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

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-1β and TNF-α 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-1β, TNF-α and infiltration of inflammatory cells remained high with the exception of IL-1β 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-α in the regulation of NHE-3 expression in IBD.