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

J Clin Invest. 2001 Aug;108(4):601-9. doi: 10.1172/JCI12821.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Cytokines
  • DNA-Binding Proteins
  • Oligodeoxyribonucleotides, Antisense
  • Receptors, Transforming Growth Factor beta
  • SMAD3 protein, human
  • SMAD7 protein, human
  • Smad3 Protein
  • Smad7 Protein
  • TGFB1 protein, human
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I