title: Loss of transforming growth factor beta signalling in the intestine contributes to tissue injury in inflammatory bowel disease.
abstract: BACKGROUND
  Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract caused by an abnormal and uncontrolled immune response to one or more normally occurring gut constituents.
  
  
  OBJECTIVE
  Given the effects of transforming growth factor beta1 (TGF-beta1) on both the immune system and extracellular matrix, we postulated that alterations in TGF-beta signalling in intestinal epithelial cells may play an important role in the development of IBD.
  
  
  METHODS
  TGF-beta signalling was inactivated in mouse intestine by expressing a dominant negative mutant form of the TGF-beta type II receptor under the control of the mouse intestinal trefoil peptide (ITF)/TFF3 promoter. Transgenic mice (ITF-dnRII) developed spontaneous colitis presenting with diarrhoea, haematochezia, and anal prolapse when not maintained under specific pathogen free (SPF) conditions. Under SPF conditions we induced colitis by mixing dextran sodium sulphate (DSS) in drinking water to examine the significance of loss of TGF-beta signalling in the pathogenesis of IBD.
  
  
  RESULTS
  Transgenic mice showed increased susceptibility to DSS induced IBD, and elicited increased expression of major histocompatibility complex class II, generation of autoantibodies against intestinal goblet cells, and increased activity of matrix metalloproteinase in intestinal epithelial cells compared with wild-type littermates challenged with DSS.
  
  
  CONCLUSIONS
  Deficiency of TGF-beta signalling specifically in the intestine contributes to the development of IBD. Maintenance of TGF-beta signalling may be important in regulating immune homeostasis in the intestine
authors.affiliation: Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Library Dr, Bethesda, MD 20892, USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Hahm
authors.forename: Y H
authors.initials: YH
authors.lastname: Im
authors.forename: T W
authors.initials: TW
authors.lastname: Parks
authors.forename: S H
authors.initials: SH
authors.lastname: Park
authors.forename: S
authors.initials: S
authors.lastname: Markowitz
authors.forename: H Y
authors.initials: HY
authors.lastname: Jung
authors.forename: J
authors.initials: J
authors.lastname: Green
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015153:Blotting, Western; D002450:Cell Communication / Q000502:physiology*; D005802:Genes, MHC Class II; D005856:Germ-Free Life; D020397:Goblet Cells / Q000276:immunology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000503:physiopathology*; D008163:Luminescent Measurements; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D019278:Matrix Metalloproteinase 3 / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; D011506:Proteins / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000071165:Trefoil Factor-3
chemical_list: D001323:Autoantibodies; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; D011506:Proteins; D018125:Receptors, Transforming Growth Factor beta; C082495:TFF3 protein, human; D016212:Transforming Growth Factor beta; D000071165:Trefoil Factor-3; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9