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-gamma 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 alpha nor beta 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.
Musch
Mark W
MW
The Martin Boyer Laboratories, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Clarke
Lane L
LL
Mamah
Daniel
D
Gawenis
Lara R
LR
Zhang
Zheng
Z
Ellsworth
William
W
Shalowitz
David
D
Mittal
Navdha
N
Efthimiou
Petros
P
Alnadjim
Ziad
Z
Hurst
Steve D
SD
Chang
Eugene B
EB
Barrett
Terrence A
TA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology; D017252:CD3 Complex / Q000276:immunology; D002463:Cell Membrane Permeability; D005576:Colforsin / Q000494:pharmacology; D003967:Diarrhea / Q000276:immunology* / Q000503:physiopathology; D018928:Immunity, Mucosal; D007371:Interferon-gamma / Q000172:deficiency; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007413:Intestinal Mucosa / Q000201:enzymology / Q000503:physiopathology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D017252:CD3 Complex; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D005576:Colforsin; D007371:Interferon-gamma; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase