012333:RNA, Messenger; C080866:cagA protein, Helicobacter pylori; D017506:H(+)-K(+)-Exchanging ATPase