Epithelial NF-kappaB enhances transmucosal fluid movement by altering tight junction protein composition after T cell activation.
In inflammatory bowel disease (IBD), aberrant activation of innate and adaptive immune responses enhances mucosal permeability through mechanisms not completely understood. To examine the role of epithelial nuclear factor (NF-kappaB) in IBD-induced enhanced permeability, epithelial-specific IkappaBalpha mutant (NF-kappaB super repressor) transgenic (TG) mice were generated. NF-kB activation was inhibited in TG mice, relative to wild-type mice, following T cell-mediated immune cell activation using an anti-CD3 monoclonal antibody. Furthermore, epithelial NF-kappaB super repressor protein inhibited diarrhea and blocked changes in transepithelial resistance and transmucosal flux of alexa350 (0.35 kDa) and dextran3000 (3 kDa). In vivo perfusion loop studies in TG mice revealed reversed net water secretion and reduced lumenal flux of different molecular probes (bovine serum albumin, alexa350, and dextran3000). Cell-imaging and immunoblotting of low-density, detergent-insoluble membrane fractions confirmed that tight junction proteins (occludin, claudin-1 and zona occludens-1) are internalized through an NF-kappaB-dependent pathway. Taken together, these data suggest that IBD-associated diarrhea results from NF-kappaB-mediated tight junction protein internalization and increased paracellular permeability. Thus, reduction of epithelial NF-kappaB activation in IBD may repair defects in epithelial barrier function, reduce diarrhea, and limit protein (eg, serum albumin) losses. Epithelial NF-kappaB activation induced by mucosal T cells, therefore, actively plays a role in opening paracellular spaces to promote transmucosal fluid effux into the intestinal lumen.
Tang
Yueming
Y
Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Clayburgh
Daniel R
DR
Mittal
Navdha
N
Goretsky
Tatiana
T
Dirisina
Ramanarao
R
Zhang
Zheng
Z
Kron
Michelle
M
Ivancic
David
D
Katzman
Rebecca B
RB
Grimm
Gery
G
Lee
Goo
G
Fryer
Jonathan
J
Nusrat
Asma
A
Turner
Jerrold R
JR
Barrett
Terrence A
TA
D000818:Animals; D003967:Diarrhea / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D046911:Macromolecular Substances / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009928:Organ Specificity; D010539:Permeability; D012212:Rheology; D013601:T-Lymphocytes / Q000276:immunology*; D019108:Tight Junctions / Q000378:metabolism* / Q000473:pathology
D020672:I-kappa B Proteins; D046911:Macromolecular Substances; D008565:Membrane Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha