title: Epithelial-derived nuclear IL-33 aggravates inflammation in the pathogenesis of reflux esophagitis.
abstract: BACKGROUND
  IL-33 is a new tissue-derived cytokine constitutively expressed in epithelial cells and plays a role in sensing damage caused by inflammatory diseases. The function of IL-33 in the esophageal mucosa has not been previously described. Accordingly, we examined the expression of IL-33 and its role in the pathogenesis of reflux esophagitis (RE).
  
  
  METHODS
  IL-33 in the esophageal mucosa of RE patients and in an in vitro stratified normal esophageal squamous epithelial model was examined at the messenger RNA and protein levels. The correlation of the level of IL-33 and IL-8 or IL-6 was examined. Cell layers were stimulated with bile acids and cytokines. IL-33 was knocked down by small interfering RNA (siRNA). Pharmacological inhibitors and signal transducer and activator of transcription 1 (STAT1) siRNA were used.
  
  
  RESULTS
  IL-33 was significantly upregulated in RE patients, and was located in the nuclei of basal and suprabasal layers. Upregulated IL-33 messenger RNA expression was correlated with IL-8 and IL-6 expression. In vitro, IL-33 was upregulated in the nuclei of basal and suprabasal layers by interferon-γ (IFNγ), and the upregulation was aggravated by the combination of deoxycholic acid (DCA) and IFNγ. IL-33 knockdown dampened IFNγ- and DCA-induced IL-8 and IL-6 production. IFNγ-induced IL-33 was inhibited by a Janus kinase inhibitor, a p38 mitogen-activated protein kinase inhibitor, and STAT1 siRNA.
  
  
  CONCLUSIONS
  Nuclear IL-33 is upregulated in erosive mucosa of RE patients and is correlated with IL-8 and IL-6 levels. The normal esophageal epithelial model enables us to show for the first time that epithelial-cell-derived nuclear but not exogenous IL-33 is located upstream of the production of inflammatory cytokines and can aggravate the inflammation.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Jing
authors.initials: J
authors.lastname: Shan
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Oshima
authors.forename: Taichiro
authors.initials: T
authors.lastname: Muto
authors.forename: Koubun
authors.initials: K
authors.lastname: Yasuda
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Fukui
authors.forename: Jiro
authors.initials: J
authors.lastname: Watari
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miwa
mesh_terms: D016022:Case-Control Studies; D002467:Cell Nucleus / Q000276:immunology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology; D004942:Esophagitis, Peptic / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D055785:Gene Knockdown Techniques; D006801:Humans; D018928:Immunity, Mucosal; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D000067596:Interleukin-33 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000096:biosynthesis; D008297:Male; D009092:Mucous Membrane / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D018836:Inflammation Mediators; D000067596:Interleukin-33; D007378:Interleukins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D007371:Interferon-gamma