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Biochemical elucidation of LTA4 hydrolase in immune cells

Research Project

Project/Area Number 17K08664
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pathological medical chemistry
Research InstitutionKumamoto University

Principal Investigator

KOGA TOMOAKI  熊本大学, 発生医学研究所, 助教 (30615092)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsLTA4水解酵素 / 脂質メディエーター / GPCR / ロイコトリエンB4 / 炎症 / 肥満 / 生理活性脂質 / 樹状細胞 / 免疫細胞 / 脂質免疫学 / 脂質エピゲノム / 炎症反応
Outline of Final Research Achievements

Leukotriene B4 (LTB4) is produced from arachidonic acid by leukotriene A4 hydrolase (LTA4H). LTA4H adds water molecule on LTA4 to generate LTB4 and also degrades proteins by using its aminopeptidase activity. LTA4H thus uses lipid and protein as substrates. In the present study, I generated LTA4H knockout mice and analyzed the biological significance of LTA4H in vivo. I found that contact dermatitis was ameliorated and obesity was improved in LTA4H deficient mice. The former is dependent on the LTB4 producing activity of LTA4H, but the latter is independent on the activity. In addition, I identified novel lipid mediator namely RvEx produced by LTA4H.These results suggested the biological significance of LTA4H in inflammation and obesity.

Academic Significance and Societal Importance of the Research Achievements

本研究ではCRISPR/Cas9システムを用いてLTA4H遺伝子欠損マウスを世界で初めて樹立した。また、LTB4産生酵素として知られるLTA4Hであるが、LTB4産生に関わる酵素に比べてかなり広範に発現する理由に関しては長年の謎であった。今回見出した接触性皮膚炎の表現型に関してはLTB4受容体BLT1の遺伝子欠損マウスで矛盾しない結果が得られるため、LTB4依存的であると考えられたが、肥満の表現型はBLT1遺伝子欠損マウスでは見られないため、LTB4非依存的であると考えられた。この発見は学術的に興味深いだけでなく、抗肥満薬の標的としてLTA4Hを提起した重要な知見であった。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (17 results)

All 2020 2019 2018 2017

All Journal Article (9 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 9 results,  Open Access: 7 results) Presentation (7 results) (of which Invited: 1 results) Book (1 results)

  • [Journal Article] Leukotriene B4 receptor 1 exacerbates inflammation following myocardial infarction.2020

    • Author(s)
      Horii Y, Nakaya M, Ohara H, Nishihara H, Watari K, Nagasaka A, Nakaya T, Sugiura Y, Okuno T, Koga T, Tanaka A, Yokomizo T, Kurose H.
    • Journal Title

      FASEB Journal

      Volume: 印刷中 Issue: 6 Pages: 8749-8763

    • DOI

      10.1096/fj.202000041r

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Computational analysis of morphological and molecular features in gastric cancer tissues.2020

    • Author(s)
      Yasuda Y, Tokunaga K, Koga T, Goldberg I, Sakamoto C, *Saitoh N, *Nakao M
    • Journal Title

      Cancer Med

      Volume: 9 Issue: 6 Pages: 2223-2234

    • DOI

      10.1002/cam4.2885

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] α1-acid glycoprotein attenuates adriamycin-induced nephropathy via CD163 expressing macrophages induction2020

    • Author(s)
      Fujimura Rui、Watanabe Hiroshi、Nishida Kento、Fujiwara Yukio、Koga Tomoaki、Bi Jing、Imafuku Tadashi、Kobayashi Kazuki、Komori Hisakazu、Miyahisa Masako、Maeda Hitoshi、Tanaka Motoko、Matsushita Kazutaka、Wada Takashi、Fukagawa Masafumi、Maruyama Toru
    • Journal Title

      Kidney360

      Volume: ー Issue: 5 Pages: 343-353

    • DOI

      10.34067/kid.0000782019

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] BLT1 mediates commensal bacteria-dependent innate immune signals to enhance antigen-specific intestinal IgA responses.2019

    • Author(s)
      Nagatake T, Hirata SI, Koga T, Kuroda E, Suzuki H, Hosomi K, Matsumoto N, Yanrismet Y, Shimojou M, Morimoto S, Sasaki F, Ishii KJ, Yokomizo T, Kunisawa J.
    • Journal Title

      Mucosal Immunology

      Volume: 印刷中

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models.2018

    • Author(s)
      Sasaki F., Koga T., Ohba M., Saeki K., Okuno T., Ishikawa K., Nakama T., Nakao S., Yoshida S., Ishibashi T., Ahmadieh H., Kanavi M. R., Hafezi-Moghadam A., Penninger J. M., Sonoda K. H., Yokomizo T.
    • Journal Title

      JCI Insight

      Volume: 3 Issue: 18 Pages: 96902-96902

    • DOI

      10.1172/jci.insight.96902

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Profiling of bioactive lipids in different dendritic cell subsets using an improved multiplex quantitative LC-MS/MS method.2018

    • Author(s)
      Ohba M., Saeki K., Koga T., Okuno T., Kobayashi Y., Yokomizo T.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 504 Issue: 3 Pages: 562-568

    • DOI

      10.1016/j.bbrc.2018.06.026

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic Fusion of Type-I Interferon to a Recombinant Albumin Mutant with polymannosylated N-linked oligosaccharide attached is a Novel and Superior Kupffer Cell Targeting Agent for the Treatment of Hepatitis.2018

    • Author(s)
      Minayoshi Y, Maeda H, Yanagisawa H, Hamasaki K, Mizuta Y, Nishida K, Kinoshita R, Enoki Y, Imafuku T, Chuang VTG, Koga T, Fujiwara Y, Takeya M, Sonoda K, Wakayama T, Taguchi K, Ishima Y, Ishida T, Iwakiri Y, Tanaka M, Sasaki Y, Watanabe H, Otagiri M, Maruyama T.
    • Journal Title

      Drug Delivery

      Volume: 25 Issue: 1 Pages: 1067-1077

    • DOI

      10.1080/10717544.2018.1464083

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inhibition of local macrophage growth ameliorates focal inflammation and suppresses atherosclerosis.2018

    • Author(s)
      Yamada S, Senokuchi T, Matsumura T, Morita Y, Ishii N, Fukuda K, Murakami S, Nishida S, Kawasaki S, Motoshima H, Furukawa N, Komohara Y, Fujiwara Y, Koga T, Yamagata K, Takeya M, Araki E
    • Journal Title

      Arteriosclerosis, Thrombosis, and Vascular Biology

      Volume: 印刷中 Issue: 5 Pages: 994-1006

    • DOI

      10.1161/atvbaha.117.310320

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Profiling of bioactive lipids in different dendritic cell subsets using an improved multiplex quantitative LC-MS/MS method2018

    • Author(s)
      Ohba M, Saeki K, Koga T, Okuno T, Kobayashi Y, Yokomizo T.
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 印刷中

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Regulation of Monocytic cell subset by Lipid mediator and Epigenome2019

    • Author(s)
      Tomoaki Koga、Fumiyuki Sasaki、Takehiko Yokomizo、Mitsuyoshi Nakao
    • Organizer
      第42回日本分子生物学会年会 2019年12月5日 福岡
    • Related Report
      2019 Annual Research Report
  • [Presentation] 炎症・免疫細胞サブセットにおけるエピゲノム因子の機能解析2019

    • Author(s)
      古賀友紹、横溝岳彦、中尾光善
    • Organizer
      第43回蛋白質と酵素の構造と機能に関する九州シンポジウム 2019年9月5日~7日 福岡
    • Related Report
      2019 Annual Research Report
  • [Presentation] 脂質メディエーターとエピゲノムによる単球系サブセットの制御機構2019

    • Author(s)
      古賀友紹、横溝岳彦、中尾光善
    • Organizer
      第13回日本エピジェネティクス研究会年会 2019年5月28日~29日 横浜
    • Related Report
      2019 Annual Research Report
  • [Presentation] 生理活性脂質 LTB4 及びその受容体 BLT1 による 新規樹状細胞サブセット制御機構2018

    • Author(s)
      古賀友紹, 佐々木文之, 佐伯和子, 奥野利明, 中尾光善, 横溝岳彦.
    • Organizer
      第15回 東京呼吸器リサーチフォーラム
    • Related Report
      2018 Research-status Report
  • [Presentation] ロイコトリエンB4第一受容体により規定される新規樹状細胞サブセットの同定2018

    • Author(s)
      古賀友紹、中尾光善、横溝岳彦
    • Organizer
      第12回 日本エピジェネティクス研究会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 生理活性脂質ロイコトリエンB4とその受容体BLT1による生体防御応答2017

    • Author(s)
      古賀友紹、中尾光善、横溝岳彦
    • Organizer
      第7回 オルソオルガノジェネシス検討会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 生理活性脂質ロイコトリエンB4とその受容体BLT1による免疫制御機構の解析2017

    • Author(s)
      古賀友紹、中尾光善、横溝岳彦
    • Organizer
      第41回 蛋白質と酵素の構造と機能に関する九州シンポジウム
    • Related Report
      2017 Research-status Report
  • [Book] 臨床免疫・アレルギー科 第70巻 ロイコトリエンB4とその受容体による免疫調節機構2018

    • Author(s)
      古賀友紹, 佐伯和子, 横溝岳彦.
    • Total Pages
      10
    • Publisher
      科学評論社
    • Related Report
      2018 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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