Rika posted this to co-cure today
[if: oops - should I have posted this to the related research section?]
Nature advance online publication 11 April 2010 | doi:10.1038/nature08922; Received 12 August 2009; Accepted 10 February 2010; Published online 11 April 2010
IκBζ regulates TH17 development by cooperating with ROR nuclear receptors
Kazuo Okamoto1,2,3, Yoshiko Iwai4, Masatsugu Oh-hora1,2, Masahiro Yamamoto5, Tomohiro Morio6, Kazuhiro Aoki7, Keiichi Ohya7, Anton M. Jetten8, Shizuo Akira9, Tatsushi Muta10 & Hiroshi Takayanagi1,2,3
1. Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University,
2. Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases,
3. Japan Science and Technology Agency (JST), ERATO, Takayanagi Osteonetwork Project, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan
4. Medical Top Track Program, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan
5. Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan
6. Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan
7. Department of Hard Tissue Engineering (Pharmacology), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan
8. Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive Research Triangle Park, North Carolina 27709, USA
9. Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Yamada-oka 3-1, Suita, Osaka 565-0871, Japan
10. Laboratory of Cell Recognition and Response, Graduate School of Life Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Correspondence to: Hiroshi Takayanagi1,2,3 Correspondence and requests for materials should be addressed to H.T. (Email: taka.csi@tmd.ac.jp).
Top of page
Abstract
Interleukin (IL)-17-producing helper T (TH17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases1, 2, 3. IL-6 and transforming growth factor-β (TGF-β) induce TH17 development, in which the orphan nuclear receptors, RORγt and RORα, have an indispensable role4, 5, 6. However, in the absence of IL-6 and TGF-β, the ectopic expression of RORγt or RORα leads to only a modest IL-17 production5, 7, 8. Here we identify a nuclear IκB family member, IκBζ (encoded by the Nfkbiz gene), as a transcription factor required for TH17 development in mice. The ectopic expression of IκBζ in naive CD4+ T cells together with RORγt or RORα potently induces TH17 development, even in the absence of IL-6 and TGF-β. Notably, Nfkbiz-/- mice have a defect in TH17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of IκBζ was clearly demonstrated by the resistance to EAE of the Rag2-/- mice into which Nfkbiz-/- CD4+ T cells were transferred. In cooperation with RORγt and RORα, IκBζ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying TH17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.
[if: oops - should I have posted this to the related research section?]
Nature advance online publication 11 April 2010 | doi:10.1038/nature08922; Received 12 August 2009; Accepted 10 February 2010; Published online 11 April 2010
IκBζ regulates TH17 development by cooperating with ROR nuclear receptors
Kazuo Okamoto1,2,3, Yoshiko Iwai4, Masatsugu Oh-hora1,2, Masahiro Yamamoto5, Tomohiro Morio6, Kazuhiro Aoki7, Keiichi Ohya7, Anton M. Jetten8, Shizuo Akira9, Tatsushi Muta10 & Hiroshi Takayanagi1,2,3
1. Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University,
2. Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases,
3. Japan Science and Technology Agency (JST), ERATO, Takayanagi Osteonetwork Project, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan
4. Medical Top Track Program, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan
5. Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan
6. Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan
7. Department of Hard Tissue Engineering (Pharmacology), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan
8. Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive Research Triangle Park, North Carolina 27709, USA
9. Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Yamada-oka 3-1, Suita, Osaka 565-0871, Japan
10. Laboratory of Cell Recognition and Response, Graduate School of Life Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Correspondence to: Hiroshi Takayanagi1,2,3 Correspondence and requests for materials should be addressed to H.T. (Email: taka.csi@tmd.ac.jp).
Top of page
Abstract
Interleukin (IL)-17-producing helper T (TH17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases1, 2, 3. IL-6 and transforming growth factor-β (TGF-β) induce TH17 development, in which the orphan nuclear receptors, RORγt and RORα, have an indispensable role4, 5, 6. However, in the absence of IL-6 and TGF-β, the ectopic expression of RORγt or RORα leads to only a modest IL-17 production5, 7, 8. Here we identify a nuclear IκB family member, IκBζ (encoded by the Nfkbiz gene), as a transcription factor required for TH17 development in mice. The ectopic expression of IκBζ in naive CD4+ T cells together with RORγt or RORα potently induces TH17 development, even in the absence of IL-6 and TGF-β. Notably, Nfkbiz-/- mice have a defect in TH17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of IκBζ was clearly demonstrated by the resistance to EAE of the Rag2-/- mice into which Nfkbiz-/- CD4+ T cells were transferred. In cooperation with RORγt and RORα, IκBζ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying TH17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.
