title: Serotonin disrupts esophageal mucosal integrity: an investigation using a stratified squamous epithelial model.
abstract: BACKGROUND
  Serotonin regulates gastrointestinal function, and mast cells are a potential nonneuronal source of serotonin in the esophagus. Tight junction (TJ) proteins in the esophageal epithelium contribute to the barrier function, and the serotonin signaling pathway may contribute to epithelial leakage in gastroesophageal reflux disease. Therefore, the aim of this study was to investigate the role of serotonin on barrier function, TJ proteins, and related signaling pathways.
  
  
  METHODS
  Normal primary human esophageal epithelial cells were cultured with use of an air-liquid interface system. Serotonin was added to the basolateral compartment, and transepithelial electrical resistance (TEER) was measured. The expression of TJ proteins and serotonin receptor 7 (5-HT7) was assessed by Western blotting. The involvement of 5-HT7was assessed with use of an antagonist and an agonist. The underlying cellular signaling pathways were examined with use of specific blockers.
  
  
  RESULTS
  Serotonin decreased TEER and reduced the expression of TJ proteins ZO-1, occludin, and claudin 1, but not claudin 4. A 5-HT7antagonist blocked the serotonin-induced decrease in TEER, and a 5-HT7agonist decreased TEER. Inhibition of p38 mitogen-activated protein kinase (MAPK) reduced the serotonin-induced decrease in TEER. Inhibition of p38 MAPK blocked the decrease of ZO-1 levels, whereas extracellular-signal-regulated kinase (ERK) inhibition blocked the decrease in occludin levels. Cell signaling pathway inhibitors had no effect on serotonin-induced alterations in claudin 1 and claudin 4 levels. Serotonin induced phosphorylation of p38 MAPK and ERK, and a 5-HT7antagonist partially blocked serotonin-induced phosphorylation of p38 MAPK but not that of ERK.
  
  
  CONCLUSIONS
  Serotonin disrupted esophageal squamous epithelial barrier function by modulating the levels of TJ proteins. Serotonin signaling pathways may mediate the pathogenesis of gastroesophageal reflux disease.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.|Department of Gastroenterology, The Third People's Hospital of Chengdu, Chengdu, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Wu
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. t-oshima@hyo-med.ac.jp.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Oshima
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ohda
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Fukui
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Watari
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miwa
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000071041:Esophageal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D011985:Receptors, Serotonin / Q000378:metabolism / Q000502:physiology; D012701:Serotonin / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D062725:Tight Junction Proteins / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D011985:Receptors, Serotonin; D062725:Tight Junction Proteins; C104425:serotonin 7 receptor; D012701:Serotonin; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Air–liquid interface; Serotonin; Stratified epithelium; Tight junction protein; Transepithelial electrical resistance