Regulation of Immune Responses by the transcription regulatior IkappaBzeta and its binding protein

• Project/Area Number: 16K08747
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Toho University
• Principal Investigator: YAMAZAKI Soh 東邦大学, 医学部, 准教授 (70315084)
• Research Collaborator: KATAGIRI Takaharu
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: IkappaBzeta / JunB / Th17 / 自己免疫疾患 / ヘルパーT細胞 / Th17細胞 / 制御性T細胞 / IκBζ / NF-κB / 自然免疫 / マクロファージ / 発現制御 / 免疫学

Outline of Final Research Achievements

Although IL-17-producing T helper (Th17) cells are associated with autoimmune diseases such as multiple sclerosis, development of the cells has not been fully understood. While the transcription factor JunB is known to be involved in barrier function of skin and regulation of myeloid cells, it role in immune cells was not known. We elucidated that Junb-deficient naive CD4+ T cells were incapable of differentiating into Th17 cells, and that mice deficient in JunB are totally resistant to EAE, an animal model for human multiple sclerosis.

Academic Significance and Societal Importance of the Research Achievements

多発性硬化症をはじめ、リウマチ関節炎や乾癬などの自己免疫疾患は治療戦略はもとより、病態の発症メカニズムについても詳細が不明だった。今回の発見に基づき、JunBのはたらきを阻害するというアプローチにより自己免疫疾患を抑えるという新しい治療法の可能性が開けた。

Research Products

• [Journal Article] Development of novel methods that monitor necroptosis and the release of DMAPs at the single cell resolution. (2019)
  • Author(s): Nakano Hiroyasu、Murai Shin、Yamaguchi Yoshifumi、Shirasaki Yoshitaka、Nakabayashi Osamu、Yamazaki Soh
  • Journal Title: Cell Stress Volume: 3 Pages: 66-69
  • DOI: 10.15698/cst2019.02.177
  • Peer Reviewed / Open Access
• [Journal Article] A murine model of acute lung injury identifies growth factors to promote tissue repair and their biomarkers (2019)
  • Author(s): Kurosawa Takeyuki、Miyoshi Shion、Yamazaki Soh、Nishina Takashi、Mikami Tetuo、Oikawa Akira、Homma Sakae、Nakano Hiroyasu
  • Journal Title: Genes Cells Volume: 24 Pages: 112-125
  • DOI: 10.1111/gtc.12659
  • Peer Reviewed
• [Journal Article] AP-1転写因子JunBによるTh17細胞分化の制御 (2018)
  • Author(s): 山﨑 創
  • Journal Title: 臨床免疫・アレルギー科 Volume: 70 Pages: 275-282
• [Journal Article] Ubiquitin ligase SPSB4 diminishes cell repulsive responses mediated by EphB2. (2017)
  • Author(s): Yamazaki Soh、Tanaka Yoshihiko、Araki Hiromitsu、Kohda Akira、Sanematsu Fumiyuki、Arasaki Tomoko、Duan Xuefeng、Miura Fumihito、Katagiri Takaharu、Shindo Ryodai、Nakano Hiroyasu、Ito Takashi、Fukui Yoshinori、Endo Shogo、Sumimoto Hideki
  • Journal Title: Mol. Biol. Cell. Volume: 7 Pages: 17402-17402
  • DOI: 10.1038/s41598-017-17597-3
  • Peer Reviewed / Open Access
• [Journal Article] 肝炎の制御における骨髄由来細胞の役割 (2017)
  • Author(s): 山崎 創, 朴 雪花, 中野 裕康
  • Journal Title: 臨床免疫・アレルギー科 Volume: 68 Pages: 455-462
• [Journal Article] Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum (2017)
  • Author(s): Piao X, Yamazaki S, Komazawa-Sakon S, Miyake S, Nakabayashi O, Kurosawa T, Mikami T, Tanaka M, Van Rooijen N, Ohmuraya M, Oikawa A, Kojima Y, Kakuta S, Uchiyama Y, Tanaka M, Nakano H.
  • Journal Title: Hepatology Volume: 65 Pages: 237-252
  • DOI: 10.1002/hep.28878
  • NAID: 120006528815
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Critical contribution of nuclear factor erythroid 2-related factor 2 (NRF2) to electrophile-induced interleukin-11 production (2017)
  • Author(s): Nishina T, Deguchi Y, Miura R, Yamazaki S, Shinkai Y, Kojima Y, Okumura K, Kumagai Y, Nakano H.
  • Journal Title: J. Biol. Chem. Volume: 292 Pages: 205-216
  • DOI: 10.1074/jbc.m116.744755
  • NAID: 130006581894
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Nuclear Protein IκBζ Forms a Transcriptionally Active Complex with Nuclear Factor-κB (NF-κB) p50 and the Lcn2 Promoter via the N- and C-terminal Ankyrin Repeat Motifs. (2016)
  • Author(s): Kohda A, Yamazaki S, Sumimoto H.
  • Journal Title: J Biol Chem Volume: 291 Pages: 20739-20752
  • DOI: 10.1074/jbc.m116.719302
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Short form FLICE-inhibitory protein promotes TNFalpha-induced necroptosis in fibroblasts derived from CFLARs transgenic mice. (2016)
  • Author(s): Shindo, R. Yamazaki, S. Ohmuraya, M. Araki, K. Nakano, H.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 480 Pages: 23-28
  • DOI: 10.1016/j.bbrc.2016.10.015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] A crucial role of JunB in attenuating epithelial damage-induced colitis through induction of regulatory T cells (2018)
  • Author(s): Soh Yamazaki, Takaharu Katagiri, Hideki Sumimoto, Hiroyasu Nakano
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] 腸管上皮バリアにおける転写因子JunBの役割 (2018)
  • Author(s): 片桐 翔治, 山﨑 創, 三上 哲夫, 遠藤 昌吾, 住本 英樹, 亀田 秀人, 中野 裕康
  • Organizer: 第91回日本生化学会大会
• [Presentation] RIPK3-dependent necroptosis of intestinal epithelial cells results in RORgt+ innate lymphoid cells-dependent lethal ileitis (2018)
  • Author(s): Ryodai Shindo, Masaki Ohmuraya, Sachiko Komazawa-Sakon, Sanae Miyake, Soh Yamazaki, Takashi Nishina, Manolis Pasparakis, Kimi Araki, Hiroyasu Nakano
  • Organizer: 2nd Australia-Japan Meeting on Cell Death
  • Int'l Joint Research
• [Presentation] The AP-1 transcription factor JunB is essential for development of Th17 cells (2017)
  • Author(s): Yamazaki S, Tanaka Y, Fukui Y, Sumimoto H
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] RORgammat-positive cells mediate RIPK3-and MLKL-dependent lethal ileitis in neonatal mice (2017)
  • Author(s): Shindo R, Yamazaki S, Nakano H
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] 肝特異的cFLIP低発現マウスを用いた肝障害モデルの解析 (2017)
  • Author(s): 山崎 創, 朴 雪花, 駒澤-左近 幸子, 三宅 早苗, 中林 修, 田中 稔, 大村谷 昌樹, 及川 彰, 角田 宗一郎, 内山 安男, 田中 正人, 中野 裕康
  • Organizer: 第26回日本Cell Death学会学術集会
• [Presentation] RORgammat陽性細胞はRIPK3およびMLKL依存性に小腸炎を誘導する (2017)
  • Author(s): 進藤 綾大, 大村谷 昌樹, 駒澤 幸子, 三宅 早苗, 山崎 創, 仁科 隆史, 小西 博之, 木山 博資, 三上 哲夫, 荒木 喜美, 中野 裕康
  • Organizer: 第26回日本Cell Death学会学術集会
• [Presentation] II型肺胞上皮細胞の障害と再生に関する解析 (2017)
  • Author(s): 三好 嗣臣, 黒澤 武介, 仁科 隆史, 山崎 創, 本間 栄, 中野 裕康
  • Organizer: 第26回日本Cell Death学会学術集会
• [Presentation] 細胞死制御因子cFLIPの肝細胞特異的欠損マウスを用いた肝障害モデルにおけるクッパー細胞および骨髄由来細胞の役割 (2016)
  • Author(s): 朴 雪花, 山﨑 創, 駒澤-左近 幸子, 三宅 早苗, 中林 修, 田中 稔, 大村谷 昌樹, 及川 彰, 角田 宗一郎, 内山 安男, 田中 正人, 中野 裕康
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター／東北大学川内北キャンパス (宮城県・仙台市)
  • Year and Date: 2016-09-26
• [Presentation] アポトーシス細胞は腸内細菌非依存的にReg3βを産生し腸管の恒常性を維持する (2016)
  • Author(s): 進藤 綾大, 大村谷 昌樹, 駒澤 幸子, 三宅 早苗, 山﨑 創, 仁科 隆史, 小西 博之, 木山 博資, 三上 哲夫, 荒木 喜美, 中野 裕康
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター／東北大学川内北キャンパス (宮城県・仙台市)
  • Year and Date: 2016-09-26
• [Presentation] 転写因子NF-κBとそのパートナータンパク質IκBζによる転写活性化複合体の形成機構 (2016)
  • Author(s): 神田 朗, 山﨑 創, 住本 英樹
  • Organizer: 第27回日本生体防御学会学術総会
  • Place of Presentation: 九州大学病院キャンパス内コラボステーションⅠ視聴覚ホール (福岡県・福岡市)
  • Year and Date: 2016-07-09