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Roles for MD molecules in endotoxin recognition

Research Project

Project/Area Number 14021012
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe University of Tokyo

Principal Investigator

MIYAKE Kensuke  The University of Tokyo, The Institute of Medical Science, Professor, 医科学研究所, 教授 (60229812)

Co-Investigator(Kenkyū-buntansha) 赤司 祥子  東京大学, 医科学研究所, 助手 (00325599)
Project Period (FY) 2002 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥56,000,000 (Direct Cost: ¥56,000,000)
Fiscal Year 2005: ¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2004: ¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2003: ¥16,000,000 (Direct Cost: ¥16,000,000)
Fiscal Year 2002: ¥10,000,000 (Direct Cost: ¥10,000,000)
Keywordsendotoxin / Toll-like receptor / innate immunity / Toll-like receptor / Lipopolysaccharide / MD-2 / Toll like receptor / Lipopolyaccharide / 病原体
Research Abstract

Little is known about mechanisms underlying microbial recognition in the innate immune system. Toll-like receptors (TLR) sense the presence of pathogens and trigger defense responses by transducing activating signals. This project focuses on endotoxin (LPS, lipopolysaccharide) recognition and aim to reveal molecular mechanism for LPS recognition. We previously discovered MD-2 that is associated with TLR4 and indispensable for LPS responses by TLR4. Further, we showed direct interaction between LPS and the receptor complex consisting of TLR4 and MD-2 (TLR4/MD-2). We next focused on the event following ligand interaction with TLR4/MD-2, oligomerization of TLR4/MD-2. Further, antagonistic lipid A analogue lipid IVa was found to bind to TLR4/MD-2 but not to induce oligomerization. These results suggest that LPS responses are triggered not by ligand binding but by the following receptor oligomerization. MD-2 has a critical role in triggering TLR4/MD-2 oligomerization. LPS, a ligand to TLR4/MD-2 is not homogenous but differ in its structure with Gram-negative bacteria. TLR4/MD-2 is able to discriminate such a difference in structure between bacteria and MD-2 has a critical role in the discrimination.

Report

(5 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (41 results)

All 2006 2005 2004 Other

All Journal Article (25 results) Publications (16 results)

  • [Journal Article] A molecule that is associated with Toll-like receptor 4 and regulates its cell surface expression.2006

    • Author(s)
      今野和典
    • Journal Title

      Biochem Biophys Res Commun 339

      Pages: 1076-1082

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Agonistic Antibody to Toll-like receptor 4/MD-2 Protects Mice from Acute Lethal Hepatitis Induced by Tumor Necrosis Factor-α2006

    • Author(s)
      赤司祥子
    • Journal Title

      Journal of Immunology 176

      Pages: 6211-6218

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Regulatory Roles for MD-2 and Toll-like receptor 4 (TLR4) in Ligand-induced Receptor Clustering.2006

    • Author(s)
      小林真紀子
    • Journal Title

      Journal of Immunology 176

      Pages: 4244-4251

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A Protein Associated with Toll-like Receptor 4 (PRAT4A) Regulates Cell Surface Expression of TLR4.2006

    • Author(s)
      若林靖隆
    • Journal Title

      Journal of Immunology 177

      Pages: 1772-1779

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A molecule that is associated with Toll-like receptor 4 and regulates its cell surface expression.2006

    • Author(s)
      Konno K, et al.
    • Journal Title

      Biochem Biophys Res Commun. 339

      Pages: 1076-1082

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Agonistic Antibody to Toll-like receptor 4/MD-2 Protects Mice from Acute Lethal Hepatitis Induced by Tumor Necrosis Factor-a2006

    • Author(s)
      Akashi-Takamura S, et al.
    • Journal Title

      J. Immunol. 176

      Pages: 4244-4251

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Regulatory Roles for MD-2 and Toll-like receptor 4 (TLR4) in Ligand-induced Receptor Clustering.2006

    • Author(s)
      Kobayashi M, et al.
    • Journal Title

      J. Immunol. 176

      Pages: 6211-6218

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A Protein Associated with Toll-like Receptor 4 (PRAT4A) Regulates Cell Surface Expression of TLR4.2006

    • Author(s)
      Wakabayashi Y, et al.
    • Journal Title

      J. Immunol. 177

      Pages: 1772-1779

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A molecule that is associated with Toll-like receptor 4 and regulates its cell surface expression.2006

    • Author(s)
      Konno K
    • Journal Title

      Biochem Biophys Res Commun. 339

      Pages: 1076-1082

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Agonistic Antibody to Toll-like receptor 4/MD-2 Protects Mice from Acute Lethal Hepatitis Induced by Tumor Necrosis Factor-α2006

    • Author(s)
      Akashi-Takamura S
    • Journal Title

      J.Immunol. (印刷中)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Regulatory Roles for MD-2 and Toll-like receptor 4 (TLR4) in Ligand-induced Receptor Clustering.2006

    • Author(s)
      Kobayashi M
    • Journal Title

      J.Immunol. (印刷中)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] The Radioprotective 105/MD-1 Complex Links Toll-like Receptor 2 (TLR2) and TLR4/MD-2 in Antibody Response to Microbial Membranes.2005

    • Author(s)
      長井良憲
    • Journal Title

      Journal of Immunology 174

      Pages: 7043-7049

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The Radioprotective 105/MD-1 Complex Links Toll-like Receptor 2 (TLR2) and TLR4/MD-2 in Antibody Response to Microbial Membranes2005

    • Author(s)
      Nagai Y, et al.
    • Journal Title

      J. Immunol. 174

      Pages: 7043-7049

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The Radioprotective 105/MD-1 Complex Links Toll-like Receptor 2 (TLR2) and TLR4/MD-2 in Antibody Response to Microbial Membranes.2005

    • Author(s)
      Nagai Y
    • Journal Title

      J.Immunol. 174

      Pages: 7043-7049

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Two waves of memory B-cell generation in the primary immune response.2005

    • Author(s)
      Inamine A
    • Journal Title

      Int Immunol. 17

      Pages: 581-589

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Association of SIGNR1 with TLR4-MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria.2005

    • Author(s)
      Nagaoka K
    • Journal Title

      Int Immunol. 17

      Pages: 827-836

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling.2005

    • Author(s)
      Shinohara H.
    • Journal Title

      J Exp Med. 201

      Pages: 333-339

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll-like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomerization.2004

    • Author(s)
      斉藤 伸一郎
    • Journal Title

      International Immunology 16

      Pages: 961-969

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll-like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomerization.2004

    • Author(s)
      Saitoh, S., et al.
    • Journal Title

      Int Immunol. 16

      Pages: 961-969

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Endotoxin recognition molecules, Toll-like receptor 4-MD-2.2004

    • Author(s)
      Miyake K.
    • Journal Title

      Semin Immunol. 16

      Pages: 11-16

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The role of IL-5 for mature B-1 cells in homeostatic proliferation, cell survival, and Ig production.2004

    • Author(s)
      Moon BG.
    • Journal Title

      J Immunol. 172

      Pages: 6020-6029

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll-like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomerization.2004

    • Author(s)
      Saitoh S.
    • Journal Title

      Int Immunol. 16

      Pages: 961-969

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Endotoxin recognition molecules MD-2 and toll-like receptor 4 as potential targets for therapeutic intervention of endotoxin shock.2004

    • Author(s)
      Miyake K.
    • Journal Title

      Curr Drug Targets Inflamm Allergy. 3

      Pages: 291-297

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Interaction of Soluble Form of Recombinant Extracellular TLR4 Domain with MD-2 Enables Lipopolysaccharide Binding and Attenuates TLR4-Mediated Signaling.2004

    • Author(s)
      Hyakushima N.
    • Journal Title

      J Immunol. 173

      Pages: 6949-6954

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Different domains of Pseudomonas aeruginosa exoenzyme S activate distinct TLRs.2004

    • Author(s)
      Epelman S.
    • Journal Title

      J Immunol. 173

      Pages: 2031-2040

    • Related Report
      2004 Annual Research Report
  • [Publications] Miyake, K.: "Innate recognition of lipopolysaccharide by CD14 and toll-like receptor 4-MD-2:unique roles for MD-2."Int Immunopharmacol.. 1. 119-128 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Okamoto M.: "Involvement of Toll-Like Receptor 4 Signaling in Interferon-gamma Production and Antitumor Effect by Streptococcal Agent OK-432."J.Natl.Cancer Inst.. 95. 316-326 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] T Matsunaga: "Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia."Nat.Med.. 9. 1158-1165 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Adib-Conquy M: "Toll-like receptor-mediated tumor necrosis factor and interleukin-10 production differ during systemic inflammation."Am J Respir Crit Care Med.. 168. 158-164 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] S Akashi: "Lipopolysaccharide Interaction with Cell Surface Toll-like Receptor 4-MD-2:Higher Affinity than that with MD-2 or CD14."J.Exp.Med.. 198. 1035-1042 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kimoto M: "Role of TLR4/MD-2 and RP105/MD-1 in innate recognition of lipopolysaccharide."Scand J Infect Dis.. 35. 568-572 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Miyake K.: "Endotoxin recognition molecules, Toll-like receptor 4-MD-2."Semin Immunol.. 16. 11-16 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Termeer, C.: "Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4"J. Exp. Med.. 195. 99-111 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagai, Y.: "Requirement for MD-1 in Cell Surface Expression of RP105/CD180 and B Cell Responsiveness to Lipopolysaccharide"Blood. 99. 1699-1705 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Bosisio D.: "Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-gamma : a molecular basis for priming and synergism with bacterial lipopolysaccharide"Blood. 99. 3427-3431 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagai, Y.: "Essential role of MD-1 in lipopolysaccharide responsiveness and Toll-like receptor 4 distribution"Nat. Immunol.. 3. 667-672 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Matsumoto, M.: "Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling"Biochem. Biophys. Res. Commu.. 293. 1364-1369 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Abel B.: "Toll-like receptor 4 expression is required to control chronic Mycobacterium tuberculosis infection in mice"J. Immunol.. 169. 3155-3162 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ogawa, T.: "Cell activation by Porphyromonas gingivalis lipid A molecule through Toll-like receptor 4-and myeloid differentiation factor 88-dependent signaling pathway"Int Immunol.. 11. 1325-1332 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hijiya, N.: "Possible involvement of toll-like receptor 4 in endothelial cell activation of larger vessels in response to lipopolysaccharide"Pathobiology. 70. 18-25 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Miyake, K.: "Innate recognition of lipopolysaccharide by CD14 and toll-like receptor 4-MD-2 : unique roles for MD-2"Int Immunopharmacol.. 1. 119-128 (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2018-03-28  

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