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Hypoxia-inducible ERO1-α acts as a member of pre-peptide loading complex and regulates immune responses in the context of MHC class I and class II molecules

Research Project

Project/Area Number 21590400
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Human pathology
Research InstitutionSapporo Medical University

Principal Investigator

TAMURA Yasuaki  札幌医科大学, 医学部, 講師 (80322329)

Project Period (FY) 2009 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2011: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords分子病理 / ERO1 / 低酸素 / ジスルフィド結合 / MHCクラスI / 細胞傷害性T細胞 / MHCクラスII / 宿主免疫監視機構 / 抗原提示 / ストレス蛋白質 / ORP150 / S-S結合 / 低酸素環境 / MHC class I
Research Abstract

The human endoplasmic reticulum oxidoreductin like(ERO1-α) is an oxidizing enzyme that exists in endoplasmic reticulum and is induced under stress environment such as the hypoxia. It regulates a redox state of various kinds of protein through protein disulfide isomerase(PDI). Interestingly, although the expression of ERO1-α in the normal tissue was comparatively limited, various types of cancer cells expressed the large amount of ERO1-α. As the major histocompatibility complex(MHC) class I molecule carries the intramolecular disulfide bonds, we examined whether the hERO1-La plays a role in the oxidative folding and the expression of MHC class I molecules in cancer cells. We established ERO1-α overexpressed and knockdown SW480 cells. As a result, surface expression of MHC class I molecule was up-regulated in the ERO1-α-overexpressed SW480 and down-regulated in the ERO1-α knockdown SW480. Moreover, we have observed that the oxidized form of MHC class I was increased in the hERO1-La-overe … More xpressed SW480. In addition, we have observed that the hERO1-La knockdown SW480 have an impaired response to cytotoxic T lymphocyte(CTL). Interestingly, ERO1-α is highly expressed in the antigen presenting cells such as B cells and dendritic cells among the normal cells. As the major histocompatibility complex(MHC) class II molecule also carries the intramolecular disulfide bonds, we examined whether the ERO1-α plays a role in the oxidative folding and the expression of MHC class II molecules in B cell line. Because human B cell lymphoma line BALL-1 showed high expression of ERO1-α, we generated BALL-1 cells with ERO1-α knockdown using shRNA. As a result, surface expression of MHC class II molecule was down-regulated in the ERO1-Lα-knockdown cells compared to wild type cells. Moreover, knockdown of hERO1-α resulted in the decrease of oxidized form of MHC class II, thereby decreasing the stable peptide-MHC class II complexes. These data suggested that ERO1-α may play an important role in the immune responses against foreign antigens. These data suggested that the ERO1-α regulates immune response via modulation of MHC class I and class II expression and the quality. Less

Report

(4 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (26 results)

All 2011 2010 2009 Other

All Journal Article (12 results) (of which Peer Reviewed: 11 results) Presentation (10 results) Remarks (3 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Tumor-Produced Secreted Form of Binding of Immunoglobulin Protein(BiP) elicits Antigen Specific Tumor Immunity2011

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

      J Immunology

      Volume: 186 Pages: 4325-4330

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Extracellular Heat Shock Protein 90 Translocates Chaperoned Antigen from Endosome to Proteasome for Generating Antigenic Peptide to be Cross-presented by Dendritic Cells2011

    • Author(s)
      Oura J, Tamura Y
    • Journal Title

      Int Immunol

      Volume: 23 Pages: 223-237

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Tumor-Produced Secreted Form of Binding of Immunoglobulin Protein Elicits Antigen-Specific Tumor Immunity.2011

    • Author(s)
      Tamura Y, Hirohashi Y, Kutomi G, Nakanishi K, Kamiguchi K, Torigoe T, Sato N.
    • Journal Title

      J. Immunol

      Volume: 186 Issue: 7 Pages: 4325-4330

    • DOI

      10.4049/jimmunol.1004048

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Extracellular heat shock protein 90 plays a role in translocating chaperoned antigen from endosome to proteasome for generating antigenic peptide to be cross-presented by dendritic cells.2011

    • Author(s)
      Oura, J., Tamura, Y., Kamiguchi, K., Kutomi, G., Sahara, H., Torigoe, T., Himi, T., and Sato, N.
    • Journal Title

      Int. Immunol

      Volume: 23 Issue: 4 Pages: 223-237

    • DOI

      10.1093/intimm/dxq475

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Tumor-Produced Secreted Form of Binding of Immunoglobulin Protein (BiP) elicits Antigen Specific Tumor Immunity.2011

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

      J Immunology

      Volume: 186 Pages: 4320-4330

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Extracellular Heat Shock Protein 90 Translocates Chaperoned Antigen from Endosome to Proteasome for Generating Antigenic Peptide to be Cross-presented by Dendritic Cells.2011

    • Author(s)
      Oura J, Tamura Y, et al.
    • Journal Title

      International Immunology

      Volume: 23 Pages: 223-237

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Spatiotemporal regulation of heat shock protein 90-chaperoned self-DNA and CpG-oligodeoxynucleotide for type-I interferon induction via targeting to static early endosome2010

    • Author(s)
      Okuya K., Tamura Y, Saito K, Kutomi G, Torigoe T, Hirata K, Sato N.
    • Journal Title

      J Immunol

      Volume: 15(184) Pages: 7092-9

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Melanoma-targeted chemo-thermo-immuno (CTI)-therapy using N-propionyl-4-S-cysteaminylphenol-magnetite nanoparticles elicits CTL response via heat shock protein-peptide complex release.2010

    • Author(s)
      Sato A, Tamura Y, et al.
    • Journal Title

      Cancer Science

      Volume: 101 Pages: 1939-1946

    • NAID

      10027831209

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Spatiotemporal regulation of heat shock protein 90-chaperoned self-DNA and CpG-oligodeoxynucleotide for type-I interferon induction via targeting to static early endosome2010

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

      J.Immunology 182(in press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Targeting to Static Endosome is Required for Efficient Cross-Presentation of ER-resident Oxygen Regulated Protein 150-Peptide Complexes2009

    • Author(s)
      Kutomi G, Tamura Y.
    • Journal Title

      J Immunol

      Volume: 183 Pages: 5861-5869

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Targeting to Static Endosome is Required for Efficient Cross-Presentation of ER-resident Oxygen Regulated Protein 150-Peptide Complexes2009

    • Author(s)
      Kutomi G., et al
    • Journal Title

      J.Immunology 181

      Pages: 5861-5869

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 熱ショック蛋白質を用いた癌免疫2009

    • Author(s)
      田村保明
    • Journal Title

      実験医学 27

      Pages: 2201-2205

    • Related Report
      2009 Annual Research Report
  • [Presentation] human endoplasmic reticulum oxidoreductase 1 like(hERO1-L)によるMHC class I分子の発現制御2011

    • Author(s)
      久木田和晴、田村保明
    • Organizer
      日本病理学会
    • Place of Presentation
      横浜
    • Year and Date
      2011-04-28
    • Related Report
      2011 Final Research Report
  • [Presentation] human endoplasmic reticulum oxidoreductase 1 like (hERO1-L)によるMHC class I分子の発現制御2011

    • Author(s)
      久木田和晴、田村保明
    • Organizer
      日本病理学会
    • Place of Presentation
      横浜
    • Year and Date
      2011-04-28
    • Related Report
      2011 Annual Research Report
  • [Presentation] Hypoxia-inducible human endoplasmic reticulum oxidoreductase 1-Lα(hEro1-Lα) regulates immune response of cancer cells via modulation of MHC class I expression2011

    • Author(s)
      久木田和晴、田村保明
    • Organizer
      日本癌学会
    • Place of Presentation
      名古屋
    • Related Report
      2011 Final Research Report
  • [Presentation] Human endoplasmic reticulum oxidoreductase 1-likeα(hERO1-Lα) governs expression of MHC class II molecules through redox state on the antigen presenting cells2011

    • Author(s)
      田村保明
    • Organizer
      日本癌学会
    • Place of Presentation
      名古屋
    • Related Report
      2011 Final Research Report
  • [Presentation] Hypoxia-inducible human endoplasmic reticulum oxidoreductase 1-Lα (hErol-Lα) regulates immune response of cancer cells via modulation of MHC class I expression2011

    • Author(s)
      久木田和晴、田村保明
    • Organizer
      日本癌学会
    • Place of Presentation
      名古屋
    • Related Report
      2011 Annual Research Report
  • [Presentation] Human endoplasmic reticulum oxidoreductase 1-like α (hERO1-Lα)governs expression of MHC class II molecules through redox state on the antigen presenting cells2011

    • Author(s)
      田村保明
    • Organizer
      日本癌学会
    • Place of Presentation
      名古屋
    • Related Report
      2011 Annual Research Report
  • [Presentation] Spatiotemporal regulation of heat shock protein 90-chaperoned self-DNA and CpG-oligodeoxynucleotide for type-I interferon induction via targeting to static early endosome.2010

    • Author(s)
      Tamura Y.
    • Organizer
      14^<th> International Congress on Immunology
    • Place of Presentation
      神戸
    • Year and Date
      2010-08-23
    • Related Report
      2010 Annual Research Report
  • [Presentation] 自然免疫内因性リガンドとしてのストレス蛋白質による自己免疫疾患病態制御2009

    • Author(s)
      田村保明
    • Organizer
      第37回日本臨床免疫学会
    • Place of Presentation
      東京
    • Year and Date
      2009-11-13
    • Related Report
      2009 Annual Research Report
  • [Presentation] Development of HSP-based cancer vaccine and its mechanism2009

    • Author(s)
      田村保明
    • Organizer
      ストレス蛋白質国際学会CSSI2009
    • Place of Presentation
      札幌
    • Year and Date
      2009-10-08
    • Related Report
      2009 Annual Research Report
  • [Presentation] Targeting "immune"-competent endosome by heat shock proteins(HSPs)for enhancing cancer immunotherapeutic potential2009

    • Author(s)
      田村保明
    • Organizer
      日本癌学会(international symposium)
    • Place of Presentation
      横浜
    • Year and Date
      2009-10-03
    • Related Report
      2009 Annual Research Report
  • [Remarks]

    • URL

      http://web.sapmed.ac.jp/pathol/

    • Related Report
      2011 Final Research Report
  • [Remarks]

    • URL

      http://web.sapmed.ac.jp/pathol/

    • Related Report
      2011 Annual Research Report
  • [Remarks]

    • URL

      http://web.sapmed.ac.jp/pathol/

    • Related Report
      2010 Annual Research Report
  • [Patent(Industrial Property Rights)] インターフェロンα産生阻害剤2010

    • Inventor(s)
      田村保明, 他
    • Industrial Property Rights Holder
      田村保明, 他
    • Industrial Property Number
      2010-219422
    • Filing Date
      2010-09-29
    • Related Report
      2010 Annual Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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