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Innate immune host defense mediated by pulmonary sutfactant proteins and Toll-like receptors, and its clinical application.

Research Project

Project/Area Number 14370198
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionSapporo Medical University

Principal Investigator

KUROKI Yoshto  Sapporo Medical University, School of Medicine, Professor, 医学部, 教授 (70161784)

Co-Investigator(Kenkyū-buntansha) IWAKI Daisuke  Sapporo Medical University, School of Medicine, Research Associate, 医学部, 助手 (10315492)
SANO Hitomi  Sapporo Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (80295344)
TAKAHASHI Hiroki  Sapporo Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (60231396)
TAKAHASHI Toru  Sapporo Medical University, School of Medicine, Research Associate, 医学部, 助手 (40347159)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2003: ¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 2002: ¥7,600,000 (Direct Cost: ¥7,600,000)
Keywordspulmonary surfactant / SP-A / SP-D / Toll-like receptor / scavenger receptor A / mannose receptor / alveolar macrophage / zymosan / コレクチン / 自然免疫 / ペプチドグリカン / ザイモザン
Research Abstract

The purpose of this project was to investigate the molecular mechanisms of hg and recognition by lung collectins, SP-A and SP-D, and Toll-like receptor(TLR) and of the colletin-mediated and-inflammatory function and modulation of macrophage functions.
1.A soluble form of recombinant TLR2 consisting of Met1-Arg587(sTLR2) was generated and expressed by baculovirus-insect cell expression system. sTLR2 was found to bind directly to peptidoglycn derived from Staphylococcus aureus and zymosan.
2.SP-A bound to sTLR2 and the binding of SP-A to sTLR2 significantly attenuated the binding of sTLR2 to peptidoglycan and zymosan.
3.SP-D as well as SP-A interacted with sTLR2.
4.SP-A bound to Streptococcus pneumoniae and Mycobacterium avium in a manner dependent upon the SP-A concentrations and Ca2+. SP-A augemented the phagocytosis of S.pneumoniae and M.avium by its direct interaction with alveolar macrophages independent of its binding to the bacteria. In addition, SP-A stimualted the scavenger receptor A-mediated phagocytosis of S.pneumoniae and the mannose receptor-mediated phagocytosis of M.avium. Although SP-D augmented the M.avium phagocytosis, this protein did not enhance the phagocytosis of S.pneumoniae, indicating the different mechanisms of the bacterial phagocytosis stimulated by lung collectins.
5.A soluble form of recombinant TLR4 extracellular domain(sTLR4) and recombinant MD-2 were generated and expressed in bacluovirus-insect cell expression system. MD-2 was demonstrated to bind directly to sTLR4 but not to sTLR2. A complex of sTLR4 and MD-2 was able to bind to LPS covalenrly linked to sepharose beads although sTLR4 alone failed to bind LPS.
6.These results suggest that lung collectins, SP-A and SP-D, sTLR2 and sTLR4 can function as mudulators for TLR-mediated inflammation and for macrophage phagocytosis.

Report

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

    (63 results)

All Other

All Publications (63 results)

  • [Publications] Murakami S: "Surfactant protein a inhibits peptidoglycan-induced TNF-α secretion in U937 cells and alveolar macrophages by direct interaction with Toll-like receptor 2."J Biol Chem. 277. 6830-6837 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwaki D: "The extracellular Toll-like receptor 2 domain directly binds pepyidoglycan derived from Staphylococcus aureus."J Biol Chem. 277. 24315-24320 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Greene K: "Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis."Eur Respir J. 19. 439-446 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ohkawa H: "Ethanol-induced augmentation of annexin IV in cultures cells and the enhancement of cytotoxicity by overexpression of annexin IV by ethanol"Biochim Biophys Acta. 1588. 217-225 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takezawa C: "Assessment of differentiation in adenocarcinoma cells from pleural effusion by peripheral airway cell markers and their diagnostic values."Lung Cancer. 38. 273-281 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 黒木由夫: "サーファクタント蛋白質-D(SP-D)ノックアウトマウス"分子呼吸器病. 6. 409-414 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 黒木由夫: "サーファクタントと自然免疫"呼吸. 21. 409-414 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 黒木由夫: "気道における自然免疫生体防御-生体防御レクチンとエンドトキシン受容体"気管支学. 24. 595-602 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 高橋弘毅: "肺サーファクタント蛋白質定量の血清学的臨床応用"日本界面医学会雑誌. 33. 14-19 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sato M: "Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-κB activation and TNF-α secretion are downregulated by lung collectin surfactant protein A."J Immunol. 171. 417-425 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sano H: "Lactoferin and surfactant protein A exhibit distinct binding specificity to F protein, and differently modulate respiratory syncytial virus infection."Eur J Immunol. 33. 2894-2902 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fujita M: "Involvement of leucine residues at positions 107,112 and 115 in a leucine-rich repeat motif of human Toll-like receptor 2 in the recognition of diacylated lipoproteins and lipopeptides and Staphylococcus sureus peptidoglycan."J Immunol. 171. 3657-3683 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yokota S: "Prevalence of HSP47 antigen and autoantibodies to HSP47 in the sera of patients with mixed connective tissue disease."Biochem Biophys Res Commun. 303. 413-418 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ohnishi T: "Secondary pulmonary alveolar proteinosis associated with myelodysplastic syndrome"Int Med. 42. 187-190 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yamada G: "Invasive thymoma with paraneoplastic retinopathy."Hum Pathol. 34. 717-719 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakatsugawa M: "Hericium serinacem (Yamabushitake) extract-induced acute respiratory distress syndrome monitored by serum surfactant proteins."Am J Respir Crit Care Med. 168. 1495-1499 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Okusawa T: "Reduction of bleomycin induced lung fibrosis by candersartan cilexetil, an angiotensin II type I receptor antagonist."Thorax. 59. 31-38 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 佐野仁美: "肺コレクチンの生体防御機構"生化学. 75. 285-288 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 黒木由夫: "肺コレクチンによる自然免疫生体防御-CD14・TLRとの相互作用を介する細胞応答制御-"医学のあゆみ. 205. 11-16 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 佐野仁美: "肺サーファクタント蛋白質による自然免疫の分子機構"分子呼吸器病. 7. 220-224 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 黒木由夫: "生体防御レクチンとToll-likeレセプター"分子細胞治療. 2. 605-611 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 黒木由夫: "肺サーファクタント蛋白質-SP-AとSP-D"臨床化学. 32. 216-226 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 大野 敬: "細胞内小胞輸送と脂質結合ドメイン"Surgery Frontier. 11. 49-53 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kuronuma K: "Pulmonary surfactant protein A augments the phagocytosis of Streptpcoccus pneumoniae by alveolar macrophages through a casin kinase 2-dependent icrease of cell surface localization of scavenger receptor A."J Biol Chem. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kudo K: "Pulmonary collectins enhance phagocytosis of Mycobacterium avium through increased activity of mannose receptor."J Immunol. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inomata S: "Acute lung injury as an adverse event of gefitinib."Anti-Cancer Drug. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 黒木由夫: "Annual Review 免疫 2003(分担執筆)"中外医学社. 290 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Murakami S: "Surfactant protein A inhibits peptidoglycan-induced TNF-α secretion in U937 cells and alveolar macrophages by direct interaction with Toll-like receptor 2."J Biol Chem. 277. 6830-6837 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwaki D: "The extracellular Toll-like receptor 2 domain directly binds peptidoglycan derived from Staphylococcus aureus."J Biol Chem. 277. 24315-24320 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Greene K: "Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis."Eur Respir J. 19. 439-446 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ohkawa H: "Ethanol-induced augmentation of annexin IV in cultured cells and the enhancement of cytotoxicity by overexpression of annexin IV by ethanol."Biochim Biophys Acta. 1588. 217-225 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takezawa C: "Assesment of differentiation in adenocarcinoma cells from pleural effusion by peripheral airway markers and their diagnostic values."Lung Cancer. 38. 273-281 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sato M: "Direct・binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-κB activation and TNF-a secretion are downregulated by lung collectin surfactant protein A."J Immunol. 171. 417-425 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sano H: "Lactoferrin and surfactant protein A exhibit distinct binding epecificity to F protein and differently modulate respiratory syncytial virus infection."Eur J Immunol. 33. 2864-2902 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fujita M: "Involvement of leucine residues at positions 107,112 and 115 in a leucine-rich motif of human Toll-like recptor 2 in the recognition of doacylated lipoproteins and lipopeptides and Staphylococcus aureus peptidoglycan."J Immunol. 171. 3657-3683 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yokota S: "Prevalence of HSP47 antigen and autoantibodies to HSP47 in the sera of patients with mixed connextive tissue diseases."Biochem Biophys Res Coomun. 303. 413-418 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ohnishi T: "Secondary pulmonary alveolar proteinosis associated with myelodysplastic syndrome."Internal Med. 42. 187-190 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yamada G: "Invasive thymoma with paraneoplastic retinopathy."Hum Pathol. 34. 717-719 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakatsugawa M: "Hericiurn serinacem(Yamabushitake) extract-induced acute respiratory distress syndrome monitored by serum surfactant proteins."Am J Respir Crit Care Med. 168. 1495-1499 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Okusawa T: "Reduction of bleomycin induced lung fibrosis by cabdersartan cilexeti, an angiotension II type receptor antagonist."Thorax. 59. 31-38 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kuronuma K: "Pulmonary surfactant protein A augments the phagocytosis of Streptococcus pneumoniae by alveolar macrophages through a casin kinase 2-dependent increase of cell surface localization of scavenger receptor A."J Biol Chem. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kudo K: "Pulmonary collectins enhance phagocytosis of Mycobacterium avium through increased activity of mannose receptor."J Immunol. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Inomata S: "Acute lung injury as an adverse event of gefitinib."Anti-Cancer Drug. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sato, M.: "Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-kB activation and TNF-a secretion are down-regulated by lung collectin surfactant protein A."J.Immunol.. 171. 417-425 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fujita, M.: "Involvement of leucine residues at positions 107, 112, and 115 in a leucine-rich repeat Motif of human Toll-like receptor 2 in the recognition of diacylated lipoproteins and lipopeptides and Staphylococcus aureus peptidoglycan."J.Immunol.. 171. 3675-3683 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 黒木由夫: "肺コレクチンによる自然免疫生体防御 -CD14・TLR2の相互作用を介する細胞応答制御-"医学のあゆみ. 205. 11-16 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 佐野仁美: "肺サーファクタント蛋白質による自然免疫の分子機構"分子呼吸器病. 7. 220-224 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 黒木由夫: "肺サーファクタント蛋白質-SP-AとSP-D"臨床化学. 32. 216-226 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 黒木由夫: "生体防御レクチンとToll-likeレセプター"分子細胞治療. 2. 605-611 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sano, H.: "Lacroferrin and surfactant protein A exhibit distinct binding specificity to F protein, and differently modulate respiratory syncytial virus infection."Eur.J.Immunol.. 33. 2894-2902 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Okusawa, T.: "Relationship between structures and biological activities of Mycoplasmal diacylated lipopeptides and their recognition by Toll-like receptors 2 and 6."Infect.Immun.. 72. 1657-1665 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kuronuma, K.: "Pulmonary surfactant protein A augments the phagocytosis of Streptococcus pneumoniae by alveolar macrophages through a casein kinase 2-dependent increase of cell surface localization of scavenger receptor A."J.Biol.Chem.. (In press).

    • Related Report
      2003 Annual Research Report
  • [Publications] 佐野仁美: "モデル動物の作成と維持"サーファクタントアポ蛋白欠損モデル(印刷中).

    • Related Report
      2003 Annual Research Report
  • [Publications] Murakami S: "Surfactant protein A inhibits peptidoglycan-induced TNF-α secretion in 937 cells and alveolar macrophages by direct interaction with Toll-like receptor 2"J Biol Chem. 277. 6830-6837 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Iwaki D: "The extracellular Toll-like receptor 2 domain directly binds peptidoglycan derived from staphylococcus aureus"J Biol Chem. 277. 24315-25320 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Greene KE: "Serum surfactant protein A and D as biomarkers in idiopathic pulmonary fibrosis"Eur Repir J. 19. 439-446 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takezawa C: "Assesment of differentiation in adenocarcinoma cells from pleural effusion by peripheral airway cell markers and their diagnostic values"Lung Cancer. 38. 273-281 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 黒木由夫: "サーファクタント蛋白質-D(SP-D)ノックアウトマウス"分子呼吸器病. 6. 409-414 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 黒木由夫: "サーファクタントと自然免疫"呼吸. 21. 1065-1075 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 黒木由夫: "気道における自然免疫生体防御-生体防御レクチンとエンドトキシン受容体-"気管支学. 24. 595-602 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sato M: "Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-κB activation and TNF-α secretion are downregulated by lung collectin surfactant protein A"J Immunol. (In press).

    • Related Report
      2002 Annual Research Report
  • [Publications] 黒木由夫: "肺コレクチンによる自然免疫生体防御-CD14・TLRとの相互作用を介する細胞応答制御"医学のあゆみ. (印刷中).

    • Related Report
      2002 Annual Research Report
  • [Publications] 黒木由夫: "Annual Review 免疫2003:TLRによるリガンド認識機構"中外医学社. 285 (2002)

    • Related Report
      2002 Annual Research Report

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

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