TY - JOUR
T1 - Smad2 and Smad3 Inversely Regulate TGF-β Autoinduction in Clostridium butyricum-Activated Dendritic Cells
AU - Kashiwagi, Ikkou
AU - Morita, Rimpei
AU - Schichita, Takashi
AU - Komai, Kyoko
AU - Saeki, Keita
AU - Matsumoto, Makoto
AU - Takeda, Kiyoshi
AU - Nomura, Masatoshi
AU - Hayashi, Atsushi
AU - Kanai, Takanori
AU - Yoshimura, Akihiko
N1 - Funding Information:
A.H. is supported by Miyarisan Pharmaceutical Co., Ltd. We thank M. Asakawa, S. Tsuruta, and R. Komine for technical assistance. This work was supported by special grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Intramural Research Grant (22-4) for Neurological and Psychiatric Disorders of National Center of Neurology and Psychiatry (NCNP), the SENSHIN Research Foundation, the Kanae Foundation for the Promotion of Medical Science, the Mochida Memorial Foundation, the Uehara Memorial Foundation, and the Takeda Science Foundation.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/7/21
Y1 - 2015/7/21
N2 - 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.
AB - 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.
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U2 - 10.1016/j.immuni.2015.06.010
DO - 10.1016/j.immuni.2015.06.010
M3 - Article
C2 - 26141582
AN - SCOPUS:84937724740
SN - 1074-7613
VL - 43
SP - 65
EP - 79
JO - Immunity
JF - Immunity
IS - 1
ER -
