title: Helicobacter pylori sensitizes TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human gastric epithelial cells through regulation of FLIP.
abstract: Helicobacter pylori (H. pylori) infection is associated with chronic gastritis, peptic ulcer and gastric cancer. Apoptosis induced by microbial infections is implicated in the pathogenesis of H. pylori infection. Here we show that human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death receptor signaling. Human gastric epithelial cells are intrinsically resistant to TRAIL-mediated apoptosis. The induction of TRAIL sensitivity by H. pylori is dependent on the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex (DISC) through downregulation of cellular FLICE-inhibitory protein (FLIP). Overexpression of FLIP abolished the H. pylori-induced TRAIL sensitivity in human gastric epithelial cells. Our study thus demonstrates that H. pylori induces sensitivity to TRAIL apoptosis by regulation of FLIP and assembly of DISC, which initiates caspase activation, resulting in the breakdown of resistance to apoptosis, and provides insight into the pathogenesis of gastric damage in Helicobacter infection. Modulation of host apoptosis signaling by bacterial interaction adds a new dimension to the pathogenesis of Helicobacter.
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: W-C
authors.initials: WC
authors.lastname: Lin
authors.affiliation: 1] Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, Taipei, Taiwan [2] Gradute Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: H-F
authors.initials: HF
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Liao
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Tang
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University and Hospital, Taichung, Taiwan.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Veterans General Hospital-Kaohsiung, Kaohsiung, Taiwan.
authors.forename: P-I
authors.initials: PI
authors.lastname: Hsu
authors.affiliation: 1] Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan [2] Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: A-L
authors.initials: AL
authors.lastname: Cheng
authors.affiliation: 1] Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan [2] Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: P-N
authors.initials: PN
authors.lastname: Hsu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism; D016481:Helicobacter Infections / Q000382:microbiology*; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013270:Stomach / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D045304:Cytochromes c; C505530:CASP8 protein, human; D053181:Caspase 8