Role of IL-17F in severe asthma

• Project/Area Number: 15K09209
• 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: University of Tsukuba
• Principal Investigator: Kawaguchi Mio 筑波大学, 医学医療系, 講師 (50365748)
• Research Collaborator: NAKAJIMA Masayuki ; FUJITA Junichi ; OTA Kyoko ; HIZAWA Nobuyuki
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 難治性喘息 / インターロイキン17Ｆ / 気道平滑筋 / インターロイキン8 / P-TEFb / ステロイド / 喘息 / 気道平滑筋細胞 / IL-17F / 気道炎症 / IL-6 / IL-8 / TAK1 / NF-κB

Outline of Final Research Achievements

IL-17F is involved in the pathogenesis ofsevere asthma. However, the effects of steroids on the function of IL-17F signaling mechanisms are largely unknown. One of the transcription elongation factors, P-TEFb composed of cyclin T1 and CDK9, is known as a novel checkpoint regulator of gene expression via Brd4. We reported that IL-17F markedly induced the expression of the IL-8 in human airway smooth muscle cells . Pretreatment of CDK9 inhibitor and transfection of siRNAs targeting CDK9 abrogated IL-17F-induced IL-8 production. Transfection of siRNAs targeting Brd4 and cyclin T1 diminished IL-17F-induced phosphorylation of CDK9 and IL-8 production. Moreover, budesonide decreased CDK9 phosphorylation and markedly inhibited IL-17F-induced IL-8 production. P-TEFb is involved in IL-17F-induced IL-8 expression and that steroids diminish it via the inhibition of CDK9 phosphorylation. IL-17F and P-TEFb might be novel therapeutic targets for severe asthma.

Research Products

• [Journal Article] Transcription elongation factor P-TEFb is involved in IL-17F signaling in airway smooth muscle cells. (2018)
  • Author(s): Nakajima Masayuki, Kawaguchi Mio, Matsuyama Masashi, Ota Kyoko, Fujita Jun, Matsukura Satoshi, Huang Shau-Ku, Morishima Yuko, Ishii Yukio, Satoh Hiroaki, Sakamoto Tohru, Hizawa Nobuyuki.
  • Journal Title: Int Arch Allergy Immunol Volume: 印刷中 Issue: 2 Pages: 83-90
  • DOI: 10.1159/000488154
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-17F induces IL-6 via TAK1-NFκB pathway in airway smooth muscle cells (2017)
  • Author(s): Masayuki Nakajima, Mio Kawaguchi, Kyoko Ota, Junichi Fujita, Satoshi Matsukura, Shau-Ku Huang, Yuko Morishima, Yukio Ishii, Hiroaki Satoh, Tohru Sakamoto, Nobuyuki Hizawa.
  • Journal Title: Immunity, Inflammation and Disease Volume: 3 Issue: 2 Pages: 1-8
  • DOI: 10.1002/iid3.149
  • NAID: 120007129102
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Role of IL-17F in the Pathogenesis of Psoriasis (2017)
  • Author(s): Masayuki Nakajima, Mio Kawaguchi, Hideaki Watanabe, Yuko Morishima, Shau-Ku Huang, Hiroaki Satoh, Nobuyuki Hizawa
  • Journal Title: Current Immunology Reviews Volume: 12 Issue: 2 Pages: 112-117
  • DOI: 10.2174/1573395513666161214121923
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ウイルス・細菌感染と喘息」に寄せる ウイルス感染による喘息増悪のメカニズム (2016)
  • Author(s): 川口 未央, 中嶋真之、檜澤 伸之
  • Journal Title: アレルギーの臨床 Volume: 36 Pages: 52-56
  • Peer Reviewed
• [Presentation] IL-17Fによる気道平滑筋細胞からのIL-6発現とその分子機構 (2017)
  • Author(s): 中嶋真之、太田恭子、藤田純一、川口未央、松倉聡、塩澤利博、中澤健介、増子裕典、際本拓未、松野洋輔、森島祐子、佐藤浩昭、坂本透、檜澤伸之
  • Organizer: 日本呼吸器学会学術講演会
• [Presentation] IL-17FによるIL-8の発現機構：P-TEFbの関与 (2016)
  • Author(s): 中嶋真之、川口未央、藤田純一、太田恭子、國分二三男、松倉聡、増子裕典、際本拓未、松野洋輔、森島祐子、佐藤浩昭、坂本透、檜澤伸之
  • 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: 2016-06-17
• [Presentation] 気道平滑筋細胞におけるIL-17FによるIL-8の発現機構 (2016)
  • Author(s): 太田恭子、川口未央、中嶋真之、藤田純一、國分二三男、松倉聡、中澤健介、塩澤利博、増子裕典、際本拓未、松野洋輔、森島祐子、佐藤浩昭、坂本透、檜澤伸之
  • Organizer: 第56日本呼吸器学会学術講演会
  • Place of Presentation: 国立京都国際会館 京都府京都市
  • Year and Date: 2016-04-08
• [Presentation] 気道平滑筋細胞からのIL-17Fによる炎症性サイトカインの発現とステロイドの抑制機構. (2015)
  • Author(s): 藤田 純一, 川口 未央, 太田 恭子, 國分 二三男, 松倉 聡, 黒川 真嗣, 際本 拓未, 森島 祐子, 石井 幸雄, 坂本 透, 佐藤 浩昭, 檜澤 伸之
  • Organizer: 第64回日本アレルギー学会学術大会
  • Place of Presentation: グランドプリンスホテル新高輪
  • Year and Date: 2015-05-26
• [Presentation] IL-17F induces IL-8 in airway smooth muscle cells via NF-κB-independent pathway. (2015)
  • Author(s): Mio Kawaguchi, Kyoko Ota, Junichi Fujita, Fumio Kokubu, Yuko Morishima, Satoshi Matsukura, Yukio Ishii, Hiroaki Satoh, Tohru Sakamoto, Nobuyuki Hizawa
  • Organizer: International Conference of American Thoracic Society
  • Place of Presentation: デンバー（米国）
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Presentation] IL-17Fによる気道平滑筋細胞からのサイトカイン発現とステロイドの抑制効果 (2015)
  • Author(s): IL-17Fによる気道平滑筋細胞からのサイトカイン発現とステロイドの抑制効果
  • Organizer: 第55回日本呼吸器学会学術講演会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2015-04-17