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1997 Fiscal Year Final Research Report Summary

Production of erythrocytes, granulocytes and megakaryocytes by gp130 signalling and related molecular mechanisms.

Research Project

Project/Area Number 07407023
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionThe University of Tokyo

Principal Investigator

NAKAHATA Tatsutoshi  Institute of Medical Science University of Tokyo Professor, 医科学研究所, 教授 (20110744)

Co-Investigator(Kenkyū-buntansha) WATANABE Sumiko  Institute of Medical Science University of Tokyo Research Associate, 医科学研究所, 助手 (60240735)
TSUJI Kohichiro  Institute of Medical Science University of Tokyo Associate Professor, 医科学研究所, 助教授 (50179991)
Project Period (FY) 1995 – 1997
Keywordsgp130 / c-kit / EPOR / soluble IL-6 receptor (sIL-6R) / erythropoiesis / GATA-1 / STAT5 / HML
Research Abstract

Eryhropoietin(EPO) is the primary humoral regulator of erythropoiesis and no other factor has previously been reported to support proliferation and terminal maturation of erythroid cells from hemopoietic stem cells. We found that stimulation of gp130 by a combination of recombinant human soluble IL-6 receptor (sIL-6R) and IL-6 can support proliferation, differentiation and terminal maturation of erythroid cells in the absence of EPO from purified human CD34^+ cells in suspensin culture containing stem cell factor (SCF) or flk2/flt3 ligand. The addition of anti-gp130 mAbs but not anti-EPO Ab to the same culture completely abrogated the generation of erythroid cells. These results clearly demonstrate that mature erythroid cells can be emerged from hemopoietic progenitors without EPO in vitro. HML/SE is a GM-CSF-or SCF-dependent cell line established from a children with M7 leukemia. Although HML/SE cells neither proliferate nor in the presense of EPO alone, these cells can proliferate an … More d produce hemoglobin by a combinaation of recombinant human sIL-6R and IL-6. SCF and activation of gp130 activated the human EPO receptor promoter and induced EPO receptor gene expression. Taken together, we speculate that HML/SE cells acquired responsiveness to EPO via the EPO receptor induced by SCF and gp130 signallings. Mutation analysis of putative transcription factor binding sites in the human EPO receptor promoter suggested that Spl, rather than the GATA-1 binding site, contributed to the induction of the hEPOR gene. While it is well documented that hematopoietic stem cells and primitive progenitors require both an early-actimg cytokine and a kineage specific cytokine to differntiate to a certain lineage, related mechanisms are not well understood. Together with the previous reports that human sera contain derectable levels of sIL-6R,IL-6 and SCF,normal erythropoiesis may be regulated physiologically by two different pathways ; the EPO-mediated signalling and a novel mechanism with gp130 in combination with c-KIT signalling. Less

  • Research Products

    (52 results)

All Other

All Publications (52 results)

  • [Publications] Muraoka K.: "Defective response to thrombopoietin and impared expression of c-mpl mRAD in bone marrow cells in congenital amegakaryocytic thrombocytopenia." Brit.J.Haematol.96. 287-292 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Eguchi M.: "Morphological and cytochemical changes in human mast cells during culture." Med.Electron Microsc.30. 25-30 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Toru H.: "Interleukin-4 induces homotypic aggregation of humman mast cells by promoting LFA-1/ICAM-1 adhesion molecules." Blood. 89. 3296-3302 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yanagiba M.: "Effect of a chymotrypsin-like inhibitor,TPCK,on histamine release from cultured human mast cells." J.Pharm.Pharmth.49. 537-541 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ishiguro A.: "Effects and serum levels of thrombopoietin in a case of chronic thrombocytopenia with achondroplasia." Int,J.Hematol.66. 99-102 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Muraoka K.: "Thrombopoietin-independent effect of interferon-γ on the proliferation of human megakatyocyte progenitors." Brit.J.Haematol.98. 265-273 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishijima I.: "Hemopoietic and lymphopoietic responses in human GM-CSF receptor transgenic mice injected with human GM-CSF." Blood. 90. 1031-1038 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshida M.: "Thrombopoietin alone stimulates the early proliferation and survival of human erythroid,myeloid,and multipotential progenitors in serum-free culture." Brit.J.Haematol.98. 254-264 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Umemoto Y.: "Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells." Blood. 90. 3438-3443 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Akasaka T.: "The role of mel-18,a Mammalian Polycomb group gene,during the IL-7-dependent proliferation of lymphocyte precursors." Immunity. 7. 135-146 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ebihara Y.: "Synergistic action of Flt3 and gp130 signalings in human hematopoiesis." Blood. 90. 4363-4368 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tsuji K.: "Role of soluble interleukin-6 receptor with interleukin-6 in human hematopoiesis." Hematology. 2. 143-149 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Suzuki H.: "An increase in peripheral blood progenitor cells in primates by co-administration of recombinant human interleukin 6 and recombinant human granulocyte colony-stimulating fator." Transplantation. 64. 1468-1473 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Bessho M.: "Treatment of the anemia of aplastic anemia patients with recombinant human erythropoietin in combination with granulocyte colony-stimulating factor:a multicenter randomized controlled study." Eur.J.Haematol.58. 265-272 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Suzuki H.: "Early and late events in FcεRI signal transduction in human cultured mast cells." The Journal of Immunology. 159. 5881-5888 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takahashi T.: "A novel molecular approach to exvivo hematopoietic expansion with recombinant EGFR-expressing adenovirus vector." Blood. (in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Toru H.: "IL-4 promotes the development oftryptase and chymase double positive human mast cells accompanied with cell maturation." Blood. (in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Manabe A.: "Characterization of leukemic cells in CD2/CD19 double positive acute lymphoblastic leukemia." Int.J.Hematol.(in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sui X.: "Soluble IL-6 receptor with IL-6 stimulates megakaryopoiesis from human CD34+cells through gp130 signaling." Blood. (in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakahata T.: "Ex vivo expansion of human primitive hemopoietic progenitors." Stem Cells.(in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mukouyama Y.: "Induction of hematopoiesis by oncostatin M in the AGM region." Immunity. (in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishijima I.: "Human granulocyte-macrophage colony stimulating factor(hGM-CSF) dependent in vitro and in vivo proliferation anddifferentiation of all hematopoietic progenitor cells in hGM-SCF receptor transgenic mice." Allergy and Clin.Immunol.(in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishihara M.: "A combination of stem cell factor and granulocyte xolony-stimulating factor enhances proliferation and differentiation of human progenitor cells supported by murine stromal cell line MS-5." Euro.J.Immunol.(in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tsuji K.: "Interferon-γ and human megakaryopoiesis." Leukemia and Lymphoma. (in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tajika K.: "IL-6 and SCF exart different effects on megakaryocyte maturation." Brit.J.Haematol.(in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Maruyama K.: "Characterization of peripheral blood progenitor cells mobilized by Nartograstim(N-terminal replaced granulocyte colony-stimulating factor)in normal volunteers." Bone Marrow Transplant.(in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Xu M.: "Stimulation of human primitive hematopoiesis by murine AGM-derived stromal cells." Blood. (in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ishiguro A.: "Elevation of serum thrombopoietin precedes thrombocytopoiesis in Kawasaki disease." Thromb.Haemostasis. (in press.).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Muraoka K., Nakahata T., et al: "Defective response to thrombopoietin and impared expression of c-mpl mRAD in bone marrow cells in congenital amegakaryocytic thrombocytopenia." Brit.J.Haematol.96. 287-292 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Toru H., Nakahata T.: "IL-4 induces homotypic aggregation of human mast cells by promoting LFA-1/ICAM-1 adhesion molecules." Blood. 89. 3296-3302 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yanagida M., Fukamachi H., Nakahata T.: "Inhibitory effect of a chymotrypsinlike inhibitor, N-tosyl-L-phenylalanyl chloromethyl ketone on histamine release from cultured human mast cells." J.Pharm.Pharmth.49. 537-541 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishiguro A., Nakahata T., et al.: "Effects and serum levels of thrombopoietin in a case of chronic thrombocytopenia with achondroplasia." Int.J.Hematol.66. 99-102 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Muraoka K., Tsuji K., Nakahata T.: "Thrombopoietin-independent effect of interferon-gamma on the proliferation of human megakaryocyte progenitors." Brit.J.Haematol.98. 265-273 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishijima I., Nakahata T., et al: "Hemopoietic and lymphopoietic responses in human GM-CSF receptor transgenic mice injected with human GM-CAF." Blood. 90. 1031-1038 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshida M., Tsuji K., Nakahata T.: "Thrombopoietin alone stimulates the early proliferation and survival of human erythroid, myeloid and multipotential progenitors in serum-free culture." Brit.J.Haematol.98. 254-264 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Akasaka T., Nakahata T., et al: "The role of mel-18, a mammalian homolog of Drosophila Polycomb group gene, during the IL-7-dependent proliferation of lymphocyte precursors." Immunity. 7. 135-146 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Umemoto Y., Tsuji K., Nakahata T.: "Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells." Blood. 90. 3438-3443 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ebihara Y., Tsuji K., Nakahata T.: "Synergistic action of Flt 3 and gp130 signalings in human hematopoiesis." Blood. 90. 4363-4368 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Suzuki H., Nakahata T.: "An increase in peripheral blood progenitor cells in primates by co-administration of recombinant human interleukin 6 and recombinant human granulocyte colony-stimulating factor." Transplantation. 64. 1468-1473 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsuji K., Nakahata T.: "Role of soluble interleukin-6 receptor with interleukin-6 in human hematopoiesis." Hematology. 2. 143-149 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Toru H., Nakahata T.: "IL-4 promotes the development of tryptase and chymase double positive human mast cells accompanied with cell maturation." Blood. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sui X., Tsuji K., Nakahata T.: "Soluble IL-6 receptor with IL-6 stimulates megakaryopoiesis from human CD34_+ cells through gp130 signaling." Blood. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takahashi T., Nakahata T., el al: "A novel molecular approach to ex vivo hematopoietic expansion with recombinant EGFR-expressing adenovirus vector." Blood. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mukouyama Y., Nakahata T., et al: "Induction of hematopoiesis by oncostatin M in the AGM region." Immunity. 8. 105-114 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Suzuki H., Nakahata T., et al: "Early and late events in FcepsilonRI sigunal transduction in human cultured mast cells." J.Immunol.(in press.).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishijima I., Nakahata T., et al: "Human granulocyte-macrophage colony stimulating factor (hGM-CSF) dependent in vitro and in vivo proliferation and differentiation of all hematopoietic progenitor cells in hGM-CSF receptor transgenic mice." Allergy and Clin.Immunol.(in press.).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishihara M., Nakahata T., et al: "A combination of stem cell factor and granulocyte colony-stimulating factor enhances proliferation and defferentiation of human progenitor cells supported by murine stromal cell line MS-5." Euro.J.Immunol.(in press.).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsuji K., Muraoka K., Nakahata T.: "Interferon-gamma and human megakaryopoiesis." Leukemia and Lymphoma. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tajika K., Nakahata T., et al: "IL-6 and SCF exart different effects on megakaryocyte maturation." Brit.J.Haematol. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Xu M., Tsuji K., Nakahata T.: "Stimulation of human primitive hematopoiesis by murine AGM-derived stromal cells." Blood. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishiguro A., Nakahata T.: "Elevation of serum thrombopoietin precedes thrombocytopoiesis in Kawasaki disease." Thromb.Haemostasis. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshida K., Nakahata T., et al: Myocardial, hematological, and placental disorders caused by targeted disruption of gp130, acommon signal transducer for IL-6 family of cytokines.Contemporary Immunology : Cytokine Knockouts (Durum S.K.& Muegge K.eds), Humana Press Inc.Totowa, NJ, 259-289 (1998)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-16  

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