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      Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease.

      The Journal of clinical investigation

      Activin Receptors, Type I, Adolescent, Adult, Cells, Cultured, drug effects, Child, Colitis, Ulcerative, metabolism, pathology, Crohn Disease, Cytokines, biosynthesis, genetics, DNA-Binding Proteins, antagonists & inhibitors, physiology, Female, Gene Expression Regulation, Humans, Inflammatory Bowel Diseases, Interferon-gamma, Intestinal Mucosa, Male, Middle Aged, Oligodeoxyribonucleotides, Antisense, pharmacology, Organ Culture Techniques, Phosphorylation, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad3 Protein, Smad7 Protein, Trans-Activators, Transforming Growth Factor beta, Transforming Growth Factor beta1, Tumor Necrosis Factor-alpha

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          TGF-beta1 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-beta1 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-beta1. TGF-beta1 cannot inhibit proinflammatory cytokine production in isolated lamina propria mononuclear cells from patients with Crohn disease (CD), but inhibition of Smad7 restores TGF-beta1 signaling and enables TGF-beta1 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-beta1. These results show that Smad7 blockade of TGF-beta1 signaling helps maintain the chronic production of proinflammatory cytokines that drives the inflammatory process in IBD and that inhibition of Smad7 enables endogenous TGF-beta to downregulate this response.

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