Trends in Immunology
Smad7 in TGF-β-mediated negative regulation of gut inflammation
Section snippets
Smad signaling with particular relevance to inflammatory bowel disease (IBD)
Presence or absence of TGF-β1 is not a particularly accurate reflection of the role of this cytokine in tissues. Between 1996 and 1999, great advances were made in elucidating the TGF-β1-associated signalling pathway, which has informed understanding of how TGF-β1 regulates immune responses at the mucosal level. The first clues came from genetic studies of TGF-β1-related family members in Drosophila and Caenorhabditis elegans, which led to the functional characterisation of ‘Smad’ proteins 14,
Control and localisation of Smad7 in cells
If Smad7 is the crucial regulator of whether or not a cell can respond to TGF-β1, then an obvious question is what controls the expression and localisation of Smad7 in cells? The first studies suggested a simple linear pathway with Smad7 being transcriptionally regulated by external stimuli. Smad7 is induced in cell lines by the STAT1 (signal transducer and activator of T cells 1) pathway following activation with interferon-γ (IFN-γ) or interleukin-7 (IL-7), or by activated NF-κB following
Functional relevance of Smad7 in the gut mucosa
If TGFβ1 is suppressing pathogenic T-cell responses to the bacterial flora in the gut, it would be expected that mice whose T cells overexpress Smad7 would develop an IBD. Surprisingly, however, these mice are essentially normal, despite the fact that their T cells do not respond to TGFβ-1 with Smad2 phosphorylation [38]. However, given what is now known about the control of Smad7 inside cells, there is the possibility that, in vivo, most of the overexpressed Smad7 in the transgenic mice
Smad7 and Tr cells
At the moment, there is very little evidence for Tr-cell activity as an important determinant of clinical gut inflammation. Murine studies clearly suggest a role for TGF-β1, either secreted by T cells or membrane bound, in the control of IBD in the SCID (severe combined immunodeficiency) and RAG transfer model of colitis by CD4, CD25+ Tr cells 2, 40. However, the limitations of this model need to be pointed out and, even in mice, there is little evidence for Tr cells suppressing colitis in an
Concluding remarks
There is absolutely no doubt that TGF-β1 is a cytokine of crucial importance in dampening tissue-damaging immune responses, especially in the gut. However, we propose that the effects of TGF-β1 in the microenvironment are not linearly related to its relative abundance. Inhibitory Smads, such as Smad7, control the strength of the signal from the cell surface to the nucleus and thus control cell function. This, then, logically puts regulation of Smad7 inside the cell as a topic of considerable
Acknowledgements
We have received support for work on the role of Smad7 in the gut from the Eli and Edythe L Broad Foundation, Crohn's in Childhood Research Appeal, The Belmont Trust, the European Union and the Fondazione ‘Umberto Di Mario’, Rome.
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