Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease

Abstract

TGF-1 functions as a negative regulator of T cell immune responses, signaling to target cells using the Smad family of proteins.We show here that Smad7, an inhibitor of TGF-1 signaling, is overexpressed in inflammatory bowel disease (IBD) mucosa and purified mucosal T cells.Both whole tissue and isolated cells exhibit defective signaling through this pathway, as measured by phospho-Smad3 immunoreactivity.Specific antisense oligonucleotides for Smad7 reduce Smad7 protein expression in cells isolated from patients with IBD, permitting the cells to respond to exogenous TGF-1.TGF-1 cannot inhibit proinflammatory cytokine production in isolated lamina propria mononuclear cells from patients with Crohn disease (CD), but inhibition of Smad7 restores TGF-1 signaling and enables TGF-1 to inhibit cytokine production.In inflamed mucosal tissue explants from patients with CD, inhibition of Smad7 also restores p-Smad3 and decreases proinflammatory cytokine production, an effect that is partially blocked by anti-TGF-1.These results show that Smad7 blockade of TGF-1 signaling helps maintain the chronic production of proinflammatory cytokines that drives the inflammatory process in IBD and that inhibition of Smad7 enables endogenous TGF- to downregulate this response.