Toxicity of Helicobacter pylori VacA and its mutual effect with CagA

• Project/Area Number: 19209014
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Bacteriology (including Mycology)
• Research Institution: Nagasaki University
• Principal Investigator: HIRAYAMA Toshiya Nagasaki University, 熱帯医学研究所, 教授 (50050696)
• Co-Investigator(Kenkyū-buntansha): ISOMOTO Hajime 長崎大学, 大学病院, 講師 (90322304)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥49,920,000 (Direct Cost: ¥38,400,000、Indirect Cost: ¥11,520,000); Fiscal Year 2009: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2008: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2007: ¥24,180,000 (Direct Cost: ¥18,600,000、Indirect Cost: ¥5,580,000)
• Keywords: ヘリコバクター・ピロリ / VacA / 細菌毒素 / 毒性発現 / CagA / エフェクター / 毒素侵入 / エンドサイトーシス / P38 MAP kinase / ATF-2経路 / PI3K / Akt経路 / GSK3β / ATF-2 経路 / COX-2 / IL-8

Research Abstract

1) VacA may induce apoptosis by downregulation of anti-apoptotic Bcl-2 subfamily proteins via STAT3 inhibition. 2) VacA enhances PGE2 production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter. 3) In promonocytic U937 cells, VacA directly increases IL-8 production by activation of the p38 MAPK via intracellular Ca^<2+> release, leading to activation of the transcription factors, ATF-2, CREB, and NF-kB. 4) VacA stimulated protein kinase B (Akt) activity via activation of PI3K, resulting in increased phosphorylation of its substrate, GSK3, with subsequent release of ■-catenin from a GSK3/■-catenin complex and its translocation to the nucleus, leading to activation of the cyclin D1 promoter. 5) Translocated CagA from H. pylori into gastric epithelial cells inhibit uptake and cytotoxicity of VacA via endocytosis inhibition in the cells. However, transfection of cagA gene did not affect the activation of p38 MAPK caused by VacA.

Research Products

• [Journal Article] MicroRNA signatures in Helicobacter pylori-infected gastric mucosa. (2010)
  • Author(s): Matsushima K, Isomoto H, Inoue N, Nakayama T, Hayashi T, Nakayama M, Nakao K, Hirayama T, Kohno S.
  • Journal Title: Int J Cancer (in press)
  • Peer Reviewed
• [Journal Article] Pleiotropic actions of Helicobacter pylori vacuolating cytotoxin, VacA. (2010)
  • Author(s): Isomoto H, Moss J, Hirayama T.
  • Journal Title: Tohoku J Exp Med. 220 Pages: 3-14
  • NAID: 10027082787
  • Peer Reviewed
• [Journal Article] Pleiotropic actions of Helicobacter pylori vacuolating cytotoxin, VacA. (2010)
  • Author(s): Isomoto H, et al.
  • Journal Title: Tohoku J Exp Med. 220 Pages: 3-14
  • NAID: 10027082787
  • Peer Reviewed
• [Journal Article] Helicobacter pylori VacA activates NF-kappaB in T cells via the classical but not alternative pathway. (2009)
  • Author(s): Takeshima E, Tomimori K, Takamatsu R, Ishikawa C, Kinjo F, Hirayama T, Fujita J, Mori N.
  • Journal Title: Helicobacter 14 Pages: 271-279
  • Peer Reviewed
• [Journal Article] Helicobacter pylori-Induced Interleukin-12 p40 Expression. (2009)
  • Author(s): Takeshima E, Tomimori K, Teruya H, Ishikawa C, Senba M, D'Ambrosio D, Kinjo F, Mimuro H, Sasakawa C, Hirayama T, Fujita J, Mori N.
  • Journal Title: Infect. Immun. 77 Pages: 1337-1348
  • NAID: 120001788113
  • Peer Reviewed
• [Journal Article] Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. (2009)
  • Author(s): Nakayama M, Hisatsune J, Yamasaki E, Isomoto H, Kurazono H, Hatakeyama M, Azuma T, Yamaoka Y, Yahiro K, Moss J, Hirayama T.
  • Journal Title: J Biol Chem. 284 Pages: 1612-1619
  • Peer Reviewed
• [Journal Article] Enhanced expression of CCL20 in human Helicobacter pylori-associated gastritis. (2009)
  • Author(s): Yoshida A, Isomoto H, Hisatsune J, Nakayama M, Nakashima Y, Matsushima K, Mizuta Y, Hayashi T, Yamaoka Y, Azuma T, Moss J, Hirayama T, Kohno S.
  • Journal Title: Clin Immunol 130 Pages: 290-297
  • Peer Reviewed
• [Journal Article] ピロリ菌空胞化毒素の多機能性-感染における役割- (2009)
  • Author(s): 山崎栄樹, 磯本一, 平山壽哉
  • Journal Title: 蛋白質核酸酵素 54 Pages: 607-613
• [Journal Article] Helicobacter pylori-induced interleukin-12 p40 expression. (2009)
  • Author(s): Takeshima E, et.al.
  • Journal Title: Infection and Immunity 77 Pages: 1337-1348
  • Peer Reviewed
• [Journal Article] Helicobacter pylori VacA activates NF-κB in T cells via the classical but not alternative pathway. (2009)
  • Author(s): Takeshima E, et.al.
  • Journal Title: Helicobacter 14 Pages: 271-279
  • Peer Reviewed
• [Journal Article] Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. (2009)
  • Author(s): Nakayama M, et. al.
  • Journal Title: Journal of Biological Chemistry 284 Pages: 1612-1619
  • Peer Reviewed
• [Journal Article] Enhanced expression of CCL20 in human Helicobacter pylori-associated gastritis (2009)
  • Author(s): Yoshida A, et. al.
  • Journal Title: Clinical Immunology 130 Pages: 290-297
  • Peer Reviewed
• [Journal Article] Involvement of VAMP7 in human gastric epithelial cell vacuolation induced by Helicobacter pylori-produced VacA. (2008)
  • Author(s): Mashima H, Suzuki J, Hirayama T, Yoshikumi Y, Ohno H, Ohnishi H, Yasuda H, Fujita T, Omata M
  • Journal Title: Infect. Immun 76 Pages: 2296-2303
  • Peer Reviewed
• [Journal Article] Molecular characterization of Helicobacter pylori VacA-induction of IL-8 in U937 cells reveals a prominent role for p38MAP kinase in ATF-2, CREB and NF-kB activation. (2008)
  • Author(s): Hisatsune J, Nakayama M, Isomoto H. Kurazono H, Mukaida N, Mukhopadhyay AK, Azuma T, Yamaoka Y, Sap J, Yamasaki E, Yahiro K, Moss J, Hirayama T.
  • Journal Title: J. Immunol 180 Pages: 5017-5027
  • Peer Reviewed
• [Journal Article] Helicobacter pyloriVacAに関する最近の研究動向とわれわれの取り組み (2008)
  • Author(s): 平山壽哉, 久恒順三, 中山真彰, 山崎栄樹
  • Journal Title: Helicobacter Research 12 Pages: 266-271
• [Journal Article] Involvement of VAMP7 in human gastric epithelial cell vacuolation induced by Helicobacter pylori-produced VacA (2008)
  • Author(s): Mashima H, et al.
  • Journal Title: Infection and Immunity 76 Pages: 2296-2303
  • Peer Reviewed
• [Journal Article] Molecular characterization of Helicobacter pylori VacA-induction of IL-8 in U937 cells reveals a prominent role for p38MAP kinase in ATF-2, CREB and NF-kB activation (2008)
  • Author(s): Hisatsune J, et. al.
  • Journal Title: Journal of Immunology 180 Pages: 5017-5027
  • Peer Reviewed
• [Journal Article] Helicobacter pylori VacA enhances PGE2 production through induction of COX-2 expression via a p38 MAP kinase/ATF-2 cascade in AZ-521 cells. (2007)
  • Author(s): Hisatsune J, Yamasaki E, Nakayama M, Shirasaka D, Kurazono H, Katagata Y, Inoue H, Han J, Sap J, Yahiro K, Moss J, Hirayama T
  • Journal Title: nfect. Immun. 75 Pages: 4472-4481
  • Peer Reviewed
• [Journal Article] 変貌する細菌感染症:Helicobacter pylori感染症 (2007)
  • Author(s): 平山壽哉
  • Journal Title: 医学のあゆみ 223 Pages: 623-627
• [Journal Article] ヘリコバクター・ピロリのVacA毒素受容体と毒性発現に関する研究 (2007)
  • Author(s): 平山壽哉
  • Journal Title: 日本細菌学雑誌 62 Pages: 387-396
  • NAID: 10020277798
• [Journal Article] Helicobacter pylori VacA Enhances Prostaglandin E_2 Production through Inductionof Cyclooxygenase 2 Expression via a p38 Mitogen-Activated Protein Kinase/Activating Transcription Factor 2 Cascade in AZ-521 Cells (2007)
  • Author(s): Hisatsune J, et. al.
  • Journal Title: Infection and Immunity 75 Pages: 4472-4481
  • Peer Reviewed
• [Journal Article] 変貌する細菌感染症: Helicobacter pylori 感染症 (2007)
  • Author(s): 平山 壽哉
  • Journal Title: 医学のあゆみ 223 Pages: 623-627
• [Presentation] Pleiotropic action of VacA toxin of Helicobacter pylori: VacA induces GSK3 inhibition trough the PI3K/Akt signaling pathway. (2009)
  • Author(s): Toshiya Hirayama
  • Organizer: Internationa Sympojium on TGF-βSignaling, Inflammation and Cancer Prevention.
  • Place of Presentation: Incheon, Korea
  • Year and Date: 2009-11-20
• [Presentation] Helicobacter pylori VacA induces GSK3 inhibition through the PI3K/Akt signaling pathway (2009)
  • Author(s): Hirayama T, et al.
  • Organizer: XXII International Workshop on Helicobacter and related bacteria in chronic digestive inflammation and gastric cancer
  • Place of Presentation: ポルト, ポルトガル
  • Year and Date: 2009-09-18
• [Presentation] Helicobacter pylori VacA induces GSK3 inhibition through the PI3K/Akt signaling pathway. (2009)
  • Author(s): Toshiya Hirayama, Masaaki Nakayama, Hajime Isomoto, Masanori Hatakeyama, Takeshi Azuma, Yoshio Yamaoka, Joel Moss
  • Organizer: XXII International Workshop on Helicobacter and related bacteria in chronic digestive inflammation and gastric cancer
  • Place of Presentation: Porto, Portugal
• [Presentation] Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. (2009)
  • Author(s): Toshiya Hirayama, Masaaki Nakayama, Hajime Isomoto, Junzo Hisatsune, Shigeru Kohno, Eiki Yamasaki, Hisao Kurazono, Joel Moss
  • Organizer: 109th General Meeting of American Society for Microbiology
  • Place of Presentation: Philadelphia, USA
• [Presentation] Molecular Characterization of Helicobacter pylori VacA Induction of IL-8 in U937 Cells Reveals a Prominent Role for p38 MAPK in ATF-2, CREB Protein, and NF-kB Activation. (2008)
  • Author(s): Hajime Isomoto, Toshiya Hirayama
  • Organizer: The 9th Korea-Japan International Symposium on Microbiology
  • Place of Presentation: Soul, Korea
• [Presentation] Helicobacter pylori VacA increases IL-8 production by p38 MAPK activation via intracellular Ca 2+-release, leading to ATF-2, CREB and NF-kB activation (2008)
  • Author(s): Toshiya Hirayama, Junzo Hisatsune, Hisao Kurazono, Hajime Isomoto, Joel Moss
  • Place of Presentation: Istanbul, Turkey
• [Presentation] Helicobacter pylori VacA-induced IL-8 production in U937 cells is mediated by an increase in intracellular Ca2+ Junzou Hisatsune, Masaaki Nakayama, , followed by activation of ATF-2, CREB and NF-kB. (2008)
  • Author(s): Toshiya Hirayama, Junzo Hisatsune, Kayo Matsushima, Hajime Isomoto, Shigeru Kohno, Hisao Kurazono, Joel Moss
  • Organizer: 108th General Meeting of American Society for Microbiology
  • Place of Presentation: Boston, USA
• [Presentation] HELICOBACTER PYROLI VACA ENHANCES PGE2 PRODUCTION THROUGH INDUCTION OF COX-2 EXPRESSION VIA p38 MAP KINASE/ATF-2 CASCADE IN AZ-521 CELLS. (2008)
  • Author(s): Hajime Isomoto, Joel Moss, Toshiya Hirayama
  • Organizer: 7th China-Korea-Japan Joint Conference on Helicobacter Infection
  • Place of Presentation: Kyoto, Japan
• [Presentation] Helicobacter pylori VacA increases IL-8 production by p38 MAPK activation via intracellular Ca^<2+>release, leading to ATF-2, CREB and NF-kB activation (2008)
  • Author(s): Hirayama T, et al.
  • Organizer: 12th International Congress of Bacteriology and Applied Microbiology
  • Place of Presentation: Istanbul, Turkey
• [Presentation] Pleotropic action of Helicobacter pylori vacuolating cytotoxin, VacA on esophageal cell types. (2007)
  • Author(s): Hajime Isomoto
  • Organizer: The American Society for Cell Biology 48th Annual Meeting
  • Place of Presentation: Washington DC, USA
• [Presentation] Helicobacter pylori VacA Enhances PGE2 Production Trough Induction of COX-2 Expression via p38 MAP Kinase/ATF-2 Cascade in AZ-521 Cells. (2007)
  • Author(s): Toshiya Hirayama
  • Organizer: 42nd Annual Joint Meeting of Cholera and Other Bacterial Enteric Infections
  • Place of Presentation: Austin, USA
• [Presentation] Helicobacter pylori VacA induces COX-2 expression via p38 MAP Kinase/ATF-2 cascade. (2007)
  • Author(s): Toshiya Hirayama
  • Organizer: 14th International Workshop on Campylobacter, Helicobacter and Related Organisms
  • Place of Presentation: Rotterdam, The Netherlands
• [Presentation] Vacuolating Cytotoxin of Helicobacter pylori Enhances PGE2 Production Through Induction of COX-2 Expression via a p38 MAP Kinase/ATF-2 Cascade in AZ-521 Cells. (2007)
  • Author(s): Toshiya Hirayam
  • Organizer: 107th General Meeting of American Society for Microbiology
  • Place of Presentation: Toronto, Canada
• [Presentation] Pleotropic action of Helicobacter pylori vacuolating cytotoxin, VacA, on esophageal cell types (2007)
  • Author(s): Isomoto H, et. al.
  • Organizer: 47 th Annual Meeting The American Society for Cell Biology
  • Place of Presentation: Washington, DC, USA
• [Book] 生物資源としての細菌毒素 (2009)
  • Author(s): 平山壽哉, 中山真彰, 久恒順三
  • Publisher: 微生物資源国際戦略ガイドブック
• [Book] 微生物資源国際戦略ガイドブック (2009)
  • Author(s): 辨野義己, ら
  • Total Pages: 447
  • Publisher: SCIENCE FORUM
• [Book] 微生物資源国際戦略ガイドブック (2008)
  • Author(s): 辨野 義己, ら(分担)
  • Publisher: サイエンスフォーラム(印刷中)