title: Toll-interacting protein modulates colitis susceptibility in mice.
abstract: BACKGROUND
  The intestinal epithelium accommodates with a myriad of commensals to maintain immunological homeostasis, but the underlying mechanisms regulating epithelial responsiveness to flora-derived signals remain poorly understood. Herein, we sought to determine the role of the Toll/interleukin (IL)-1 receptor regulator Toll-interacting protein (Tollip) in intestinal homeostasis.
  
  
  METHODS
  Colitis susceptibility was determined after oral dextran sulfate sodium (DSS) administration or by breeding Tollip on an IL-10 background. The intestinal flora was depleted with 4 antibiotics before DSS exposure to assess its contribution in colitis onset. Bone marrow chimeras were generated to identify the cellular compartment, whereby Tollip may negatively regulate intestinal inflammation in response to DSS. Tollip-dependent epithelial barrier functions were studied in vitro by using Tollip-knockdown in Caco-2 cells and in vivo by immunohistochemistry and fluorescein isothiocyanate-labeled dextran gavage.
  
  
  RESULTS
  Genetic ablation of Tollip did not lead to spontaneous intestinal inflammatory disorders. However, Tollip deficiency aggravated spontaneous disease onset in IL-10 mice and increased susceptibility to DSS colitis. Increased colitis severity in Tollip-deficient mice was not improved by bacterial flora depletion using broad-spectrum antibiotics. In addition, DSS exposure of bone marrow chimeric mice revealed a protective role for Tollip in nonhematopoietic cells. Knockdown of Tollip in epithelial cells led to exaggerated NFκ-B activity and proinflammatory cytokine secretion. Finally, DSS-treated Tollip mice showed enhanced intestinal permeability and increased epithelial apoptosis when compared with wild-type controls, a finding that coincided with tight junction alterations on injury.
  
  
  CONCLUSIONS
  Overall, our data show an essential role for Tollip on colitis susceptibility in mice.
authors.affiliation: *Service of Gastroenterology and Hepatology, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; †Translational Gastroenterology Unit, Division of Experimental Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; ‡M2iSH, UMR1071 Inserm, Université d'Auvergne, USC-INRA 2018, Clermont-Ferrand, France; §Institut Universitaire de Technologie en Génie Biologique, Aubière, France; ‖Univ Lille Nord de France, Lille, France; ¶Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; **Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8204, Lille, France; ††Institut National de la Santé et de la Recherche Médicale, U1019, Team 7, Equipe FRM, Lille, France; and ‡‡La Source-Beaulieu, Lausanne, Switzerland.
authors.forename: Michel H
authors.initials: MH
authors.lastname: Maillard
authors.forename: Hristina
authors.initials: H
authors.lastname: Bega
authors.forename: Holm H
authors.initials: HH
authors.lastname: Uhlig
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barnich
authors.forename: Teddy
authors.initials: T
authors.lastname: Grandjean
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.forename: Pierre
authors.initials: P
authors.lastname: Michetti
authors.forename: Dominique
authors.initials: D
authors.lastname: Velin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D001854:Bone Marrow Cells; D018938:Caco-2 Cells; D002678:Chimera; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016264:Dextran Sulfate; D005243:Feces / Q000382:microbiology; D005260:Female; D055785:Gene Knockdown Techniques; D006487:Hemostasis; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology; D010539:Permeability; D012333:RNA, Messenger / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010457:Peptidoglycan; D012333:RNA, Messenger; C485837:Tollip protein, mouse; D016753:Interleukin-10; D016264:Dextran Sulfate