title: MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells.
abstract: Helicobacter pylori induces NF-kappaB activation, leading to mucosal inflammation via cag pathogenicity island. Although recent studies have implicated several candidate proteins of both H. pylori and host, the molecular mechanism by which H. pylori activates NF-kappaB remains unclear. The aim of this study was to analyze the mechanism of cag pathogenicity island-mediated NF-kappaB activation in epithelial cells. The responses of human cell lines and mouse embryonic fibroblasts to infection with wild-type H. pylori or cagE mutant were investigated. The effect of small interfering RNAs (siRNAs) for several NF-kappaB signaling intermediate molecules was evaluated in H. pylori-induced IkappaBalpha phosphorylation and IL-8 production. Protein interactions of exogenously expressed TNFR-associated factor 6 (TRAF6) and MyD88 or receptor-interacting protein 2 and nucleotide-binding oligomerization domain 1 or those of endogenous IkappaB kinase, TGF-beta-activated kinase 1 (TAK1), and TRAF6 were assessed by immunoprecipitation. Cag pathogenicity island-dependent NF-kappaB activation was observed in human cell lines, but not in mouse fibroblasts. In human epithelial cells, H. pylori-induced IkappaBalpha phosphorylation and IL-8 production were severely inhibited by siRNAs directed against TAK1, TRAF6, and MyD88. In contrast, siRNAs for TRAF2, IL-1R-associated kinases 1 and 4, and cell surface receptor proteins did not affect these responses. H. pylori infection greatly enhanced MyD88 and TRAF6 complex formation in a cag-dependent manner, but did not enhance Nod1 and receptor-interacting protein 2 complex formation. H. pylori also induced TAK1 and TRAF6 complexes. These results suggest that the cag pathogenicity island of H. pylori is a cell type-specific NF-kappaB activator. TAK1, TRAF6, and MyD88 are important signal transducers in H. pylori-infected human epithelial cells.
authors.affiliation: Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. yohirata-tky@umin.ac.jp
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ohmae
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Keiji
authors.initials: K
authors.lastname: Ogura
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yoshida
authors.forename: Takao
authors.initials: T
authors.lastname: Kawabe
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology*; D044404:Genomic Islands; D016480:Helicobacter pylori / Q000276:immunology / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016209:Interleukin-8; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D000099151:MAP Kinase Kinase Kinase 7; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse