title: Helicobacter pylori cag pathogenicity island (cagPAI) involved in bacterial internalization and IL-8 induced responses via NOD1- and MyD88-dependent mechanisms in human biliary epithelial cells.
abstract: Helicobacter pylori infection has been proposed to be associated with various diseases of the hepatobiliary tract, including cancer of the bile duct epithelial cells (cholangiocarcinoma, CCA). The ability of H. pylori bacteria to cause pathogenic effects in these cells has, however, yet to be investigated. Given that the cag pathogenicity island (cagPAI) is required for H. pylori pathogenesis in gastric epithelial cells, we investigated wild-type and cag mutant strains for their ability to adhere, be internalized and induce pro-inflammatory responses in two bile duct epithelial cell lines derived from cases of CCA. The findings from these experiments were compared to results obtained with the well-characterized AGS gastric cancer cell line. We showed that the cagPAI encodes factors involved in H. pylori internalization in CCA cells, but not for adhesion to these cells. Consistent with previous studies in hepatocytes, actin polymerization and α5β1 integrin may be involved in H. pylori internalization in CCA cells. As for AGS cells, we observed significantly reduced levels of NF-κB activation and IL-8 production in CCA cells stimulated with either cagA, cagL or cagPAI bacteria, when compared with wild-type bacteria. Importantly, these IL-8 responses could be inhibited via either pre-treatment of cells with antibodies to α5β1 integrins, or via siRNA-mediated knockdown of the innate immune signaling molecules, nucleotide oligomerization domain 1 (NOD1) and myeloid differentiation response gene 88 (MyD88). Taken together, the data demonstrate that the cagPAI is critical for H. pylori pathogenesis in bile duct cells, thus providing a potential causal link for H. pylori in biliary tract disease.
authors.affiliation: Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand ; Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Wongwarut
authors.initials: W
authors.lastname: Boonyanugomol
authors.forename: Chariya
authors.initials: C
authors.lastname: Chomvarin
authors.forename: Chariya
authors.initials: C
authors.lastname: Hahnvajanawong
authors.forename: Banchob
authors.initials: B
authors.lastname: Sripa
authors.forename: Maria
authors.initials: M
authors.lastname: Kaparakis-Liaskos
authors.forename: Richard L
authors.initials: RL
authors.lastname: Ferrero
mesh_terms: D001422:Bacterial Adhesion; D001426:Bacterial Proteins / Q000235:genetics* / Q000494:pharmacology; D001659:Biliary Tract / Q000166:cytology; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D044404:Genomic Islands; D016480:Helicobacter pylori / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000096:biosynthesis; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D039081:Integrin alpha5beta1; D016209:Interleukin-8; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D051193:Toll-Like Receptors