Therapeutic application to cystic fibrosis based on IL-37 and stabilized cell surface expression of SIGIRR

• Project/Area Number: 16K08291
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Sojo University
• Principal Investigator: SHUTO Keiko 崇城大学, 薬学部, 講師 (70510692)
• Research Collaborator: KAI Hirofumi
• 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 嚢胞性線維症（CF） / SIGIRR / IL-37b / Δ8-SIGIRR / スプライススイッチ / CF / 細胞膜上発現 / 嚢胞性線維症 / Toll-like receptor / 炎症制御

Outline of Final Research Achievements

Cystic Fibrosis (CF) is an inherited disorder characterized by chronic airway inflammation, which is partly due to the defective expression or function of negative regulators of toll-like receptor (TLR) that induce inflammatory signaling. In this study, we focused on SIGIRR and anti-inflammatory cytokine IL-37b, which work as a negative regulator of TLR signaling and it's ligand respectively, and functionally analyzed anti-inflammatory IL-37b-SIGIRR pathway in CF. As a result, anti-inflammatory activity via IL-37b-SIGIRR pathway was abrogated in CF airway epithelial cells due to the augmented expression of mutant SIGIRR, which causes the decrease in it's cell surface expression in CF.

Academic Significance and Societal Importance of the Research Achievements

近年CFの原因遺伝子に対する治療薬が認可され根治治療への期待が高まる一方、未だ解決できない問題として挙げられているのが、CF患者の多くで認められる感染症およびそれに伴う慢性炎症である。故にCF炎症の分子基盤の解明および感染・炎症を調節する因子の探索は、今後ますます重要となることが予想される。本研究は、未だCF研究領域において報告のないSIGIRRおよびIL37bを標的とした新たな炎症治療薬法を模索する初めての試みである。

Research Products

• [Presentation] A splice switch in SIGIRR causes a defect of Poly(I:C)-dependent anti-inflammatory IL-37b-SIGIRR negative feedback loop in cystic fibrosis airway epithelial cells (2019)
  • Author(s): Keiko Ueno-Shuto, Shunsuke Kamei, Mary Ann Suico, Hirofumi Kai, Yuji Uchida, Naofumi Tokutomi, Tsuyoshi Shuto
  • Organizer: 第92回日本薬理学会年会
• [Presentation] 嚢胞性線維症気道上皮細胞におけるSIGIRRスプライスアイソフォームの発現上昇とその炎症調節における役割 (2018)
  • Author(s): 首藤 恵子、亀井 竣輔、内田 友二、甲斐 広文、徳冨 直史、首藤 剛
  • Organizer: 第71回日本薬理学会西南部会
• [Presentation] Poly(I:C)-dependent anti-inflammatory IL-37b-SIGIRR negative feedback loop is defective in cystic fibrosis airway epithelial cells (2017)
  • Author(s): Keiko Ueno-Shuto
  • Organizer: 15th Cytokines & Inflammation Conference
  • Place of Presentation: Hard Rock Hotel in San Diego（USA, California）
  • Year and Date: 2017-02-06
  • Int'l Joint Research
• [Presentation] POLY(I:C)-DEPENDENT ANTI-INFLAMMATORY IL-37B-SIGIRR NEGATIVE FEEDBACK LOOP IS DEFECTIVE IN CYSTIC FIBROSIS AIRWAY EPITHELIAL CELLS (2017)
  • Author(s): Keiko Ueno-Shuto, Shunsuke Kamei, Mary Ann Suico, Hirofumi Kai, Yuji Uchida, Naofumi Tokutomi, Tsuyoshi Shuto
  • Organizer: Northern American Cystic Fibrosis Conference 2017 (NACFC2017)
  • Int'l Joint Research
• [Presentation] 嚢胞性線維症気道上皮細胞における炎症抑制性IL-37b-SIGIRR axisの破綻 (2017)
  • Author(s): 首藤恵子，亀井峻輔，内田友二，甲斐広文，徳富直史，首藤剛
  • Organizer: 第34回 日本薬学会 九州支部大会
• [Presentation] 嚢胞性線維症気道上皮細胞における炎症抑制性IL-37b-SIGIRR axisの破綻 (2016)
  • Author(s): 首藤 恵子
  • Organizer: 第69回 日本薬理学会西南部会
  • Place of Presentation: 松山大学（愛媛県, 松山市）
  • Year and Date: 2016-11-26