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Discovery of novel functions of brain microglia and their in vivo analysis.

Research Project

Project/Area Number 11670089
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionHiroshima University

Principal Investigator

NAKATA Yoshihiro  DEPARTMENT OF PHARMACOLOGY, INSTITUTE OF PHARMACEUTICAL SCIENCES, HIROSHIMA UNIVERSITY SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (40133152)

Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1999: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsMicroglia / ATP / TNF-α / P2X_7 receptor / Ca^<2+> / ERK / p38 / P2X_7 / ホスホリパーゼD
Research Abstract

Upon pathological changes such as brain ischemia or inflammation, microglia are rapidly activated and secrete various cytokines, including TNF-α, which plays not only harmful, but also protective roles for neurons. Despite importance of microglia-derived TNF-α, it remains unknown how the release of TNF-α is regulated. Recently it was revealed that ATP, which is released from nerve terminals, activated immune cells or damaged cells, activates microglia via cell surface P2 receptors, at least G-protein-coupled P2Y_2 and ionotropic P2X_7. In this study, we found that ATP stimulates the release of TNF-α, resulting from mRNA expression in rat cultured brain microglia. The release of TNF-α was maximally elicited by 1 mM ATP and also induced by a P2X_7 selective agonist, 2'-and 3'-O-(4-benzoylbenzoyl)-adenosine 5'-triphosphate (BzATP), and BzATP-induced TNF-α was inhibited by Brilliant Blue G, a selective antagonist of rat P2X_7 receptor. ATP-or BzATP-induced TNF-α release was inhibited by PD98059 and U-0126, inhibitors of MEK1, which activates ERK, and also by SB203580, an inhibitor of p38 MAP kinase, while BzATP-stimulated mRNA expression of TNF-α was inhibited by U-0126, but not by SB203580. These results indicate that extracellular ATP triggers TNF-α release in rat microglia at least via P2X_7 receptor and suggest that signaling to the release of TNF-α involves ERK and p38 MAP kinase, which play distinct roles at the transcriptional and the post-transcriptional levels, respectively.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (8 results)

All Other

All Publications (8 results)

  • [Publications] I.Hide,M.Tanaka,A.Inoue,K.Nakajima,S.Kohsaka,K.Inoue & Y.Nakata: "Extracellular ATP triggers tumor necrosis factor-α release from rat microglia."Journal of Neurochemistry. 75. 965-972 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] I.Hide,T.Suzuki,A.Inoue,and Y.Nakata: "Regulation of TNF-α release from microglia by ATP"Neurochemical Research. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 田中将也,鈴木智久,井上敦子,秀和泉,井上和秀,高坂新一,仲田義啓: "細胞外ATPによるラットミクログリアのTNF-α産生遊離"神経化学. 38(3). 274 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Izumi Hide, Masaya Tanaka, Atsuko Inoue, Kazuyuki Nakajima, Shinichi Kohsaka, Kazuhide Inoue, and Yoshihiro Nakata: "Extracellular ATP triggers tumor necrosis factor-α release from rat microglia."Journal of Neurochemistry. 75. 965-972 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Izumi Hide, Tomohisa Suzuki, Atsuko Inoue, and Yoshihiro Nakata: "Regulation of TNF-α release from microglia by ATP."Neurochemical Research. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] I.Hide,M.Tanaka,A.Inoue,K.Nakajima,S.Kohsaka,K.Inoue & Y.Nakata: "Extracellular ATP triggers tumor necrosis factor-α release from rat microglia."Journal of Neurochemistry. 75. 965-972 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] I.Hide,T.Suzuki,A.Inoue,and Y.Nakata: "Regulation of TNF-α release from microglia by ATP"Neurochemical Research. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 田中将也,鈴木智久,井上敦子,秀和泉,井上和秀,高坂新一,仲田義啓: "細胞外ATPによるラットミクログリアのTNF-α産生遊離"神経化学. 38(3). 274 (1999)

    • Related Report
      2000 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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