NF-kappaB p50 and p65 subunits control intestinal homeostasis.
Mice which lack the p50 subunit of NF-kappaB and are heterozygous for the p65 subunit (3X mice), are exquisitely sensitive to LPS-induced shock. Here, we demonstrate that prior to becoming moribund, 3X mice challenged with LPS develop a profound enteropathy. The enteropathy is characterized by defects in intestinal barrier function, increased epithelial apoptosis, and deregulated intestinal cytokine gene expression. The defect that sensitizes 3X mice to LPS-induced enteropathy is located within the innate immune compartment, as LPS induced similar findings in 3X mice lacking lymphocytes (3X/RAG). TNF-alpha depletion ameliorated the ability of LPS to induce pathology and TNF-alpha was able to independently induce similar findings, suggesting that TNF-alpha plays a critical role in the development of LPS-induced pathology in these mice. These data highlight that NF-kappaB subunits have essential functions in regulating intestinal homeostasis during acute inflammation.
Gadjeva
Mihaela
M
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Wang
Yanyan
Y
Horwitz
Bruce H
BH
D000818:Animals; D017209:Apoptosis; D005786:Gene Expression Regulation; D006706:Homeostasis; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D051996:Transcription Factor RelA / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D021122:Protein Subunits; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha