The regulation of IkBNS in goblet cell differentiation in asthma

• Project/Area Number: 16K09573
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Chiba University
• Principal Investigator: Tamachi Tomohiro 千葉大学, 大学院医学研究院, 助教 (20456015)
• Co-Investigator(Kenkyū-buntansha): 廣瀬 晃一 千葉大学, 大学院医学研究院, 特任教授 (90400887) ; 鈴木 浩太郎 千葉大学, 大学院医学研究院, 准教授 (90554634)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: IkBNS / Muc5ac / 杯細胞 / house dust mite / NF-kB / アレルギー・ぜんそく

Outline of Final Research Achievements

We found that IkBNS induces Muc5ac, a representative mucin in asthmatic airways, and causes airway hyper-responsiveness. IkBNS is involved in the expression of Muc5ac independently of the Spdef pathway, a master regulator of goblet cell metaplasia. IkBNS directly binds to the distal promoter of MUC5AC and enhances its activity together with NF-kB.
We also showed that IL-22 induces Reg3γ production in lung epithelial cells in a STAT3-dependent manner. Reg3γ functions on the lung epithelial cells and inhibits TSLP and IL-33 production, which leads to the suppression on allergic airway inflammation.

Academic Significance and Societal Importance of the Research Achievements

気管支喘息の病態はアレルギー性気道炎症であり、その治療は気道炎症を抑制する吸入ステロイド薬を中心に大きく進歩した。しかし 5-10%の患者は既存治療に抵抗性であり、気道上皮細胞の関与が考えられるもその機序に依然不明な点が多い。
本研究を通して気道上皮細胞におけるIkBNSの発現が杯細胞形成や気道過敏性に寄与すること、また気道上皮細胞においてIL-22刺激下で産生されるReg3γがアレルギー性気道炎症を制御することが明らかとなり、新たな治療標的となりうる可能性が示された。

Research Products

• [Journal Article] Analyses of dermal innate lymphoid cells in mice lacking T-bet and STAT6 (2018)
  • Author(s): Makita S, Takatori H, Tamachi T, Suto A, Suzuki K, Nakajima H.
  • Journal Title: Allergology International Volume: 67 Issue: Supplement.1 Pages: S51-S53
  • DOI: 10.1016/j.alit.2018.05.004
  • NAID: 130007485242
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Sox12 promotes T reg differentiation in the periphery during colitis. (2018)
  • Author(s): anaka S, Suto A, Iwamoto T, Kageyama T, Tamachi T, Takatori H, Suzuki K, Hirose K, Ohara O, Lefebvre V, Nakajima H.
  • Journal Title: J Exp Med. Volume: 215 Issue: 10 Pages: 2509-2519
  • DOI: 10.1084/jem.20172082
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-22 induces Reg3γ and inhibits allergic inflammation in house dust mite-induced asthma models. (2017)
  • Author(s): Ito T, Hirose K, Saku A, Kono K, Takatori H, Tamachi T, Goto Y, Renauld JC, Kiyono H, Nakajima H.
  • Journal Title: J Exp Med. Volume: 214 Issue: 10 Pages: 3037-3050
  • DOI: 10.1084/jem.20162108
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Key players beyond the Th2 cell pathway (2017)
  • Author(s): Hirose K, Tamachi T, Iwata A, Nakajima H
  • Journal Title: Immunol Rev Volume: 印刷中 Issue: 1 Pages: 145-161
  • DOI: 10.1111/imr.12540
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] IκBNS induces Muc5ac expression in epithelial cells and causes airway hyperresponsiveness in murine asthma models (2017)
  • Author(s): Yokota M, Tamachi T, Yokoyama Y, Maezawa Y, Takatori T, Suto A, Suzuki K, Hirose K, Takeda K, Nakajima H
  • Journal Title: Allergy Volume: 印刷中 Issue: 7 Pages: 13079-13079
  • DOI: 10.1111/all.13079
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production (2017)
  • Author(s): Matsuki A, Takatori T, Makita S, Yokota M, Tamachi T, Suto A, Suzuki K, Hirose K, Nakajima H
  • Journal Title: J. Allergy Clin. Immunol Volume: 印刷中 Issue: 4 Pages: 31023-31025
  • DOI: 10.1016/j.jaci.2016.08.022
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Dectin-1 Plays an Important Role in House Dust Mite-Induced Allergic Airway Inflammation through the Activation of CD11b+ Dendritic Cells. (2017)
  • Author(s): Ito T, Hirose K, Norimoto A, Tamachi T, Yokota M, Saku A, Takatori H, Saijo S, Iwakura Y, Nakajima H.
  • Journal Title: J Immunol. Volume: 198 Issue: 1 Pages: 61-70
  • DOI: 10.4049/jimmunol.1502393
  • Peer Reviewed
• [Presentation] TCR-mediated Sox12 induction promotes peripherally induced Treg cell differentiation under inflammatory conditions (2018)
  • Author(s): Tanaka S, Suto A, Iwamoto T, Kageyama T, Tamachi T, Takatori H, Suzuki K, Hirose K, Ohara O, Lefebvre V, Nakajima H.
  • Organizer: 第47回日本免疫学会総会・学術集会
• [Presentation] A20 (Tnfaip3 ) expressed in T cells suppresses Th2 cell-mediated allergic airway inflammation in mice. (2017)
  • Author(s): Tomohiro Tamachi, Yusuke Yokoyama, Arifumi Iwata, Yuko Maezawa, Akira Suto, Kotaro Suzuki, Koichi Hirose, Hiroaki Honda, Hiroshi Nakajima.
  • Organizer: 第46回日本免疫学会総会・学術集会
• [Presentation] 気道上皮細胞に発現するIκBNSのアレルギー性気道炎症における役割 (2016)
  • Author(s): 玉地智宏、横田雅也、横山裕亮、前澤裕子、須藤明、鈴木浩太郎、廣瀬晃一、中島裕史
  • Organizer: 第65回日本アレルギー学会学術大会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区)
  • Year and Date: 2016-06-19