Co-transfer of regulatory T cells from wild-type, but not from sCYLD/SMAD7, mice prevented the induction of colitis in Rag1<sup>-/-</sup> mice by CD4<sup>+</sup> T cells.
TGF-β had a greatly diminished capacity to induce Tregs in <i>H. polygyrus bakeri</i>-infected transgenic mice with constitutively high T cell-specific Smad7 expression.Thus, infection with <i>H. polygyrus bakeri</i> causes down-modulation in Smad7 expression in intestinal CD4<sup>+</sup> T cells, which allows the TGF-β produced in response to the infection to induce the Tregs that prevent colitis.
Consistently, silencing of Smad7 with a specific antisense oligonucleotide restores transforming growth factor-β1/Smad3 signalling, thereby leading to inhibition of inflammatory cytokine production and attenuation of experimental colitis in mice.
Indeed, studies in human IBD tissues and murine models of colitis have documented a disruption of TGF-β1 signalling marked by a block in the phosphorylation of Smad3, a signalling molecule associated with the activated TGF-β receptor, due to up-regulation of Smad7, an intracellular inhibitor of Smad3 phosphorylation.