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Modulation of neutrophil apoptosis in septic shock and its regulation by endogenous antimicrobial peptides

Research Project

Project/Area Number 15590400
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Bacteriology (including Mycology)
Research InstitutionJUNTENDO UNIVERSITY

Principal Investigator

NAGAOKA Isao  Juntendo University, School of Medicine, Professor, 医学部, 教授 (60164399)

Co-Investigator(Kenkyū-buntansha) KUWAHARA Kyoko (ARAI Kyoko)  Juntendo University, School of Medicine, Instructor, 医学部, 助手 (10167976)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsSepsis / Neutrophil / Apoptosis / Endotoxin / Cytokine / Monocyte / Macrophage / Toll-like receptor / Integrins
Research Abstract

Peptide antibiotics possess potent antimicrobial activities against invading microorganisms and contribute to innate host defense. We previously revealed that antibacterial cathelicidin CAP11 exerts protective actions against endotoxin shock model. During Gram-negative bacterial sepsis, LPS activates neutrophils and their apoptosis is suppressed. Prolonged presence of activated neutrophils causes uncontrolled release of toxic metabolites, leading to the systemic tissue injury. To evaluate a therapeutic potential of CAP11 for Gram-negative sepsis, we here investigated the action of CAP11 on LPS-induced suppression of neutrophil apoptosis.
LPS suppressed neutrophil apoptosis, accompanied with NF-kappaB activation, ERK phosphorylation, Bcl-XL expression and caspase 3 inhibition. Interestingly, CAP11 reversed the actions of LPS to trigger these changes, and induced neutrophil apoptosis. Furthermore, LPS activated monocytes to produce anti apoptotic cytokines (IL-1beta, TNF-alpha and IL-8) and suppressed neutrophil apoptosis. Importantly, CAP11 inhibited the cytokine production from monocytes, thereby inducing neutrophil apoptosis. Finally, CAP11 strongly suppressed LPS-binding to neutrophils and monocytes.
Thus, CAP11 is able to block the LPS-induced prolongation of neutrophil survival via the suppression of anti apoptotic signaling in neutrophils and cytokine production from monocytes by inhibiting LPS-binding to target cells. CAP11 is expected to have a therapeutic potential in Gram-negative sepsis to induce neutrophil apoptosis, thereby possibly attenuating tissue injury.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (20 results)

All 2005 2004 Other

All Journal Article (14 results) Book (2 results) Patent(Industrial Property Rights) (1 results) Publications (3 results)

  • [Journal Article] Augmentation of the bactericidal activities of human cathelicidin CAP18/LL-37-derived antimicrobial peptides by amino acid substitutions.2005

    • Author(s)
      Nagaoka I, Kuwahara-Arai K, Tamura H, Hiramatsu K, Hirata M
    • Journal Title

      Inflamm Res 54

      Pages: 66-73

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The effect of antibacterial peptide human beta-defensin-2 on interleukin-18 secretion by keratinocytes.2005

    • Author(s)
      Sampanthanarak P, Niyonsaba F, Ushio H, Nagaoka I, Ikeda S, Okumura K, Ogawa H
    • Journal Title

      J Dermatol Sci 37

      Pages: 188-191

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Effect of antibacterial cathelicidin peptide CAP18/LL-37 on sepsis in neonatal rats.2005

    • Author(s)
      Fukumoto K, Nagaoka I, Yamataka A, Kobayashi H, Yanai T, Kato Y, Miyano T
    • Journal Title

      Pediatr Surg Int 21

      Pages: 20-24

    • NAID

      10019041914

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Antibacterial cathelicidin peptide CAP11 inhibits the lipopolysaccharide(LPS)-induced suppression of neutrophil apoptosis by blocking the binding of LPS to target cells.2004

    • Author(s)
      Isao Nagaoka, et al.
    • Journal Title

      Inflammation Research 53

      Pages: 609-622

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Effect of antibacterial cathelicidin peptide CAP18/LL-37 on sepsis in neonatal rats.2004

    • Author(s)
      Koji Fukumoto, Isao Nagaoka et al.
    • Journal Title

      Pediatric Surgery International 21

      Pages: 20-24

    • NAID

      10019041914

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Cathelicidinファミリーの殺菌ペプチドCAP11による好中球アポトーシスの制御2004

    • Author(s)
      長岡 功, 他
    • Journal Title

      炎症・再生 24

      Pages: 166-172

    • NAID

      10026498445

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Cathelicidinファミリーの殺菌ペプチドによる好中球アポトーシスの制御-LPS刺激による好中球アポトーシスの制御におよぼすCAP11の効果2004

    • Author(s)
      長岡 功, 他
    • Journal Title

      エンドトキシン研究 7

      Pages: 55-64

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 好中球アポトーシスの分子制御2004

    • Author(s)
      長岡 功
    • Journal Title

      臨床免疫 43

      Pages: 236-242

    • NAID

      40006647018

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 炎症・白血球・ラジカル2004

    • Author(s)
      長岡 功
    • Journal Title

      日本病態生理学会誌 13

      Pages: 31-37

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Antibacterial cathelicidin peptide CAP11 inhibits the lipopolysaccharide (LPS)-induced suppression of neutrophil apoptosis by blocking the binding of LPS to target cells.2004

    • Author(s)
      Nagaoka I, Yomogida S, Tamura H, Hirata M
    • Journal Title

      Inflamm Res 53

      Pages: 609-622

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Human beta-defensin-2 functions as a chemotactic agent for tumour necrosis factor-alpha-treated human neutrophils.2004

    • Author(s)
      Niyonsaba F, Ogawa H, Nagaoka I
    • Journal Title

      Immunology 111

      Pages: 273-281

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Antibacterial cathelicidin peptide CAP11 inhibits the lipopolysaccharide (LPS)-induced suppression of neutrophil apoptosis by blocking the binding of LPS to target cells.2004

    • Author(s)
      Isao Nagaoka, et al.
    • Journal Title

      Inflammation Research 53

      Pages: 609-622

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cathelicidinファミリーの殺菌ペプチドによる好中球アポトーシスの制御-LPS刺激による好中球アポトーシスの抑制におよぼすCAP11の効果2004

    • Author(s)
      長岡 功, 他
    • Journal Title

      エンドトキシン研究 7

      Pages: 55-64

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 好中球アポトーシスの分子制御2004

    • Author(s)
      長岡 功
    • Journal Title

      臨床免疫 433

      Pages: 236-242

    • NAID

      40006647018

    • Related Report
      2004 Annual Research Report
  • [Book] 別冊・医学のあゆみ2004

    • Author(s)
      長岡 功, 諌山太郎
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 別冊・医学のあゆみ2004

    • Author(s)
      長岡 功, 諌山太郎
    • Related Report
      2004 Annual Research Report
  • [Patent(Industrial Property Rights)] 抗菌性ペプチド2004

    • Inventor(s)
      長岡 功
    • Industrial Property Rights Holder
      順天堂大学
    • Industrial Property Number
      2004-199835
    • Filing Date
      2004-07-06
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] 長岡 功 他: "Cathelicidinファミリーの殺菌ペプチドCAP11による好中球アポトーシスの制御"第50回毒素シンポジウム予稿集. 53-58 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 長岡 功 他: "Cathelicidinファミリーの殺菌ペプチドによる好中球アポトーシスの制御"炎症・再生. 24・4(印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 長岡 功 他: "LPS刺激による好中球のアポトーシス抑制におよぼす殺菌ペプチドCAP11の効果"エンドトキシン研究. 7(印刷中). (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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