title: Helicobacter pylori-associated regulation of forkhead transcription factors FoxO1/3a in human gastric cells.
abstract: BACKGROUND
  Interaction of Helicobacter pylori with gastric mucosa leads to marked cellular and humoral host immunologic responses. The signaling pathways initiated by bacteria-host interaction that result in perturbations in cell structure and function remain unclear. Forkhead transcription factors of class O (FoxO) are implicated in the regulation of apoptosis, cell survival, and pathogenesis. H. pylori infection of gastric epithelial cells induces phosphoinositide-3 kinase (PI3K)-dependent Akt activation and cell survival signaling. We investigated the role of H. pylori-activated PI3K/Akt in the regulation of FoxO1/3a in gastric cells.
  
  
  METHODS
  Immunoblot, immunoprecipitation, and fluorescence microscopy were used to assess the effect of infection of gastric epithelial cells with wild-type H. pylori and their isogenic cag pathogenicity island (PAI) or oipA mutants on the FoxO1/3a signaling pathways. Interleukin-8 release was determined by enzyme-linked immunosorbent assays.
  
  
  RESULTS
  H. pylori infection resulted in activation of the PI3K p85 subunit and inactivation of FoxO1 and FoxO3a by their phosphorylation and translocation of from the nucleus to the cytoplasm. Inhibition of PI3K or Akt kinase activity reduced FoxO1/3a phosphorylation. Akt, FoxO1, or FoxO3a siRNA reduced H. pylori-induced interleukin-8 production. Infection with oipA mutants reduced PI3K/Akt activation and inhibited FoxO1/3a phosphorylation, whereas infection with cag PAI mutants reduced PI3K/Akt activity but did not inhibit FoxO1/3a activation.
  
  
  CONCLUSIONS
  FoxO1 and FoxO3a are novel nuclear substrates of H. pylori-induced PI3K/Akt cell survival signaling pathways that partially control interleukin-8 production. OipA-regulated interleukin-8 release through PI3K/Akt is dependent on FoxO1/3a inactivation, whereas cag PAI-mediated interleukin-8 production employs FoxO1/3-independent signaling.
authors.affiliation: Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Fazal H
authors.initials: FH
authors.lastname: Tabassam
authors.forename: David Y
authors.initials: DY
authors.lastname: Graham
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamaoka
mesh_terms: D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D005786:Gene Expression Regulation; D016481:Helicobacter Infections / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology*; D016480:Helicobacter pylori / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016209:Interleukin-8; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human