title: Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction.
abstract: IL-9 is a pleiotropic cytokine that can regulate autoimmune and allergic responses. Th9 cells can develop from naive T cells or Th2 cells through stimulation by TGF-β in vitro. In this study, we demonstrated that Smad2 and Smad3 are necessary for IL-9 production from T cells in an OVA-induced asthma model using T cell-specific Smad2- and Smad3-deficient mice. Smad2 and Smad3 were also redundantly essential for TGF-β signaling to induce histone modifications for Il9 transcription. Although Smad2/3 was recruited to the Il9 promoter by TGF-β stimulation, they are not sufficient to activate the Il9 promoter. By the screening the transcription factors, we found that IFN regulatory factor 4 (IRF4) was essential for the Smad2/3-mediated Il9 promoter activation. In addition, Smad2/3 physically interacted with IRF4, and Smad2/3 did not bind to the Il9 promoter and could not induce Th9 in IRF4-deficient T cells. Similarly, IRF4 could not stimulate Il9 transcription in the absence of Smad2/3, and TGF-β enhanced IRF4 recruitment to the Il9 promoter in a Smad2/3-dependent manner. We propose that Smad2/3 and IRF4 cooperatively transactivate the Il9 promoter and play an important role in regulating allergic immune responses by inducing Th9 cells.
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Taiga
authors.initials: T
authors.lastname: Tamiya
authors.forename: Kenji
authors.initials: K
authors.lastname: Ichiyama
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kotani
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Fukaya
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekiya
authors.forename: Takashi
authors.initials: T
authors.lastname: Shichita
authors.forename: Kiri
authors.initials: K
authors.lastname: Honma
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Yui
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Matsuyama
authors.forename: Takako
authors.initials: T
authors.lastname: Nakao
authors.forename: Satoru
authors.initials: S
authors.lastname: Fukuyama
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Inoue
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nomura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006967:Hypersensitivity / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000276:immunology* / Q000378:metabolism; D016906:Interleukin-9 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D051899:Smad2 Protein / Q000276:immunology* / Q000378:metabolism; D051900:Smad3 Protein / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D015533:Transcriptional Activation; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D016906:Interleukin-9; D051899:Smad2 Protein; D051900:Smad3 Protein; D000099218:Interferon Regulatory Factor-4; C497783:Smad2 protein, mouse; C497791:Smad3 protein, mouse