Helicobacter pylori-induced interleukin-12 p40 expression.
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.
Takeshima
Eriko
E
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
Tomimori
Koh
K
Teruya
Hiromitsu
H
Ishikawa
Chie
C
Senba
Masachika
M
D'Ambrosio
Daniele
D
Kinjo
Fukunori
F
Mimuro
Hitomi
H
Sasakawa
Chihiro
C
Hirayama
Toshiya
T
Fujita
Jiro
J
Mori
Naoki
N
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
D053762:Interleukin-12 Subunit p40; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases