The Novel IL-1 Cytokines Family Members in Severe Infectious Diseases

• Project/Area Number: 18K08424
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Tohoku University
• Principal Investigator: AOYAGI TETSUJI 東北大学, 医学系研究科, 准教授 (50581609)
• Co-Investigator(Kenkyū-buntansha): 久志本 成樹 東北大学, 医学系研究科, 教授 (50195434) ; 工藤 大介 東北大学, 医学系研究科, 講師 (30455844)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: IL-36サイトカイン / 細胞外小胞体 / 敗血症 / IL-36Ra / IL-36gamma / 凝固 / 血管内皮細胞傷害 / 炎症 / 好中球 / 単球・リンパ球 / 菌血症 / IL-36 agonists / IL-36 antagonists / Microparticles / Exosomes

Outline of Final Research Achievements

This study aims to investigate the role of IL-36 cytokines in sepsis. We found that the concentration of IL-36gamma elevated in the patients with sepsis,and IL-36Ra packed in extracellular vesicles was released from neutrophils. IL-36gamma enhanced inflammation in inflammatory cells and coagulation and cell injury in endothelial cells. Whereas, IL-36Ra inhibited IL-36gamma induced inflammation, coagulation and cell injury.Indicating that IL-36 cytokines deeply involved in the pathogenesis of sepsis. Finally, we confirmed that IL-36Ra is a potential therapeutic candidate for sepsis using a sepsis mouse model.

Academic Significance and Societal Importance of the Research Achievements

本研究はIL-36Raが好中球より産生され、特に細胞外小胞体に包埋される細胞外に分泌されていることを明らかにした。細胞外小胞体は細胞間コミュニケーションを円滑に行うためのツールであるが、感染症による誘導されるIL-36gammaを抑制すために生体内で重要な働きを行っていることを示している。
また、細胞、動物実験を通してIL-36Raが敗血症における治療補薬剤のひとつになる可能性も示した。

Research Products

• [Journal Article] Ba813 harboring Bacillus cereus, genetically closely related to Bacillus anthracis, causing nosocomial bloodstream infection: Bacterial virulence factors and clinical outcome (2020)
  • Author(s): Tetsuji Aoyagi, Kengo Oshima, Shiro Endo, Hiroaki Baba, Hajime Kanamori, Makiko Yoshida, Koichi Tokuda, Mitsuo Kaku 3
  • Journal Title: PLoS One Volume: 15 Issue: 7 Pages: e0235771-e0235771
  • DOI: 10.1371/journal.pone.0235771
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of Ba813 harbouring Bacillus cereus in patients with haematological malignancy and hospital environments at a medical centre in Japan (2020)
  • Author(s): Tetsuji Aoyagi, Yasuhiro Kishihara, Miho Ogawa, Yuki Ito, Sakie Tanaka, Ryozo Kobayashi, Koichi Tokuda, Mistuo Kaku
  • Journal Title: J Med Microbiol . Volume: 69 Issue: 7 Pages: 999-1004
  • DOI: 10.1099/jmm.0.001212
  • Peer Reviewed
• [Journal Article] 単球/マクロファージ制御による致死性急性呼吸窮迫症候群（ARDS）の治療 (2020)
  • Author(s): 青柳 哲史, 佐藤 由紀夫, 川上 和義, 賀来 満夫
  • Journal Title: 日化療会誌 Volume: 68 Pages: 563-575
  • Peer Reviewed
• [Journal Article] The Effect of Gut Microbiota and Probiotic Organisms on the Properties of Extended Spectrum Beta-Lactamase Producing and Carbapenem Resistant Enterobacteriaceae Including Growth, Beta-Lactamase Activity and Gene Transmissibility (2019)
  • Author(s): Kunishima H, Ishibashi N, Wada K, Oka K, Takahashi M, Yamasaki Y, Aoyagi T, Takemura H, Kitagawa M, Kaku M.
  • Journal Title: Journal of Infection and Chemother Volume: 25 Issue: 11 Pages: 894-900
  • DOI: 10.1016/j.jiac.2019.04.021
  • Peer Reviewed
• [Journal Article] Genomic Analysis of Shiga Toxin-Producing Escherichia Coli From Patients and Asymptomatic Food Handlers in Japan. (2019)
  • Author(s): Baba H, Kanamori H, Kudo H, Kuroki Y, Higashi S, Oka K, Takahashi M, Yoshida M, Oshima K, Aoyagi T, Tokuda K, Kaku M.
  • Journal Title: PLoS One Volume: 14 Issue: 11 Pages: e0225340-e0225340
  • DOI: 10.1371/journal.pone.0225340
  • Peer Reviewed / Open Access
• [Journal Article] Mutant selection window of disinfectants for Staphylococcus aureus and Pseudomonas aeruginosa. (2019)
  • Author(s): Kawamura M, Fujimura S, Tokuda K, Aoyagi T, Endo S, Kanamori H, Watanabe A,Kaku M.
  • Journal Title: Journal of Global Antimicrobial Resistance Volume: 17 Pages: 316-320
  • DOI: 10.1016/j.jgar.2019.01.015
  • Peer Reviewed
• [Journal Article] 2014年臨床分離好気性グラム陰性菌の薬剤感受性サーベイランス (2019)
  • Author(s): 阿南直美・山城秀仁・高橋俊司・菅野のぞみ・賀来満夫・青柳哲史・森兼啓太・中島啓喜・小野由可・長田ゆかり・松尾収二・西 功・草野展周・能勢資子・田仲祐子・野上 智・宮本仁志・村上 忍・平松和史・三浦慎和・森永芳智・栁原克紀・上地幸平・前田士郎・吉田 立
  • Journal Title: The Japanese Journal of Antibiotics Volume: 73 Pages: 219-244
  • NAID: 40022032031
  • Peer Reviewed
• [Journal Article] Etoposide and Corticosteroid Combination Therapy Improves Acute Respiratory Distress Syndrome in Mice (2018)
  • Author(s): Aoyagi Tetsuji、Sato Yukio、Toyama Masahiko、Oshima Kengo、Kawakami Kazuyoshi、Kaku Mitsuo
  • Journal Title: SHOCK Volume: - Issue: 1 Pages: 83-91
  • DOI: 10.1097/shk.0000000000001231
  • Peer Reviewed
• [Journal Article] Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense against Murine Legionella pneumophila Pneumonia (2018)
  • Author(s): Nanjo Yuta、Newstead Michael W.、Aoyagi Tetsuji、Zeng Xianying、Takahashi Kazuhisa、Yu Fu Shin、Tateda Kazuhiro、Standiford Theodore J.
  • Journal Title: Infection and Immunity Volume: 87 Issue: 1
  • DOI: 10.1128/iai.00583-18
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Severe epidemic myalgia with an elevated level of serum interleukin-6 caused by human parechovirus type 3: a case report and brief review of the literature (2018)
  • Author(s): Nakamura Kiwamu、Saito Kyoichi、Hara Yasuka、Aoyagi Tetsuji、Kitakawa Kadzuhiro、Abe Yoshinobu、Takemura Hiromu、Ikeda Fumihito、Kaku Mitsuo、Kanemitsu Keiji
  • Journal Title: BMC Infectious Diseases Volume: 18 Issue: 1 Pages: 381-381
  • DOI: 10.1186/s12879-018-3284-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Attenuated accumulation of regulatory T cells and reduced production of interleukin 10 lead to the exacerbation of tissue injury in a mouse model of acute respiratory distress syndrome (2018)
  • Author(s): Toyama Masahiko、Kudo Daisuke、Aoyagi Tetsuji、Miyasaka Tomomitsu、Ishii Keiko、Kanno Emi、Kaku Mitsuo、Kushimoto Shigeki、Kawakami Kazuyoshi
  • Journal Title: Microbiology and Immunology Volume: 62 Issue: 2 Pages: 111-123
  • DOI: 10.1111/1348-0421.12564
  • NAID: 40021481369
  • Peer Reviewed
• [Presentation] IL-36Ra in Microparticles Secreted from Neutrophils Diminished Inflammation and Coagulation during Sepsis (2020)
  • Author(s): Aoyagi T, Takei E, Kawazoe Y, Nanjo Y, Baba H, Kanamori H, Oshima K, Yoshida M, Tokuda K, Kushimoto S, Standiford TJ, Kaku M
  • Organizer: ASM microbe 2020
• [Presentation] 炎症性単球/マクロファージに着目した呼吸器感染症増悪メカニズムと治療戦略 (2019)
  • Author(s): 青柳 哲史
  • Organizer: 第93回日本感染症学会総会・学術講演会
  • Invited
• [Presentation] IL-36 Cytokines in Extracellular Vesicles Secreted from Human Phagocytic Cells are Involved in Pathogenesis (2019)
  • Author(s): T Aoyagi, E Takei, Y Kawazoe, Y Nanjo, H Kanamori, K
  • Organizer: ASM Microbe 2019
• [Presentation] 敗血症における細胞外小胞体に包埋される IL-36 サイトカインの基礎的検討 (2019)
  • Author(s): 青柳 哲史 馬場 啓聡 、金森 肇、 大島 謙吾、吉田 眞紀子、徳田 浩一、賀来 満夫
  • Organizer: 第68回日本感染症学会東日本地方会学術集会・第67回日本化学療法学会東日本支部総会
• [Presentation] 臨床課題解決を目指した基礎研究～感染病態におけるIL-36 cytokinesに着目して～ (2018)
  • Author(s): 青柳哲史
  • Organizer: 第92回日本感染症学会学術講演会 第66回日本化学療法学会総会 合同学会
  • Invited
• [Presentation] Clinical and bacteriological characteristics of Ba813 harboring Bacillus cereus in bloodstream infection in hospital setting (2018)
  • Author(s): Tetsuji Aoygai, Mina Kawauchi, Hajime Kanamori, Kengo Oshima, Makiko Yoshida, Koichi Tokuda, Mistuo Kaku
  • Organizer: ASM microbe 2018
  • Int'l Joint Research