Helicobacter pylori induces gastric mucosal intestinal metaplasia through the inhibition of interleukin-4-mediated HMG box protein Sox2 expression

Sho Asonuma, Akira Imatani, Naoki Asano, Tomoyuki Oikawa, Hidetomo Konishi, Katsunori Iijima, Tomoyuki Koike, Shuichi Ohara, Tooru Shimosegawa

研究成果: Article査読

40 被引用数 (Scopus)

抄録

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-γ, IL-1β, or TNF-α. 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-γ 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-γ 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.

本文言語English
ページ(範囲)G312-G322
ジャーナルAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
297
2
DOI
出版ステータスPublished - 2009 8月

ASJC Scopus subject areas

  • 生理学
  • 肝臓学
  • 消化器病学
  • 生理学(医学)

フィンガープリント

「Helicobacter pylori induces gastric mucosal intestinal metaplasia through the inhibition of interleukin-4-mediated HMG box protein Sox2 expression」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル