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Infection and Immunity, April 2009, p. 1337-1348, Vol. 77, No. 4
0019-9567/09/$08.00+0 doi:10.1128/IAI.01456-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Helicobacter pylori-Induced Interleukin-12 p40 Expression
Eriko Takeshima,1,2
Koh Tomimori,1,2
Hiromitsu Teruya,1,2
Chie Ishikawa,1,3
Masachika Senba,4
Daniele D'Ambrosio,5
Fukunori Kinjo,6
Hitomi Mimuro,7
Chihiro Sasakawa,7
Toshiya Hirayama,8
Jiro Fujita,2 and
Naoki Mori1*
Divisions of Molecular Virology and Oncology,1 Control and Prevention of Infectious Diseases,2 Graduate School of Medicine, Division of Child Health and Welfare, Faculty of Medicine,3 Department of Endoscopy, University Hospital, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan,6 Departments of Pathology,4 Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan,8 Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan,7 BioXell SpA, Milan, Italy5
Received 28 November 2008/ Returned for modification 6 January 2009/ Accepted 21 January 2009
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-
B. The transfection of IB kinase and NF-B-inducing kinase dominant-negative mutants inhibited H. pylori-induced IL-12 p40 activation. Inhibitors of NF-B, 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-B, 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.
* Corresponding author. Mailing address: Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. Phone: 81-98-895-1130. Fax: 81-98-895-1410. E-mail: n-mori{at}med.u-ryukyu.ac.jp
Published ahead of print on 29 January 2009.
Infection and Immunity, April 2009, p. 1337-1348, Vol. 77, No. 4
0019-9567/09/$08.00+0 doi:10.1128/IAI.01456-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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