title: Helicobacter pylori infection interferes with epithelial Stat6-mediated interleukin-4 signal transduction independent of cagA, cagE, or VacA.
abstract: Helicobacter pylori is a bacterial pathogen evolved to chronically colonize the gastric epithelium, evade immune clearance by the host, and cause gastritis, peptic ulcers, and even gastric malignancies in some infected humans. In view of the known ability of this bacterium to manipulate gastric epithelial cell signal transduction cascades, we determined the effects of H. pylori infection on epithelial IL-4-Stat6 signal transduction. HEp-2 and MKN45 epithelial cells were infected with H. pylori strains LC11 or 8823 (type 1; cagA(+)/cagE(+)/VacA(+)), LC20 (type 2; cagA(-), cagE(-), VacA(-)), and cagA, cagE, and vacA isogenic mutants of strain 8823, with some cells receiving subsequent treatment with the Th2 cytokine IL-4, a known Stat6 activator. Immunofluorescence showed a disruption of Stat6-induced nuclear translocation by IL-4 in LC11-infected HEp-2 cells. IL-4-inducible Stat6 DNA binding in HEp-2 and MKN45 cells was abrogated by infection, but MKN45 cell viability was unaffected. A decrease in IL-4-mediated Stat6 tyrosine phosphorylation in nuclear and whole cell lysates was also observed following infection with strains LC11 and LC20, while neither strain altered IL-4 receptor chain alpha or Janus kinase 1 protein expression. Furthermore, parental strain 8823 and its isogenic cagA, cagE, and vacA mutants also suppressed IL-4-induced Stat6 tyrosine phosphorylation to comparable degrees. Thus, H. pylori did not directly activate Stat6, but blocked the IL-4-induced activation of epithelial Stat6. This may represent an evolutionarily conserved strategy to disrupt a Th2 response and evade the host immune system, allowing for successful chronic infection.
authors.affiliation: Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Ceponis
authors.forename: Derek M
authors.initials: DM
authors.lastname: McKay
authors.forename: Rena J
authors.initials: RJ
authors.lastname: Menaker
authors.forename: Esther
authors.initials: E
authors.lastname: Galindo-Mata
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Jones
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000942:Antigens, Bacterial / Q000502:physiology*; D001426:Bacterial Proteins / Q000502:physiology*; D016923:Cell Death / Q000276:immunology; D002461:Cell Line, Transformed; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D016480:Helicobacter pylori / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D053613:Janus Kinase 1; D010766:Phosphorylation; D021122:Protein Subunits / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D019948:Receptors, Interleukin-4 / Q000096:biosynthesis; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C103937:PicB protein, Helicobacter pylori; D021122:Protein Subunits; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; C074689:VacA protein, Helicobacter pylori; C080866:cagA protein, Helicobacter pylori; D015847:Interleukin-4; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1