Regulation of RANTES Promoter Activation in Gastric Epithelial Cells Infected withHelicobacter pylori

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Abstract
RANTES, a CC chemokine, plays an important role in the inflammatory response associated withHelicobacter pyloriinfection. However, the mechanism by whichH. pyloriinduces RANTES expression in the gastric mucosa is unknown. We cocultured gastric epithelial cells with wild-typeH. pylori, isogenicoipAmutants,cagpathogenicity island (PAI) mutants, or double knockout mutants. Reverse transcriptase PCR showed that RANTES mRNA was induced byH. pyloriand that the expression was both OipA andcagPAI dependent. Luciferase reporter gene assays and electrophoretic mobility shift assays showed that maximalH. pylori-inducedRANTESgene transcription required the presence of the interferon-stimulated responsive element (ISRE), the cyclic AMP-responsive element (CRE), nuclear factor-interleukin 6 (NF-IL-6), and two NF-κB sites. OipA- andcagPAI-dependent pathways included NF-κB→NF-κB/NF-IL-6/ISRE pathways, andcagPAI-dependent pathways additionally included Jun N-terminal kinase→CRE/NF-κB pathways. The OipA-dependent pathways additionally included p38→CRE/ISRE pathways. We confirmed the in vitro effects in vivo by examining RANTES mRNA levels in biopsy specimens from human gastric antral mucosa. RANTES mRNA levels in the antral mucosa were significantly higher for patients infected withcagPAI/OipA-positiveH. pylorithan for those infected withcagPAI/OipA-negativeH. pylorior uninfected patients. The mucosal inflammatory response toH. pyloriinfection involves different signaling pathways for activation of the RANTES promoter, with both OipA and thecagPAI being required for full activation of the RANTES promoter.