ACTIVATION OF IL-8 GENE-EXPRESSION BY HELICOBACTER-PYLORI IS REGULATED BY TRANSCRIPTION FACTOR NUCLEAR FACTOR-KAPPA-B IN GASTRIC EPITHELIAL-CELLS

In vivo, gastric infection with Helicobacter pylori leads to substanti al production of the inflammatory cytokines IL-1, IL-6, TNF-alpha, and IL-8. H. pylori strains that contain the cag pathogenicity island (ca g(+)) and are associated with ulceration and gastric carcinoma induce greater cytokine production than cag(-) strains, Expression of these c ytokines is often regulated by the transcription factor complex, nucle ar factor-kappa B (NF-kappa B) through kappa B-binding elements in the enhancer/promoter regions of their genes, We report that more virulen t cag(+) H, pylori strains induce increased NF-kappa B-DNA binding act ivity, which elevates IL-8 expression in AGS gastric epithelial cells. The cag(+) H. pylori strains induce significant stimulation of IL-8 p romoter-driven reporter activity, while cag(-) strains do not, Further more, mutation of specific genes within the cag island (picA1 and picB ) ablates enhanced NF-kappa B activation and IL-8 transcription, Incre ased IL-8 expression is inhibited by mutation in either the NF-kappa B or NF-IL-6 binding element. The cag(+) strains, compared with the cag (-) strains, induce enhanced nuclear localization of a RelA-containing NF-kappa B binding complex, but no increase in NF-IL-6 binding activi ty, These studies demonstrate that the ability of different types of H . pylori strains to activate NF-kappa B correlates with their ability to induce IL-8 transcription and indicate a mechanism for the heighten ed inflammatory response seen in subjects infected with cag(+) H. pylo ri strains.