Suppression of Na+/H+ exchanger isoform-3 in human inflammatory bowel disease: lack of reversal by 5'-aminosalicylate treatment

Scand J Gastroenterol. 2009;44(1):56-64. doi: 10.1080/00365520802321253.


Objective: Na+/H+ exchanger isoform 3 (NHE-3) is responsible for net uptake of NaCl and water from the gastrointestinal (GI) tract. However, its status in human inflammatory bowel diseases (IBDs) such as ulcerative colitis(UC) and Crohn's disease (CD) remains poorly understood. The aim of this study was to investigate the underlying mechanism of NHE-3 isoform expression and its modulation by 5'-aminosalicylate in human CD and UC.

Material and methods: Subjects were divided into three groups: 1) controls; 2) untreated/new IBD cases (n = 13) and 3) 5'-aminosalicylate-treated IBD patients (n = 13). Subjects presenting with abdominal pain but with endoscopically normal colons served as normal controls. Inflammation was confirmed by the level of myeloperoxidase (MPO) activity, malondialdehyde (MDA) concentrations and by histologic evaluation. Expressions of NHE-3 protein and mRNA, sodium pump activity and IL-1beta and TNF-alpha mRNA were estimated in the colonic biopsies using ECL-Western blot analysis,reverse transcription-polymerase chain reaction (RT-PCR) and enzyme assays.

Results: The level of NHE-3 protein and sodium pump activity was reduced (p < 0.05) in both the untreated and treated CD and UC patients. NHE-3 mRNA was reduced only in CD patients but not in those with UC. The treatment reversed the symptoms, but levels of MPO activity, MDA concentration, IL-1beta, TNF-alpha and infiltration of inflammatory cells remained high with the exception of IL-1beta mRNA in the treated patients.

Conclusions: NHE-3 suppression is regulated differentially in CD and UC, which together with suppression of sodium pump activity will reduce NaCl and water uptake from the colonic lumen. These findings suggest a role of TNF-a in the regulation of NHE-3 expression in IBD.

MeSH terms

  • Adult
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Biopsy
  • Blotting, Western
  • Case-Control Studies
  • Colitis, Ulcerative / drug therapy
  • Colitis, Ulcerative / metabolism
  • Colon / chemistry
  • Colon / metabolism
  • Colon / pathology
  • Crohn Disease / drug therapy
  • Crohn Disease / metabolism
  • Female
  • Humans
  • Inflammatory Bowel Diseases / drug therapy*
  • Inflammatory Bowel Diseases / metabolism*
  • Inflammatory Bowel Diseases / pathology
  • Interleukin-1beta
  • Male
  • Malondialdehyde / metabolism
  • Middle Aged
  • Peroxidase / metabolism
  • Protein Isoforms / drug effects
  • Protein Isoforms / metabolism
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Salicylates / therapeutic use*
  • Sodium Chloride / metabolism
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / drug effects
  • Sodium-Hydrogen Exchangers / metabolism*
  • Sodium-Potassium-Exchanging ATPase / drug effects
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*
  • Water / metabolism


  • Anti-Inflammatory Agents, Non-Steroidal
  • Interleukin-1beta
  • Protein Isoforms
  • RNA, Messenger
  • SLC9A3 protein, human
  • Salicylates
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Tumor Necrosis Factor-alpha
  • Water
  • Sodium Chloride
  • Malondialdehyde
  • Peroxidase
  • Sodium-Potassium-Exchanging ATPase