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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

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-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.

Published ahead of print on 25 June 2007.

Editor: F. C. Fang

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