title: Helicobacter pylori-induced interleukin-12 p40 expression.
abstract: Interleukin-12 (IL-12) is a heterodimeric cytokine produced by antigen-presenting cells that promotes the development of T-helper lymphocyte 1 (Th1). Chronic gastritis induced by Helicobacter pylori is considered a Th1-mediated process. IL-12 levels in gastric biopsy samples of H. pylori-infected patients are higher than in those of uninfected individuals, but the cellular source of IL-12 remains elusive. IL-12 staining was detected in mucosal epithelial cells, lymphocytes, and macrophages in specimens of patients with H. pylori-positive gastritis. Therefore, we investigated IL-12 p40 mRNA induction by H. pylori in gastric epithelial cells and T cells. Although cag pathogenicity island (PAI)-positive H. pylori induced IL-12 p40 mRNA expression, an isogenic mutant of the cag PAI failed to induce it in both cell types. Supernatants from H. pylori cultures and H. pylori VacA induced IL-12 p40 mRNA expression in T cells but not in epithelial cells. The activation of the IL-12 p40 promoter by H. pylori was mediated through NF-kappaB. The transfection of IkappaB kinase and NF-kappaB-inducing kinase dominant-negative mutants inhibited H. pylori-induced IL-12 p40 activation. Inhibitors of NF-kappaB, phosphatidylinositol 3-kinase, p38 mitogen-activated protein kinase, and Hsp90 suppressed H. pylori- and VacA-induced IL-12 p40 mRNA expression. The results indicate that H. pylori induces IL-12 p40 expression by the activation of NF-kappaB, phosphatidylinositol 3-kinase, and p38 mitogen-activated protein kinase. Hsp90 is also a crucial regulator of H. pylori-induced IL-12 p40 expression. In addition to the cag PAI, VacA might be relevant in the induction of IL-12 expression and a Th1-polarized response only in T cells.
authors.affiliation: Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Takeshima
authors.forename: Koh
authors.initials: K
authors.lastname: Tomimori
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Teruya
authors.forename: Chie
authors.initials: C
authors.lastname: Ishikawa
authors.forename: Masachika
authors.initials: M
authors.lastname: Senba
authors.forename: Daniele
authors.initials: D
authors.lastname: D'Ambrosio
authors.forename: Fukunori
authors.initials: F
authors.lastname: Kinjo
authors.forename: Hitomi
authors.initials: H
authors.lastname: Mimuro
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sasakawa
authors.forename: Toshiya
authors.initials: T
authors.lastname: Hirayama
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujita
authors.forename: Naoki
authors.initials: N
authors.lastname: Mori
mesh_terms: D000818:Animals; D001706:Biopsy; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005753:Gastric Mucosa / Q000166:cytology / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D005756:Gastritis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005786:Gene Expression Regulation; D044404:Genomic Islands; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053762:Interleukin-12 Subunit p40; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases