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The roles of interaction between adhesion molecules, chemokines and vascular endothelial cells in the pathogenesis of periodontitis

Research Project

Project/Area Number 12470401
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 病態科学系歯学(含放射線系歯学)
Research InstitutionOsaka Dental University

Principal Investigator

DOMAE Naochika  Osaka Dental Univ. Dept of Dent. Professor, 歯学部, 教授 (60115889)

Co-Investigator(Kenkyū-buntansha) UMEHARA Hisanori  Kyoto Univ. Dept of Dent. Associ. Professor, 医学部, 助教授 (70247881)
FUKUSHIMA Hisanori  Osaka Dental Univ. Dept of Dent. Professor, 歯学部, 教授 (50103099)
IMAI Hisao  Osaka Dental Univ. Dept of Dent. Professor, 歯学部, 教授 (80067024)
MIYAMAE Masami  Osaka Dental Univ. Dept of Dent. Assist.Professor, 歯学部, 講師 (20298821)
NAGANO Yutaka  Osaka Dental Univ. Dept of Dent. Assist.Professor, 歯学部, 講師 (80228048)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥12,500,000 (Direct Cost: ¥12,500,000)
Fiscal Year 2002: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2001: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥5,000,000 (Direct Cost: ¥5,000,000)
KeywordsPeriodontitis / Fractalkine / NK cell / T cell / Monocyte / Vascular endothelial cell / RANKL / THP-1細胞 / フラクタルカイン / CX_3CR1 / 慢性辺縁性歯周炎 / インテグリン / フィブロネクチン / ICAM-1
Research Abstract

Periodontitis is the chronic inflammatory disease caused by immunocomponents cells activated by oral pathologic bacteria such as Porphymonas gingivalis in dental plaque. To analyzes the pathogenic mechanisms of the chronic inflammation, we investigated the signaling roles on the activation of immunocomponents cells, such as NK cell, T cell and monocyte, and the roles on these cells-mediated endothelium damage, which may result in vascular injury. Moreover, we investigated the possible involvement of fractalkine and RANKL in the development of periodontitis.
1. The signaling roles in the activation of immunocomponents cells: 1) We analyzed tyrosine phosphorylation and interaction of Cbl with adaptor proteins, Grb2 and CrkL in NK3.3 cells. We revealed that CrkL associates with a large portion of tyrosine phosphorylated Cbl after CD2 stimulation of NK3.3 cells. In contrast to constitutive Cbl association with Grb2, tyrosine phosphorylated Cbl interacted with CrkL via its SH2 domain only af … More ter CD2 stimulation. Their tyrosine phosphorylation strongly suggests that interactions of Cbl with Grb2 and CrkL may play pivotal roles in CD2-mediated NK cell activation. 2) We revealed that tyrosine phosphorylation of adaptor protein LAT and consequent interactions between signaling molecules, Grb2, CrkL, Shc and Cbl might explain that the molecular mechanisms of the additive effects of IL-2 stimulation and CD2 cross-linking on NK cell activation. 3) We found that modulation of lipid raft integrity by aggregation of NK cell activating receptors, which leaded to the formation of complexes of LAT with PI3-K and PLC-γ1, was essential for the NK cell lytic mechanisms. 4) We also revealed that some chemokines, such as MCP-1 and RANTES, had an important role in the adhesion of T cells to fibroblasts, which might be involved in the pathogenesis of periodontitis by enhancing immunologic reaction at the inflammatory sites.
2. The roles of fractalkine in vascular endothelial cell injury by monocytes and NK cells: 1) We revealed that fractalkine might function as an adhesion molecule between monocytes and endothelial cells rather than as a chemotactic factor. 2) We found that fractalkine might induce firm adhesion between monocytes and endothelial cells not only through an intrinsic adhesion function itself, but also through activation of integrin avidity for their ligands. 3) We suggest that fractalkine plays an important role not only in the binding of NK cells to endothelial cells, but also in NK cell-mediated endothelial cell damage, which may result in vascular injury.
3. Expression of fractalkine and RANKL in human periodontitis: Positive immunoreactivities to fractalkine and RANKL have been identified in submucosal vessels of inflammatory human gingival tissue. These results suggest that fractalkine and RANKL are important molecules in the pathogenesis and progression of human periodontitis. Less

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Miyuki Nishimura et al.: "Dual functions of fractalkine/CX3C ligand 1 in trafficking of perforin^+ /granzyme B^+ cytotoxic effector lymphocytes that are defined by CX3CR1 expression"J.Immunol.. 168. 6173-6180 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hirohi Inoue et al.: "Lipid rafts as the signaling scaffold for NK cell activation : tyrosine phosphorylation and association of LAT with phosphatidylinositol 3-kinase and phospholipase C-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
      2002 Final Research Report Summary
  • [Publications] Tadakazu Kondo et al.: "Control of ceramide-induced apoptosis by IGF-1 : involvement of PI-3 kinase, caspase-3 and catalase"Cell Death and Differentiation. 9. 682-692 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hirofumi Sawai et al.: "Sphingosine-induced c-jun expression : differences between sphingosine-and C2-ceramide-mediated signaling pathways"FEBS Letters. 524. 103-106 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tadakazu Kondo et al.: "Vesnarinone causes oxidative damage by inhibiting catalase function through ceramide action in myeloid cell apoptosis"Mol.Pharmacol.. 61. 620-627 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoneda O, Imai T, Nishimura M, Miyaji M, Mimori T, Okazaki T, Domae N, Fujimoto H, Minami Y, Kono T, Bloom ET, Umehara H: "Membrane-bound form of fractalkine induces IFN-gamma production by NK cells"Eur. J. Immunol.. 33. 53-58 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishimura M, Umehara H, Nakayama T, Yoneda O, Hieshima K, Kakizaki M, Domae N, Imai T: "Dual functions of fractalkine/CX3C ligand 1 in trafficking of perforin^+/granzyme B^+ cytotoxic effector lymphocytes that are defined by CX3CR1 expression"J. Immunol.. 168. 6173-6180 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 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 phosphatidylinositol 3-kinase and phospholipase C-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
      2002 Final Research Report Summary
  • [Publications] Kondo T, Kitano T, Iwai K, Watanabe M, Taguchi Y, Yabu T, Umehara H, Domae N, Uchiyama T, Okazaki T: "Control of ceramide-induced apoptosis by IGF-1: involvement of PI-3 kinase, caspase-3 and catalase"Cell Death and Differentiation. 9. 682-692 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sawai H, Okazaki T, Domae N: "Sphingosine-induced c-jun expression: differences between sphingosine- and C2-ceramide-mediated signaling pathways"FEBS Letters. 524. 103-106 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kondo T, Suzuki Y, Kitano T, Iwai K, Watanabe M, Umehara H, Daito M, Domae N, Tashima M, Uchiyama T, Okazaki T: "Vesnarinone causes oxidative damage by inhibiting catalase function through ceramide action in myeloid cell apoptosis"Mol. Pharmacol.. 61. 620-627 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Osamu Yoneda et al.: "Membrane-bound form of fractalkine induces IFN-gamma production by NK cells"Eur.J.Immunol.. 33. 53-58 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Miyuki Nishimura et al.: "Dual functions of fractalkine/CX3C ligand 1 in trafficking of perforin^+/granzyme B^+ cytotoxic effector lymphocytes that are defined by CX3CR1 expression"J.Immunol.. 168. 6173-6180 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hiroshi Inoue et al.: "Lipid rafts as the signaling scaffold for NK cell activation : tyrosine phosphorylation and association of LAT with phosphatidylinositol 3-kinase and phospholipase C-γ following CD2 stimulation"Eur.J.Immunol.. 32. 2188-2198 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tadakazu Kondo et al.: "Control of ceramide-induced apoptosis by IGF-1:involvement of PI-3 kinase, caspase-3 and catalase"Cell Death and Differentiation. 9. 682-692 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hirofumi Sawai et al.: "Sphingosine-induced c-jun expression : differences between sphingosine-and C2-ceramide-mediated signaling pathways"FEBS Letters. 524. 103-106 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tadakazu Kondo et al.: "Vesnarinone causes oxidative damage by inhibiting catalase function through ceramide action in myeloid cell apoptosis"Mol.Pharmacol.. 61・3. 620-627 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] HISANORI UMEHARA et al.: "Fractalkine, a CX_3C-chemokine, functions predominantly as an adhesion molecule in monocyte cell line THP-1."Immunol Cell Biol. 79. 289-302 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] HISANORI UMEHARA et al.: "Fractalkine and vascular injury"Trends in Immunology. 11. 602-607 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] HISANORI UMEHARA et al.: "Role for adapter proteins in costimulatory signal of CD2 and IL-2 on NK cell activation"Moleculer Immunology. 8. 587-596 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] HIROSHI INOUE et al.: "Chemokine effects on cell adhesion PHA-activated T cells"Dentistry in Japan. 37. 117-120 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] HITOMI SHIMPUKU et al.: "A parathyroid hormone gene polymorphism in japanese adult periodontitis patients"J Osaka Dent Univ. 35. 105-110 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Naochika Domae: "CX_3C-chemokine, fractalkine predominantly functions as an adhesion molecule in monocytic cell line, THP-1 cells."Immunol.Cell Biol.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Naochika Domae: "Chemokine effects on cell adhesion of PHA-activated T cells."Dentistry in Japan 37.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Naochika Domae: "Identification of ISC1 (YER019w) as inositol phosphoshingolipid phospholipase C in saccharomyces cerevisiae."J.Biol.Chem.. 275. 39793-39798 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Naochika Domae: "CX_3C-chemokine, fractalkine enhanced adhesion of THP cells to endothelial cells through integrin-dependent and independent mechanisms."J.Irnmunol.. 164. 4313-4320 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Naochika Domae: "Fractalkine-mediated endothelial cell injury by NK cells."J.Immuol.. 164. 4055-4062 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Naochika Domae: "Role of c-jun expression increased by heat shock-and ceramide-activated caspase-3 in HL-60 cell apoptosis : Possible involvement of ceramide in heat shock-induced apoptosis."J.Biol.Chem.. 275. 7668-7676 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 堂前尚親: "日本歯科医師会雑誌"日本歯科医師会. 11 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 堂前尚親: "歯科医療"第一歯科出版. 12 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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