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Gut 49:190-198 doi:10.1136/gut.49.2.190
  • Inflammation and inflammatory bowel disease

Loss of transforming growth factor β 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.

AIM Given the effects of transforming growth factor β1 (TGF-β1) on both the immune system and extracellular matrix, we postulated that alterations in TGF-β signalling in intestinal epithelial cells may play an important role in the development of IBD.

METHODS TGF-β signalling was inactivated in mouse intestine by expressing a dominant negative mutant form of the TGF-β 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-β 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-β signalling specifically in the intestine contributes to the development of IBD. Maintenance of TGF-β signalling may be important in regulating immune homeostasis in the intestine

Footnotes

  • Abbreviations used in this paper:
    IBD
    inflammatory bowel disease
    TGF-β
    transforming growth factor β
    MMPs
    matrix metalloproteinases
    ITF
    intestinal trefoil factor
    DSS
    dextran sodium sulphate
    MHC
    major histocompatibility complex
    SPF
    specific pathogen free
    MPO
    myeloperoxidase
    HA
    haemagglutinin
    RT-PCR
    reverse transcription-polymerase chain reaction
    HAI
    histological activity index
    TNF-α
    tumour necrosis factor α
    IL
    interleukin
    IFN-γ
    interferon γ
    TIMP
    tissue inhibitor of metalloproteinase
    IEC
    intestinal epithelial cell
    APC
    antigen presenting cell
    GABs
    anti-goblet cell autoantibody