title: Repressed TGF-β signaling through CagA-Smad3 interaction as pathogenic mechanisms of Helicobacter pylori-associated gastritis.
abstract: Helicobacter pylori (H. pylori) infection causes chronic gastric inflammation, peptic ulceration, and gastric carcinogenesis, in which H. pylori cytotoxin-associated gene A (CagA) plays major pathogenic action. Since transforming growth factor-β (TGF-β) and its signaling also are principally implicated in either modulating gastric mucosal inflammatory responses or causing carcinogenesis and are attenuated after H. pylori infection, we hypothesized that dysregulated Smad signaling and repressed TGF-β might be core pathogenic mechanism for H. pylori-associated gastritis or carcinogenesis. Until now, no precise underlying mechanism how deranged TGF-β signaling developed after H. pylori infection relevant to various clinical manifestations remains unclear. In this study, we examined the molecular mechanism about the inhibition of TGF-β signaling by H. pylori CagA protein. H. pylori CagA significantly suppressed TGF-β/Smad transcriptional responses through critical inhibition of Smad3, though CagA interacted constitutively with Smad2, Smad3, and Smad4. CagA inhibited TGF-β-induced suppression of proinflammatory chemokines, such as IL-8, CXCL1 and CXCL3, as well as TGF-β-induced transcription of target genes. In conclusion, repressed TGF-β signaling associated with CagA-positive H. pylori infection could be an important determinant for the outcome of H. pylori infection. Therefore, TGF-β signaling is one of the important determinants to avoid from H. pylori CagA pathogenicity.
authors.affiliation: Laboratory of Chemoprevention, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea.
authors.forename: Thuy Trang
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: CHA University Cancer Prevention Research Center, CHA Bio Complex, 335 Pangyo-ro, Gundang-gu, Seongnam 463-400, Korea.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: CHA University Cancer Prevention Research Center, CHA Bio Complex, 335 Pangyo-ro, Gundang-gu, Seongnam 463-400, Korea.
authors.forename: Jong Min
authors.initials: JM
authors.lastname: Park
authors.affiliation: CHA University Cancer Prevention Research Center, CHA Bio Complex, 335 Pangyo-ro, Gundang-gu, Seongnam 463-400, Korea.
authors.forename: Ki Baik
authors.initials: KB
authors.lastname: Hahm
authors.affiliation: Laboratory of Chemoprevention, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea.
authors.forename: Ho-Jae
authors.initials: HJ
authors.lastname: Lee
keywords: Cytotoxin-associated gene A; Helicobacter pylori; Smad; TGF-β; inflammation