Smad2 and Smad3 Inversely Regulate TGF-β Autoinduction in Clostridium butyricum-Activated Dendritic Cells

Immunity. 2015 Jul 21;43(1):65-79. doi: 10.1016/j.immuni.2015.06.010. Epub 2015 Jun 30.


Colonization with a mixture of Clostridium species has been shown to induce accumulation of induced regulatory T (iTreg) cells in the colon. Transforming growth factor-β (TGF-β) is an essential factor for iTreg cell induction; however, the relationship between Clostridium species and TGF-β remains to be clarified. Here we demonstrated that a gram-positive probiotic bacterial strain, Clostridium butyricum (C. butyricum), promoted iTreg cell generation in the intestine through induction of TGF-β1 from lamina propria dendritic cells (LPDCs). C. butyricum-mediated TGF-β1 induction was mainly Toll-like receptor 2 (TLR2) dependent, and the ERK-AP-1 kinase pathway played an important role. In addition, the autocrine TGF-β-Smad3 transcription factor signal was necessary for robust TGF-β expression in DCs, whereas Smad2 negatively regulated TGF-β expression. Smad2-deficient DCs expressed higher concentrations of TGF-β and were tolerogenic for colitis models. This study reveals a novel mechanism of TGF-β induction by Clostridia through a cooperation between TLR2-AP-1 and TGF-β-Smad signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Clostridium Infections / immunology
  • Clostridium Infections / microbiology
  • Clostridium butyricum / immunology*
  • Colitis / immunology
  • Dendritic Cells / immunology*
  • Extracellular Signal-Regulated MAP Kinases / immunology
  • Intestines / immunology
  • Intestines / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mucous Membrane / cytology
  • Mucous Membrane / immunology
  • Promoter Regions, Genetic / genetics
  • Smad2 Protein / genetics*
  • Smad3 Protein / genetics*
  • T-Lymphocytes, Regulatory / immunology
  • Toll-Like Receptor 2 / immunology
  • Transcription Factor AP-1 / immunology
  • Transforming Growth Factor beta1 / biosynthesis*
  • Transforming Growth Factor beta1 / genetics


  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Transcription Factor AP-1
  • Transforming Growth Factor beta1
  • Extracellular Signal-Regulated MAP Kinases