Study on the function of receptor for Helicobacter pylori VacA and the mechanism of its intoxication

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By 2006 budget, we found that VacA increases PGE_2 production by AZ-521 cells by up-regulation of COX-2 expression through a signaling pathway involving the p38 MAP kinase/ATF-2 cascade, leading to activation of the CRE element on the COX-2 promoter.Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase-2 (COX-2) mRNA in a time-and dose-dependent manner. A p38 MAP kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erkl/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 PGE_2 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-kB or NF-IL6 sites, but not a mutated CRE site, suggesting direct involvement of the 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-siRNA resulted in suppression of COX-2 expression. Thus, we found that VacA enhances PGE_2 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.