Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activin Receptors, Type I*
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Adolescent
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Adult
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Cells, Cultured / drug effects
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Child
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Colitis, Ulcerative / metabolism
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Colitis, Ulcerative / pathology
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Crohn Disease / metabolism
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Crohn Disease / pathology
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Cytokines / biosynthesis
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Cytokines / genetics
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology
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Female
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Gene Expression Regulation / drug effects
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Humans
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Inflammatory Bowel Diseases / metabolism*
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Inflammatory Bowel Diseases / pathology
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Interferon-gamma / biosynthesis
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Interferon-gamma / genetics
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / pathology
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Male
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Middle Aged
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Oligodeoxyribonucleotides, Antisense / pharmacology*
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Organ Culture Techniques
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Phosphorylation
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / drug effects*
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Protein Serine-Threonine Kinases / physiology
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / drug effects*
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Receptors, Transforming Growth Factor beta / physiology
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Signal Transduction / drug effects*
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Smad3 Protein
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Smad7 Protein
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Trans-Activators / physiology
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Transforming Growth Factor beta / physiology*
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Transforming Growth Factor beta1
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
Substances
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Cytokines
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DNA-Binding Proteins
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Oligodeoxyribonucleotides, Antisense
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Receptors, Transforming Growth Factor beta
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SMAD3 protein, human
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SMAD7 protein, human
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Smad3 Protein
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Smad7 Protein
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TGFB1 protein, human
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Trans-Activators
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Tumor Necrosis Factor-alpha
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Interferon-gamma
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Receptor, Transforming Growth Factor-beta Type I