T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+-ATPase

Inflammatory bowel disease (IBD) is associated with mucosal T cell activation and diarrhea.We found that T cell activation with anti-CD3 mAb induces profound diarrhea in mice.Diarrhea was quantified by intestinal weight-to-length (wt/l) ratios, mucosal Na + /K + -ATPase activity was determined and ion transport changes were measured in Ussing chambers.Anti-CD3 mAb increased jejunal wt/l ratios by more than 50% at 3 hours, returning to base line after 6 hours.Fluid accumulation was significantly reduced in TNF receptor-1 (TNFR-1 -/-), but not IFN-γ knockout mice.Anti-CD3 mAb decreased mucosal Na + /K + -ATPase activity, which was blocked by anti-TNF mAb and occurred to a lesser degree in TNFR-1 -/-mice.Neither α nor β subunits of Na + /K + -ATPase decreased in abundance at 3 hours.Intestinal tissue from anti-CD3-treated mice exhibited increased permeability to mannitol at 1 hour and decreases in electroneutral Na + absorption, Na + -dependent glucose absorption, and cAMP-stimulated anion secretion at 3 hours.Furthermore, enteral fluid accumulation was observed in CFTR -/-mice, indicating a minor role of active anion secretion.These data suggest that diarrhea in IBD is due to TNF-mediated malabsorption rather than to secretory processes.T cell activation induces luminal fluid accumulation by increasing mucosal permeability and reducing epithelial Na + /K + -ATPase activity leading to decreased intestinal Na + and water absorption.