title: Trp53 deficiency protects against acute intestinal inflammation.
abstract: The p53 protein has not only important tumor suppressor activity but also additional immunological and other functions, whose nature and extent are just beginning to be recognized. In this article, we show that p53 has a novel inflammation-promoting action in the intestinal tract, because loss of p53 or the upstream activating kinase, ATM, protects against acute intestinal inflammation in murine models. Mechanistically, deficiency in p53 leads to increased survival of epithelial cells and lamina propria macrophages, higher IL-6 expression owing to enhanced glucose-dependent NF-κB activation, and increased mucosal STAT3 activation. Blockade or loss of IL-6 signaling reverses the protective effects of p53 deficiency. Conversely, IL-6 treatment protects against acute colitis in a manner dependent on STAT3 signaling and induction of cytoprotective factors in epithelial cells. Together, these results indicate that p53 promotes inflammation in the intestinal tract through suppression of epithelium-protective factors, thus significantly expanding the spectrum of physiological and immunological p53 activities unrelated to cancer formation.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Martina E
authors.initials: ME
authors.lastname: Spehlmann
authors.forename: Carolin F
authors.initials: CF
authors.lastname: Manthey
authors.forename: Sara M
authors.initials: SM
authors.lastname: Dann
authors.forename: Elaine
authors.initials: E
authors.lastname: Hanson
authors.forename: Sukhman S
authors.initials: SS
authors.lastname: Sandhu
authors.forename: Linus Y
authors.initials: LY
authors.lastname: Liu
authors.forename: Farid K
authors.initials: FK
authors.lastname: Abdelmalak
authors.forename: Michaela A
authors.initials: MA
authors.lastname: Diamanti
authors.forename: Kristin
authors.initials: K
authors.lastname: Retzlaff
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
authors.forename: Jean Y J
authors.initials: JY
authors.lastname: Wang
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
mesh_terms: D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D001854:Bone Marrow Cells / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000517:prevention & control; D015850:Interleukin-6 / Q000096:biosynthesis / Q000494:pharmacology; D007378:Interleukins / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D007378:Interleukins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000097043:Interleukin-22; C494087:Stat3 protein, mouse; C576325:Atm protein, mouse