Blocking Smad7 restores TGF-beta 1 signaling in chronic inflammatory boweldisease

TGF-beta1 functions as a negative regulator of T cell immune responses, sig naling to target cells using the Smad family of proteins. We show here that Smad7, an inhibitor of TGF-beta1 signaling, is overexpressed in inflammato ry bowel disease (IBD) mucosa and purified mucosal T cells. Both whole tiss ue and isolated cells exhibit defective signaling through this pathway, as measured by phospho-Smad3 immunoreactivity. Specific antisense oligonucleot ides for Smad7 reduce Smad7 protein expression in cells isolated from patie nts with IBD, permitting the cells to respond to exogenous TGF-beta1. TGF-b eta1 cannot inhibit proinflammatory cytokine production in isolated lamina propria mononuclear cells from patients with Crohn disease (CD), but inhibi tion of Smad7 restores TGF-beta1 signaling and enables TGF-beta1 to inhibit cytokine production. In inflamed mucosal tissue explants from patients wit h CD, inhibition of Smad7 also restores p-Smad3 and decreases proinflammato ry cytokine production, an effect that is partially blocked by anti-TGF-bet a1. These results show that Smad7 blockade of TGF-beta1 signaling helps mai ntain the chronic production of proinflammatory cytokines that drives the i nflammatory process in IBD and that inhibition of Smad7 enables endogenous TGF-beta to downregulate this response.