title: Smad2 and Smad3 Inversely Regulate TGF-β Autoinduction in Clostridium butyricum-Activated Dendritic Cells.
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.
authors.affiliation: Department of Microbiology and Immunology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan, and Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan.
authors.forename: Ikkou
authors.initials: I
authors.lastname: Kashiwagi
authors.affiliation: Department of Microbiology and Immunology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan, and Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan.
authors.forename: Rimpei
authors.initials: R
authors.lastname: Morita
authors.affiliation: Department of Microbiology and Immunology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan, and Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan; PRESTO (Precursory Research for Embryonic Science and Technology), Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Schichita
authors.affiliation: Department of Microbiology and Immunology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan, and Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Komai
authors.affiliation: Department of Microbiology and Immunology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan, and Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Saeki
authors.affiliation: Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, 663-8501, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nomura
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan, and Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan; Miyarisan Pharmaceutical Co., Ltd., Research Laboratory, Tokyo 114-0016, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan, and Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.affiliation: Department of Microbiology and Immunology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan, and Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan. Electronic address: yoshimura@a6.keio.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D003015:Clostridium Infections / Q000276:immunology / Q000382:microbiology; D046972:Clostridium butyricum / Q000276:immunology*; D003092:Colitis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051899:Smad2 Protein / Q000235:genetics*; D051900:Smad3 Protein / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D048049:Extracellular Signal-Regulated MAP Kinases