title: Helicobacter pylori induces gastric mucosal intestinal metaplasia through the inhibition of interleukin-4-mediated HMG box protein Sox2 expression.
abstract: Helicobacter pylori is a major cause of the transdifferentiation into intestinal metaplasia that may develop gastric cancer. However, the molecular pathogenesis of this transdifferentiation is poorly understood. A SRY-related HMG box protein Sox2 is an essential transcription factor of organ development in brain, lung, and stomach. Our aim of this study was to investigate the mechanism responsible for regulation of Sox2 in host Th1-dominant response to H. pylori. Sox2 protein was immunohistochemically expressed in both human oxyntic and pyloric glands with H. pylori infection, but not in intestinal metaplasia. Western immunoblotting of gastric epithelial cell lines showed that IL-4, a Th2-related cytokine, dose dependently enhanced Sox2 expression among H. pylori infection-mediated cytokines. Small changes of Sox2 expression were observed after each treatment with IFN-gamma, IL-1beta, or TNF-alpha. IL-4-mediated Sox2 induction was suppressed by the inhibition of STAT6 activation with STAT6 RNA interference, and electrophoretic mobility shift assay indicated that activation of the Sox2 promoter by IL-4 occurred through the action of STAT6. Furthermore, H. pylori and IFN-gamma inhibited the phosphorylation of STAT6, resulting in the suppression of IL-4-mediated Sox2 expression. Immunohistochemical analyses showed significantly the suppressed STAT6 activity in H. pylori-infected human gastric mucosa. Additionally, downregulation of Sox2 by knockdown experiments led to intestinal phenotype with expressions of Cdx2 and MUC2. These results suggest that H. pylori and IFN-gamma interfere with the differentiation into oxyntic and pyloric glands by the downregulation of Sox2 on IL-4/STAT6 signaling, which may contribute to the transdifferentiation into intestinal metaplasia.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Asonuma
authors.forename: Akira
authors.initials: A
authors.lastname: Imatani
authors.forename: Naoki
authors.initials: N
authors.lastname: Asano
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Oikawa
authors.forename: Hidetomo
authors.initials: H
authors.lastname: Konishi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iijima
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Koike
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ohara
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D000071616:CDX2 Transcription Factor; D054338:Cell Transdifferentiation; D015536:Down-Regulation; D005753:Gastric Mucosa / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D016481:Helicobacter Infections / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D008679:Metaplasia; D008969:Molecular Sequence Data; D055262:Mucin-2 / Q000378:metabolism; D010295:Parietal Cells, Gastric / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D053583:Interleukin-1beta; D019394:Ki-67 Antigen; C524625:MUC2 protein, human; D055262:Mucin-2; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma