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Effect of hypercholesteremia on lipid raft-mediated T cell activation

Research Project

Project/Area Number 14570279
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionOsaka University

Principal Investigator

KOSUGI Atsushi  Osaka Univ., Med.Sch., Associate Professor, 医学系研究科, 助教授 (90186685)

Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsT cells / lipid raft / cholesterol / hypercholesteremia / ganglioside GM1 / sphingolipid / Raft
Research Abstract

Lipid rafts are highly enriched in cholesterol and sphingolipids (glycosphingolipids (GSLs) and sphingomyelin (SM)). Among these lipid components, cholesterol has a critical function for maintaining raft structure. Cholesterol depletion from cell membranes using drugs, such as methyl-13-cyclodextrin (MβCD), generally results in disruption of raft-mediated cellular functions. Thus, despite some concerns about side effects of the drug on signaling events, this experimental approach has been widely used to verify the importance of cholesterol in raft organization and function.
In contrast to many studies manipulating the cholesterol level in lipid rafts, reports that address a role for sphingolipids in raft function are scarce. A previous study demonstrated that reduction of SM levels in Chinese hamster ovary (CHO) mutant cells induced decreased distribution of cholesterol in lipid rafts. Moreover, it was reported that addition of exogenous gangliosides to the culture of Madin-Darby canine … More kidney (MDCK) cells or CHO-K1 cells displaced glycosylphosphatidylinositol (GPI)-anchored proteins from lipid microdomains. All these studies suggested that changes in sphingolipid contents alter raft lipid and protein constituents. However, none of these studies contributed to our understanding of any functional change in membrane rafts by the manipulation of sphingolipid levels. Although an effect of GSL deficiency on functional raft formation has been suggested, whether sphingolipids are essential for raft-mediated signal transduction remains to be addressed. In the present study, we investig ated a role for sphingolipids in raft organization and function in lymphocytes, focusing particularly on a role for GSLs by the usage of a specific GSL synthesis inhibitor, D-PDMP. We demonstrated that the expression state of GPI-anchored proteins is affected by reduction of GSL levels. Further, our results showed that a reduced level of GSLs in membrane rafts modulates signaling through GPI-anchored proteins, but not through the TCR. By comparing the effect of D-PDMP with that of MMCD, we also identified that GSL and cholesterol depletion have distinctly different influences on GPI-anchored proteins in lipid rafts. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (40 results)

All Other

All Publications (40 results)

  • [Publications] Inoue H. et al.: "Lipid rafts as the signaling scaffold for NK cell activation : Tyrosine phosphorylation and association of LAT with PI 3-kinase and PLC-γ following CD2 stimulation"Eur.J.Immunol.. 32. 2188-2198 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagai Y. et al.: "Essential role of MD-2 in LPS responsiveness and TLR4 distribution"Nature Immunol.. 3. 667-672 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yasuda K. et al.: "Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells"J.Immunol.. 169. 2813-2817 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Miyake K. et al.: "Essential role of MD-2 in B-cell responses to lipopolysaccharide and Toll-like receptor 4 distribution"J.Endotoxin Res.. 8. 449-452 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tanimura N. et al.: "Dynamic changes in the mobility of LAT in aggregated lipid rafts upon T cell activation"J.Cell Biol.. 160. 125-135 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ike H.et al.: "Mechanism of Lck recruitment to the T-cell receptor cluster as studied by single molecule fluorescence video imaging"Chem.Phys.Chem.. 16. 620-626 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsuno Y. et al.: "Hepatocyte growth factor gene transfer into the liver via the portal vein using electroporation attenuates the rat liver cirrhosis."Gene Ther.. 10. 1559-1566 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tanimura N. et al.: "Analysis of the mobility of signaling molecules in lymphocytes using fluorescence photobleaching techniques"Sci STKE. 110 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ito T.et al.: "Interaction of SAP-1, a transmembrane-type protein tyrosine phosphatase, with the tyrosine kinase Lck : Roles in regulation of T cell function"J.Biol.Chem.. 278. 34854-34863 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagafuku M. et al.: "Reduction of glycosphingolipid levels in lipidrafts affects the expression state and function of GPI-anchored proteins, but does not impair signal transduction via the T cell receptor"J.Biol.Chem.. 278. 51920-51927 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Akashi S. et al.: "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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hatano N. et al.: "Essential role for ERK2 mitogen-activated protein kinase in placental development"Genes to Cells. 8. 847-856 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsuno Y. et al.: "Nonviral gene gun mediated transfer into the beating heart"ASAIO J.. 49. 641-644 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inoue H, Miyaji M, Kosugi A, Nagafuku M, Okazaki T, Mimori T, Amakawa R, Fukuhara S, Domae N, Bloom ET, Umehara H: "Lipid rafts as the signaling scaffold for NK cell activation : Tyrosine phosphorylation and association of LAT with PI 3-kinase and PLC-γ following CD2 stimulation"Eur.J.Immunol.. 32. 2188-2198 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagai Y, Akashi S, Nagafuku M, Ogata M, Iwakura Y, Akira S, Kitamura T, Kosugi A, Kimoto M, Miyake K: "Essential role of MD-2 in LPS responsiveness and TLR4 distribution."Nature Immunol.. 3. 667-672 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yasuda K, Nagafuku M, Shima T, Okada M, Yagi T, Yamada T, Minaki Y, Kato A, Tani-ichi S, Hamaoka T, Kosugi A: "Cutting Edge : Fyn is essential for tyrosine phosphorylation of Cbp/PAG in lipid rafts in resting T cells."J.Immunol.. 169. 2813-2817 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Miyake K, Nagai Y, Akashi S, Nagafuku M, Ogata M, Kosugi_A: "Essential role of MD-2 in B cell responses to Lipopolysaccharide and Toll-like receptor 4 distribution."J.Endotoxin Res.. 8. 449-452 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsuno Y, Iwata H, Yoshikawa S, Umeda Y, Iida Y, Takagi H, Mon Y, Miyazaki J, Kosugi A, Hirose H: "Suppression of graft coronary arteriosclerosis by gene gun-mediated CTLA4-Ig gene transfer."Trans.Proc.. 34. 2619-2621 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Umeda Y, Iwata H, Yoshikawa S, Matsuno Y, Marui T, Nitta T, Iida Y, Takagi H, Mon Y, Miyazaki J, Kosugi A, Hirose H: "Gene gun-mediated CTLA4Ig-gene transfer for modification of allergenic cardiac grafts."Trans.Proc.. 34. 2622-2623 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tanimura N, Nagafuku M, Minaki Y, Umeda Y, Hayashi F, Sakakura J, Kato A, Liddicoat DR, Ogata M, Hamaoka T, Kosugi A: "Dynamic changes in the mobility of LAT in aggregated lipid rafts upon T cell activation."J.Cell Biol.. 160. 125-135 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ike H, Kosugi A, Kato A, Iino R, Hirano H, Fujiwara T, Ritchie K, Kusumi A: "Mechanism of Lck recruitment to the T-cell receptor cluster as studied by single molecule fluorescence video imaging."Chemphyschem.. 16. 620-626 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsuno Y, Iwata H, Umeda Y, Takagi H, Mon Y, Kosugi A, Matsumoto K, Nakamura T, Hirose H: "Hepatocyte growth factor gene transfer into the liver via the portal vein using electroporation attenuates the rat liver cirrhosis."Gene Therapy. 10. 1559-1566 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tanimura N, Nagafuku M, Liddicoat DR, Hamaoka T, Kosugi A: "Analysis of the mobility of signaling molecules in lymphocytes using fluorescence photobleaching techniques."Sci.STKE 2003. 110 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ito T, Okazawa H, Maruyama K, Tomizawa K, Motegi SI, Ohnishi H, Kuwano H, Kosugi A, Matozaki T: "Interaction of SAP-1, a transmembrane-type protein tyrosine phosphates, with the tyrosine kinase Lck : Roles in regulation of T cell function."J.Biol.Chem.. 278. 34854-34863 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagafuku M, Kabayama K, Oka D, Kato A, Tani-Ichi S, Shimada Y, Ohno-Iwashita Y, Yamazaki S, Saito T, Iwabuchi K, Haxnaoka T, Inokuchi JI, Kosugi A: "Reduction of glycosphingolipid levels in lipid rafts affects the expression state and function of glycosyl-phosphatidylinositol-anchored proteins, but does not impair signal transduction via the T cell receptor."J.Biol.Chem.. 278. 51920-51927 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Akashi S, Saitoh S-I, Wakabayashi Y, Kikuchi T, Takamura N, Nagai Y, Kusumoto Y, Fukase K, Kusumoto S, Adachi Y, Kosugi A, Miyake K: "Lipopolysaceharide interaction with cell surface Toll-like receptor 4-MD-2: Higher affinity than that with MD-2 or CDI4."J.ExMed.. 198. 1035-1042 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hatano N, Mori Y, Oh-hora M, Kosugi A, Fujikawa T, Nakai N, Niwa H, Miyazaki J-I, Hamaoka T, Ogata M: "Essential role for ERK2 mitogen-activated protein kinase in placental development."Genes to Cells. 8. 847-856 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsuno Y, Iwata H, Umeda Y, Takagi H, Mon Y, Miyazaki J, Kosugi A, Hirose H: "Nonviral gene gun mediated transfer into the beating heart."ASAIO J.. 49. 641-644 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ito T.et al.: "Interaction of SAP-1, a transmembrane-type protein tyrosine phosphatase, with the tyrosine kinase Lck : Roles in regulation of T cell function"J.Biol.Chem.. 278. 34854-34863 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsuno Y.et al.: "Hepatocyte growth factor gene transfer into the liver via the portal vein using electroporation attenuates rat liver cirrhosis"Gene Ther.. 10. 1559-1566 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nagatuku M. et al.: "Reduction of glycosphingolipid levels in lipid rafts affects the expression state and function of glycosylphosphatidylinositol-anchored proteins but does not impair signal transduction via the T cell receptor"J.Biol.Chem.. 278. 51920-51927 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Akashi S.et al.: "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] Hatano N.et al.: "Essential role for ERK2 mitogen-activated protein kinase in placental development"Genes Cells. 8. 847-856 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsuno Y.et al.: "Nonviral gene gun mediated transfer into the beating heart"ASAIO J.. 49. 641-644 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Inoue H. et al.: "Lipid rafts as the signaling scaffold for NK cell activation : Tyrosine phosphorylation and association of LAT with PI 3 kinase and PLC-γ following CD2 stimuistion"Eur. J. Immunol.. 32. 2188-2198 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagai Y. et al.: "Essential role of MD-2 in LPS responsiveness and TLR4 distribution"Nature Immunol.. 3. 667-672 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yasuda K. et al.: "Fyn is essential for tyrosine phosphorylation of Cbp/PAG in lipid rafts in resting T cells"J. Immunol.. 169. 2813-2817 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Miyake K. et al.: "Essential role of MD-2 in B cell response to Lipopolysaccharide and Toll-like receptor 4 distribution"J. Endotoxin Res.. 8. 449-452 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanimura N. et al.: "Dynamic changes in the mobility of LAT in aggregated lipid rafts upon T cell activation"J. Cell Biol.. 160. 125-135 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ike H.et al.: "Mechanism of Lek recruitment to the T-cell receptor duster as studied by single molecule fluorescence video imaging"Chem. Phys. Chem.. (in press).

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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