title: Cytokine-dependent transcriptional down-regulation of epithelial sodium channel in ulcerative colitis.
abstract: OBJECTIVE
  The main limiting factor for sodium absorption in distal colon is the amiloride-sensitive epithelial sodium channel (ENaC). This study aimed to characterize mechanisms involved in the dysregulation of ENaC expression in ulcerative colitis (UC).
  
  
  METHODS
  Epithelial preparations from surgically removed inflamed and control sigmoid colons were used. Active electrogenic Na(+) transport (J(Na)) was determined after 8-hour aldosterone stimulation in Ussing-chambers (corrected for the altered epithelial/subepithelial resistance ratio). Subsequently, ENaC alpha-, beta-, and gamma-subunits were analyzed immunohistochemically and in Western and Northern blots (corrected for the inflammatory increase in subepithelial protein content). To study gene regulation, the promoters of beta- and gamma-ENaC were analyzed in reporter gene assays.
  
  
  RESULTS
  In controls, aldosterone stimulated J(Na) and induced ENaC beta- and gamma-subunit expression, whereas this response was virtually abolished in UC. Preservation of surface epithelium in UC was indicated by unchanged ENaC alpha-subunit expression, which points also against a mere immaturity or epithelial cell loss. Inhibition of electrogenic sodium transport as well as beta- and gamma-ENaC mRNA expression could be mimicked in control colon by in vitro preexposure for 8 hours to tumor necrosis factor alpha and interferon gamma. Promoter analysis revealed that down-regulation of beta- and gamma-ENaC gene expression was primarily induced by tumor necrosis factor alpha.
  
  
  CONCLUSIONS
  We conclude that, in UC, elevated proinflammatory cytokines selectively impair beta- and gamma-ENaC expression, which contributes to diarrhea by reducing colonic sodium absorption.
authors.affiliation: Department of Clinical Physiology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.
authors.forename: Salah
authors.initials: S
authors.lastname: Amasheh
authors.forename: Christian
authors.initials: C
authors.lastname: Barmeyer
authors.forename: Corinna Swanette
authors.initials: CS
authors.lastname: Koch
authors.forename: Shida
authors.initials: S
authors.lastname: Tavalali
authors.forename: Joachim
authors.initials: J
authors.lastname: Mankertz
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Epple
authors.forename: Maren Melanie
authors.initials: MM
authors.lastname: Gehring
authors.forename: Peter
authors.initials: P
authors.lastname: Florian
authors.forename: Anton-Josef
authors.initials: AJ
authors.lastname: Kroesen
authors.forename: Martin
authors.initials: M
authors.lastname: Zeitz
authors.forename: Michael
authors.initials: M
authors.lastname: Fromm
authors.forename: Jörg-Dieter
authors.initials: JD
authors.lastname: Schulzke
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D003093:Colitis, Ulcerative / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003967:Diarrhea / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D015536:Down-Regulation; D053503:Epithelial Sodium Channels; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D053503:Epithelial Sodium Channels; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; C507048:SCNN1B protein, human; D015222:Sodium Channels; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D012964:Sodium