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

Ikkou Kashiwagi, Rimpei Morita, Takashi Schichita, Kyoko Komai, Keita Saeki, Makoto Matsumoto, Kiyoshi Takeda, Masatoshi Nomura, Atsushi Hayashi, Takanori Kanai, Akihiko Yoshimura

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)65-80
Number of pages16
JournalImmunity
Volume43
Issue number1
DOIs
Publication statusPublished - 2015 Jul 21

Fingerprint

Clostridium butyricum
Transforming Growth Factors
Dendritic Cells
Clostridium
Toll-Like Receptor 2
Transcription Factor AP-1
Probiotics
Regulatory T-Lymphocytes
Colitis
Intestines
Colon
Mucous Membrane
Transcription Factors
Phosphotransferases

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

Cite this

Smad2 and Smad3 Inversely Regulate TGF-β Autoinduction in Clostridium butyricum-Activated Dendritic Cells. / Kashiwagi, Ikkou; Morita, Rimpei; Schichita, Takashi; Komai, Kyoko; Saeki, Keita; Matsumoto, Makoto; Takeda, Kiyoshi; Nomura, Masatoshi; Hayashi, Atsushi; Kanai, Takanori; Yoshimura, Akihiko.

In: Immunity, Vol. 43, No. 1, 21.07.2015, p. 65-80.

Research output: Contribution to journalArticle

Kashiwagi, I, Morita, R, Schichita, T, Komai, K, Saeki, K, Matsumoto, M, Takeda, K, Nomura, M, Hayashi, A, Kanai, T & Yoshimura, A 2015, 'Smad2 and Smad3 Inversely Regulate TGF-β Autoinduction in Clostridium butyricum-Activated Dendritic Cells', Immunity, vol. 43, no. 1, pp. 65-80. https://doi.org/10.1016/j.immuni.2015.06.010
Kashiwagi, Ikkou ; Morita, Rimpei ; Schichita, Takashi ; Komai, Kyoko ; Saeki, Keita ; Matsumoto, Makoto ; Takeda, Kiyoshi ; Nomura, Masatoshi ; Hayashi, Atsushi ; Kanai, Takanori ; Yoshimura, Akihiko. / Smad2 and Smad3 Inversely Regulate TGF-β Autoinduction in Clostridium butyricum-Activated Dendritic Cells. In: Immunity. 2015 ; Vol. 43, No. 1. pp. 65-80.
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