Loss of transforming growth factor beta signalling in the intestine contributes to tissue injury in inflammatory bowel disease

Background - Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract caused by an abnormal and uncontrolled immune re sponse to one or more normally occurring gut constituents. Aim-Given the ef fects of transforming growth factor beta (TGF-beta1) on both the immune sys tem and extracellular matrix, we postulated that alterations in TGF-beta si gnalling in intestinal epithelial cells may play an important role in the d evelopment of IBD. Methods - TGF-beta signalling was inactivated in mouse intestine by express ing a dominant negative mutant form of the TGF-beta type II receptor under the control of the mouse intestinal trefoil peptide (ITF)/TFF3 promoter. Tr ansgenic mice (ITF-dnRII) developed spontaneous colitis presenting with dia rrhoea, 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 sign ificance of loss of TGF-beta signalling in the pathogenesis of IBD. Results - Transgenic mice showed increased susceptibility to DSS induced IB D, and elicited increased expression of major histocompatibility complex cl ass II, generation of autoantibodies against intestinal goblet cells, and i ncreased activity of matrix metalloproteinase in intestinal epithelial cell s compared with wild-type littermates challenged with DSS. Conclusions - Deficiency of TGF-beta signalling specifically in the intesti ne contributes to the development of IBD. Maintenance of TGF-beta signallin g may be important in regulating immune homeostasis in the intestine.