title: Expression of TNFAIP3 in intestinal epithelial cells protects from DSS- but not TNBS-induced colitis.
abstract: Intestinal epithelial cells (IEC) maintain gastrointestinal homeostasis by providing a physical and functional barrier between the intestinal lumen and underlying mucosal immune system. The activation of NF-κB and prevention of apoptosis in IEC are required to maintain the intestinal barrier and prevent colitis. How NF-κB activation in IEC prevents colitis is not fully understood. TNFα-induced protein 3 (TNFAIP3) is a NF-κB-induced gene that acts in a negative-feedback loop to inhibit NF-κB activation and also to inhibit apoptosis; therefore, we investigated whether TNFAIP3 expression in the intestinal epithelium impacts susceptibility of mice to colitis. Transgenic mice expressing TNFAIP3 in IEC (villin-TNFAIP3 Tg mice) were exposed to dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS), and the severity and characteristics of mucosal inflammation and barrier function were compared with wild-type mice. Villin-TNFAIP3 Tg mice were protected from DSS-induced colitis and displayed reduced production of NF-κB-dependent inflammatory cytokines. Villin-TNFAIP3 Tg mice were also protected from DSS-induced increases in intestinal permeability and induction of IEC death. Villin-TNFAIP3 Tg mice were not protected from colitis induced by TNBS. These results indicate that TNFAIP3 expression in IEC prevents colitis involving DSS-induced IEC death, but not colitis driven by T cell-mediated inflammation. As TNFAIP3 inhibits NF-κB activation and IEC death, expression of TNFAIP3 in IEC may provide an avenue to inhibit IEC NF-κB activation without inducing IEC death and inflammation.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60611, USA.
authors.forename: Lesley
authors.initials: L
authors.lastname: Rhee
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Murphy
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Kolodziej
authors.forename: Wesley A
authors.initials: WA
authors.lastname: Grimm
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Weber
authors.forename: James P
authors.initials: JP
authors.lastname: Lodolce
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Chang
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bartulis
authors.forename: Jeannette S
authors.initials: JS
authors.lastname: Messer
authors.forename: Jeff R
authors.initials: JR
authors.lastname: Schneider
authors.forename: Shirley
authors.initials: S
authors.lastname: Paski
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Nero
authors.forename: David L
authors.initials: DL
authors.lastname: Boone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate / Q000009:adverse effects*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D012720:Severity of Illness Index; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse