Enterocyte-specific A20 deficiency sensitizes to tumor necrosis factor-induced toxicity and experimental colitis.
A20 is a nuclear factor kappaB (NF-kappaB) target gene that encodes a ubiquitin-editing enzyme that is essential for the termination of NF-kappaB activation after tumor necrosis factor (TNF) or microbial product stimulation and for the prevention of TNF-induced apoptosis. Mice lacking A20 succumb to inflammation in several organs, including the intestine, and A20 mutations have been associated with Crohn's disease. However, ablation of NF-kappaB activity, specifically in intestinal epithelial cells (IECs), promotes intestinal inflammation. As A20 deficiency sensitizes cells to TNF-induced apoptosis yet also promotes NF-kappaB activity, it is not clear if A20 deficiency in IECs would exacerbate or ameliorate intestinal inflammation. We generated mice lacking A20 specifically in IECs. These mice did not show spontaneous intestinal inflammation but exhibited increased susceptibility to experimental colitis, and their IECs were hypersensitive to TNF-induced apoptosis. The resulting TNF-driven breakdown of the intestinal barrier permitted commensal bacterial infiltration and led to systemic inflammation. These studies define A20 as a major antiapoptotic protein in the intestinal epithelium and further indicate that defects in A20 might contribute to inflammatory bowel disease in humans.
Department for Molecular Biomedical Research, VIB, B-9052 Ghent, Belgium.
Lars
L
Vereecke
Mozes
M
Sze
Conor
C
Mc Guire
Brecht
B
Rogiers
Yuanyuan
Y
Chu
Marc
M
Schmidt-Supprian
Manolis
M
Pasparakis
Rudi
R
Beyaert
Geert
G
van Loo
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001419:Bacteria / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000172:deficiency* / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects; D004198:Disease Susceptibility / Q000473:pathology; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D010641:Phenotype; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D047908:Intracellular Signaling Peptides and Proteins; D053594:Myeloid Differentiation Factor 88; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse