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: Taiga Tamiya, Kenji Ichiyama, Hitoshi Kotani, Tomohiro Fukaya, Takashi Sekiya, Takashi Shichita, Kiri Honma, Katsuyuki Yui, Toshifumi Matsuyama, Takako Nakao, Satoru Fukuyama, Hiromasa Inoue, Masatoshi Nomura, Akihiko Yoshimura
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 191 Issue 5 Pg. 2360-71 (Sep 01 2013) ISSN: 1550-6606 [Electronic] United States
• PMID: 23913959 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interferon Regulatory Factors
• Interleukin-9
• Smad2 Protein
• Smad2 protein, mouse
• Smad3 Protein
• Smad3 protein, mouse
• interferon regulatory factor-4

Topics

• Animals
• Blotting, Western
• Chromatin Immunoprecipitation
• Disease Models, Animal
• Flow Cytometry
• Hypersensitivity (immunology)
• Interferon Regulatory Factors (immunology, metabolism)
• Interleukin-9 (biosynthesis, genetics, immunology)
• Lymphocyte Activation (genetics, immunology)
• Mice
• Mice, Knockout
• Real-Time Polymerase Chain Reaction
• Smad2 Protein (immunology, metabolism)
• Smad3 Protein (immunology, metabolism)
• T-Lymphocyte Subsets (immunology, metabolism)
• Transcriptional Activation