Smad7 in TGF-β-mediated negative regulation of gut inflammation

Mice with targeted disruptions of the transforming growth factor-β1 (TGF-β1) gene or TGF-β1 intracellular signalling pathways develop intestinal inflammation. Conversely, TGF-β1-producing regulatory T cells protect against experimental colitis. Paradoxically, however, TGF-β1 production is high in the gut of patients with chronic inflammatory intestinal disease, and yet inflammation proceeds unchecked. Here we discuss the functional role of Smad7, an intracellular inhibitor of TGF-β1 signalling, in the control of gut inflammation by TGF-β1. In particular, we delineate a scenario in which the high expression of Smad7 in inflammatory cells renders them unresponsive to TGF-β1 and propose that control of Smad7, not TGF-β1 production, is a key determinant in understanding how TGF-β1 negatively regulates gut inflammation.