title: Activation of IL-8 gene expression by Helicobacter pylori is regulated by transcription factor nuclear factor-kappa B in gastric epithelial cells.
abstract: In vivo, gastric infection with Helicobacter pylori leads to substantial production of the inflammatory cytokines IL-1, IL-6, TNF-alpha, and IL-8. H. pylori strains that contain the cag pathogenicity island (cag+) and are associated with ulceration and gastric carcinoma induce greater cytokine production than cag- strains. Expression of these cytokines is often regulated by the transcription factor complex, nuclear factor-kappa B (NF-kappa B) through kappa B-binding elements in the enhancer/promoter regions of their genes. We report that more virulent cag+ H. pylori strains induce increased NF-kappa B-DNA binding activity, which elevates IL-8 expression in AGS gastric epithelial cells. The cag+ H. pylori strains induce significant stimulation of IL-8 promoter-driven reporter activity, while cag- strains do not. Furthermore, mutation of specific genes within the cag island (picA1 and picB) ablates enhanced NF-kappa B activation and IL-8 transcription. Increased 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 activity. 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 heightened inflammatory response seen in subjects infected with cag+ H. pylori strains.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Sharma
authors.forename: M K
authors.initials: MK
authors.lastname: Tummuru
authors.forename: M J
authors.initials: MJ
authors.lastname: Blaser
authors.forename: L D
authors.initials: LD
authors.lastname: Kerr
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D005753:Gastric Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000502:physiology; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000502:physiology; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D013274:Stomach Neoplasms / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D014158:Transcription, Genetic / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D001426:Bacterial Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D009687:Nuclear Proteins; C103937:PicB protein, Helicobacter pylori; D004247:DNA