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Recent studies have shown that cytokines produced by T lymphocytes and antigen presenting cells play an important role in both the induction and perpetuation of chronic intestinal inflammation.1-5 In particular, the balance between interleukin 12/interferon γ and transforming growth factor β (TGF-β) responses has been shown to regulate the occurrence of chronic intestinal inflammation.6 The TGF-β superfamily consists of multifunctional cytokines, including TGF-β 1–3, activins, inhibins, and bone morphogenetic proteins. TGF-β1 mediates its functions by binding to the accessory TGF-β type III receptor that serves as a ligand for the TGF-β type II receptor. Receptor bound TGF-β1 recruits TGF-β type I receptor into the complex leading to formation of a heteromeric complex that finally results in phosphorylation and activation of receptor regulated Smad proteins (Smad2, Smad3). The latter proteins form heteromeric complexes with Smad4 which translocate to the nucleus to control gene transcription hereby mediating the biological effects of TGF-β1.
In this issue of Gut, Hahm and colleagues7 demonstrate that inactivation of TGF-β signalling in the murine intestine by transgenic expression of a dominant negative form of the TGF-β type II receptor in the intestinal epithelium (using a ITF/TFF3 promoter construct) results in spontaneous colitis when mice are housed under non specific pathogen free (SPF) conditions (see page 190). Under SPF conditions however transgenic mice did not develop spontaneous colitis but showed enhanced susceptibility to colitis induced by dextran sulphate. These data suggest that TGF-β signalling in intestinal epithelial cells plays a crucial role in maintaining mucosal immune homeostasis. Interestingly, colitis development in transgenic animals was associated with increased expression of MHC class II molecules on intestinal epithelial cells and increased activity of matrix metalloproteinases7suggesting that TGF-β signalling in intestinal epithelial cells regulates either directly or indirectly antigen presentation and activation of matrix metalloproteinases in the intestine. Understanding the details of the pathogenesis of chronic intestinal inflammation in this novel transgenic model will require further analysis. However, this animal model may be a very useful tool to analyse the functions of TGF-β signalling in intestinal epithelial cells at an immunological and molecular level.
The present study extends various previous observations that have suggested an important regulatory role for TGF-β in controlling T cell mediated mucosal immune responses. The production of TGF-β seems to be a fundamental property of regulatory CD45Rblow CD4+ T cells that can prevent colitis when cotransferred with CD45Rbhigh T cells in SCID mice,8 as neutralising antibodies to TGF-β can suppress the protective capacities of the former cells in vivo. Furthermore, inactivation of TGF-β1 has been shown to result in multiorgan inflammation, including intestinal inflammation that is mediated by activated T lymphocytes.9-11 In addition, disruption of TGF-β signalling in Smad3 knockout mice has been shown to result in intestinal inflammation and colon carcinoma formation.12 13 Finally, Gorelik and Flavell14 recently showed that expression of a dominant negative TGF-β receptor type II under a T cell specific promoter results in spontaneous T cell differentiation and autoimmune disease, suggesting a key role for TGF-β signalling in T cell homeostasis. Taken together with the present study, these data suggest that intact TGF-β signalling in both intestinal epithelial cells and T lymphocytes is critical for maintenance of mucosal homeostasis, prevention of proinflammatory cytokine responses and chronic intestinal inflammation. The potential therapeutic relevance of this finding has been suggested by two studies showing that induction of TGF-β mediated oral tolerance15 and intranasal delivery of a TGF-β1 expressing plasmid can suppress chronic intestinal inflammation in mice.16 However, as TGF-β expression is already increased in patients with inflammatory bowel disease17 and as TGF-β has been implicated in mediating tissue fibrosis and stricture formation in this disease, further studies are necessary before modulation of TGF-β responses may be applicable to therapeutic studies in humans.
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