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Infection and Immunity, September 2007, p. 4472-4481, Vol. 75, No. 9
0019-9567/07/$08.00+0     doi:10.1128/IAI.00500-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Helicobacter pylori VacA Enhances Prostaglandin E2 Production through Induction of Cyclooxygenase 2 Expression via a p38 Mitogen-Activated Protein Kinase/Activating Transcription Factor 2 Cascade in AZ-521 Cells{triangledown}

Junzo Hisatsune,1 Eiki Yamasaki,1 Masaaki Nakayama,1 Daisuke Shirasaka,2 Hisao Kurazono,3 Yohtaro Katagata,4 Hiroyasu Inoue,5 Jiahuai Han,6 Jan Sap,7 Kinnosuke Yahiro,8 Joel Moss,8 and Toshiya Hirayama1*

Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 8528523, Japan,1 Division of Digestive Disease, Kobe University Graduate School of Medicine, Kobe 6500017, Japan,2 Laboratory of Veterinary Public Health, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 5998531, Japan,3 Department of Biochemistry and Biotechnology, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki 0368561, Japan,4 Department of Food and Nutrition, Nara Women's University, Nara 6308506, Japan,5 Department of Immunology, The Scripps Research Institute, La Jolla, California 92037,6 Department of Molecular Pathology, University of Copenhagen, Copenhagen DK-2100, Denmark,7 Pulmonary-Critical Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-15908

Received 7 April 2007/ Returned for modification 23 May 2007/ Accepted 13 June 2007

Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol-specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E2 (PGE2) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE2 production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-{kappa}B or NF-interleukin-6 sites but not a mutated cis-acting replication element (CRE) site, suggesting direct involvement of the activating transcription factor 2 (ATF-2)/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, 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.

* Corresponding author. Mailing address: Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 8528523, Japan. Phone: 81-95-849-7831. Fax: 81-95-849-7877. E-mail: hirayama{at}net.nagasaki-u.ac.jp

{triangledown} Published ahead of print on 25 June 2007.

Editor: F. C. Fang

Infection and Immunity, September 2007, p. 4472-4481, Vol. 75, No. 9
0019-9567/07/$08.00+0     doi:10.1128/IAI.00500-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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