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* Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center and
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229; and
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599
NF-
B plays a central, proinflammatory role in chronic intestinal inflammation, yet recent work suggests a predominantly protective function for this transcription factor group in some cell types of the intestine. We herein describe the conditional deletion of the NF-B RelA gene in murine intestinal epithelia and determine its function in homeostatic control of enterocyte proliferation/apoptosis and susceptibility to colonic inflammation. Mice lacking RelA in ileal and colonic enterocytes were born in expected Mendelian ratios, and RelA-null epithelia differentiated normally. Spontaneous intestinal disease and death occurred with low penetrance in neonates lacking epithelial RelA. IB
and IBβ were significantly diminished in RelA-null epithelia, and endotoxin challenge revealed elevated p50 and c-Rel DNA binding activity as compared with controls. Deletion of RelA resulted in diminished expression of antimicrobial (defensin-related cryptdin 4, defensin-related cryptdin 5, RegIII
) and antiapoptotic, prorestitution genes (Bcl-xL, RegIV, IL-11, IL-18), and basal rates of epithelial apoptosis and proliferation were elevated. Mice lacking colonic RelA were sensitive to dextran sodium sulfate-induced colitis. Although experimental colitis enhanced proliferation in cells lacking RelA, sustained epithelial cell apoptosis precluded mucosal healing and decreased animal survival. We conclude that activation of RelA is required for homeostatic regulation of cell death and division in intestinal epithelia, as well as for protection from development of severe, acute inflammation of the intestine.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by grants from the American Cancer Society, Crohn’s and Colitis Foundation of America, and University of North Carolina Center for Gastrointestinal Biology and Disease Pilot and Feasibility Grant P30 DK34987 (to K.A.S.), and by National Institutes of Health Grants R01 AI35098, R01 CA73756, and R01 CA75080 (to A.S.B.). A.S.B. is an investigator of the Samuel Waxman Cancer Research Foundation.
2 Address correspondence and reprint requests to Dr. Albert S. Baldwin, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599. E-mail address: abaldwin{at}med.unc.edu or Dr. Kris A. Steinbrecher, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229. E-mail address: Kris.Steinbrecher{at}cchmc.org
3 Abbreviations used in this paper: IKK, IB kinase; DAPA, DNA affinity protein-binding assay; Defcr, defensin-related cryptdin; DSS, dextran sulfate sodium; IEC, intestinal epithelial cell; PRR, pattern recognition receptor; Reg, regenerating islet-derived protein; TSLP, thymic stromal lymphopoietin; XIAP, X-linked inhibitor of apoptosis.
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