gp130シグナルによる赤血球、顆粒球、巨核球産生法の確立とその分子機構の解明

• 研究課題/領域番号: 07407023
• 研究種目: 基盤研究(A)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 小児科学
• 研究機関: 東京大学
• 研究代表者: 中畑 龍俊 東京大学, 医科学研究所, 教授 (20110744)
• 研究分担者: 渡辺 すみ子 東京大学, 医科学研究所, 助手 (60240735) ; 辻 浩一郎 東京大学, 医科学研究所, 助教授 (50179991)
• 研究期間 (年度): 1995 – 1997
• 研究課題ステータス: 完了 (1997年度)
• 配分額: 26,500千円 (直接経費: 26,500千円); 1997年度: 1,900千円 (直接経費: 1,900千円); 1996年度: 4,200千円 (直接経費: 4,200千円); 1995年度: 20,400千円 (直接経費: 20,400千円)
• キーワード: gp130 / c-kit / EPOR / 可溶性IL-6受容体(sIL-6R) / 赤芽球分化 / GATA-1 / STAT5 / HIML / HML / 巨核球分化 / c-Kit / HML-1 / 造血幹細胞 / 増殖・分化 / 赤芽球造血 / soluble Il-6 receptor(sIL-6R) / stem cell factor(SCF)

研究概要

FACSを用いた解析により、ヒトCD34+細胞はIL-6R+gp130+細胞とIL-6R+gp130-細胞に分類され、多能性造血前駆細胞や赤芽球系前駆細胞は後者に含まれることが明らかとなった。IL-6と可溶性IL-6受容体(sIL-6R)を用いたgp130の直接活性化により、stem cell factor(SCF)あるいはflk2/flt3 ligand存在下に、CD34+IL-6R+gp130-細胞から赤血球がEPO非存在下でも産生できることが確認された。c-kitとgp130の活性化による赤芽球や赤血球の産生は、抗L-6R抗体、抗gp130抗体で完全に抑制されるが抗EPO抗体の影響は全く受けないことから、EPOによる赤血球産生とは完全に独立したシステムであることが明らかとなった。われわれが最近樹立したヒト白血病細胞株HML-1細胞を用いても、gp130とc-kit受容体を活性化することにより赤芽球系への分化が見られた。赤芽球系細胞の増殖、分化、成熟において、両システムの細胞内シグナル伝達機構が同じであるのか、異なる細胞内シグナル伝達機構を使っても赤血球まで分化成熟させうるのか明らかにするため、赤芽球分化に関与するシグナル伝達分子、転写因子等について解析した。その結果SCFとgp130の同時活性化において赤芽球系遺伝子の発現に重要な転写因子GATA-1の発現がmRNAレベルで増強するが、それぞれ単独では増強しないこと、SCFはGATA-1非依存的にEPORの発現を促進し、限定的に初期の赤芽球分化を誘導することを示唆する結果を得た。またEPO刺激によってリン酸化を受けることが知られているSTAT5についても、SCFとgp130の同時活性化で弱くリン酸化を受けることが認められた。以上より程度の差は有るがEPO及びSCFとgp130の同時刺激系の両方で、共通の転写因子・シグナル伝達分子が使用されることが示唆された。

研究成果

• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Eguchi M.: "Morphological and cytochemical changes in human mast cells during culture." Med.Electron Microsc.30. 25-30 (1997)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Toru H.: "Interleukin-4 induces homotypic aggregation of humman mast cells by promoting LFA-1/ICAM-1 adhesion molecules." Blood. 89. 3296-3302 (1997)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Yanagiba M.: "Effect of a chymotrypsin-like inhibitor,TPCK,on histamine release from cultured human mast cells." J.Pharm.Pharmth.49. 537-541 (1997)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Ishiguro A.: "Effects and serum levels of thrombopoietin in a case of chronic thrombocytopenia with achondroplasia." Int,J.Hematol.66. 99-102 (1997)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Muraoka K.: "Thrombopoietin-independent effect of interferon-γ on the proliferation of human megakatyocyte progenitors." Brit.J.Haematol.98. 265-273 (1997)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nishijima I.: "Hemopoietic and lymphopoietic responses in human GM-CSF receptor transgenic mice injected with human GM-CSF." Blood. 90. 1031-1038 (1997)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Umemoto Y.: "Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells." Blood. 90. 3438-3443 (1997)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Ebihara Y.: "Synergistic action of Flt3 and gp130 signalings in human hematopoiesis." Blood. 90. 4363-4368 (1997)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tsuji K.: "Role of soluble interleukin-6 receptor with interleukin-6 in human hematopoiesis." Hematology. 2. 143-149 (1997)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Suzuki H.: "Early and late events in FcεRI signal transduction in human cultured mast cells." The Journal of Immunology. 159. 5881-5888 (1997)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Takahashi T.: "A novel molecular approach to exvivo hematopoietic expansion with recombinant EGFR-expressing adenovirus vector." Blood. (in press.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Toru H.: "IL-4 promotes the development oftryptase and chymase double positive human mast cells accompanied with cell maturation." Blood. (in press.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Manabe A.: "Characterization of leukemic cells in CD2/CD19 double positive acute lymphoblastic leukemia." Int.J.Hematol.(in press.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Sui X.: "Soluble IL-6 receptor with IL-6 stimulates megakaryopoiesis from human CD34+cells through gp130 signaling." Blood. (in press.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nakahata T.: "Ex vivo expansion of human primitive hemopoietic progenitors." Stem Cells.(in press.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Mukouyama Y.: "Induction of hematopoiesis by oncostatin M in the AGM region." Immunity. (in press.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tsuji K.: "Interferon-γ and human megakaryopoiesis." Leukemia and Lymphoma. (in press.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tajika K.: "IL-6 and SCF exart different effects on megakaryocyte maturation." Brit.J.Haematol.(in press.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Xu M.: "Stimulation of human primitive hematopoiesis by murine AGM-derived stromal cells." Blood. (in press.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Ishiguro A.: "Elevation of serum thrombopoietin precedes thrombocytopoiesis in Kawasaki disease." Thromb.Haemostasis. (in press.).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Umemoto Y., Tsuji K., Nakahata T.: "Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells." Blood. 90. 3438-3443 (1997)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Ebihara Y., Tsuji K., Nakahata T.: "Synergistic action of Flt 3 and gp130 signalings in human hematopoiesis." Blood. 90. 4363-4368 (1997)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tsuji K., Nakahata T.: "Role of soluble interleukin-6 receptor with interleukin-6 in human hematopoiesis." Hematology. 2. 143-149 (1997)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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.).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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.).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Takahashi T., Nakahata T., el al: "A novel molecular approach to ex vivo hematopoietic expansion with recombinant EGFR-expressing adenovirus vector." Blood. (in press.).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Mukouyama Y., Nakahata T., et al: "Induction of hematopoiesis by oncostatin M in the AGM region." Immunity. 8. 105-114 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Suzuki H., Nakahata T., et al: "Early and late events in FcepsilonRI sigunal transduction in human cultured mast cells." J.Immunol.(in press.).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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.).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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.).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tsuji K., Muraoka K., Nakahata T.: "Interferon-gamma and human megakaryopoiesis." Leukemia and Lymphoma. (in press).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tajika K., Nakahata T., et al: "IL-6 and SCF exart different effects on megakaryocyte maturation." Brit.J.Haematol. (in press.).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Xu M., Tsuji K., Nakahata T.: "Stimulation of human primitive hematopoiesis by murine AGM-derived stromal cells." Blood. (in press.).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Ishiguro A., Nakahata T.: "Elevation of serum thrombopoietin precedes thrombocytopoiesis in Kawasaki disease." Thromb.Haemostasis. (in press.).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
• [文献書誌] Eguchi M.: "Morphological and cytochemical changes in human mast cells during culture." Med.Electron Microsc.30. 25-30 (1997)
• [文献書誌] Toru H.: "Interleukin-4 induces homotypic aggregation of human mast cells by promoting LFA-1/ICAM-1 adhesion molecules." Blood. 89. 3296-3302 (1997)
• [文献書誌] Yanagida M.: "Effect of a chymotrypsin-like inhibitor,TPCK,on histamine release from cultured human mast cells." J.Pharm.Pharmth.49. 537-541 (1997)
• [文献書誌] Ishiguro A.: "Effects and serum levels of thrombopoietin in a case of chronic thrombocytopenia with achondroplasia." Int.J.Hematol.66. 99-102 (1997)
• [文献書誌] Muraoka K.: "Thrombopoietin-independent effect of interferon-γ on the proliferation of human megakaryocyte pogenitors." Brit.J.Haematol.98. 265-273 (1997)
• [文献書誌] Nishijima I.: "Hemopoietic and lymphopoietic resonses in human GM-CSF receptor transgenic mice injected with human GM-CSF." Blood. 90. 1031-1038 (1997)
• [文献書誌] 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)
• [文献書誌] Umemoto Y.: "Leptin stimulates the proliferation of murine myelicytic and primitive hematopoietic progenitor cells." Blood. 90. 3438-3443 (1997)
• [文献書誌] 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)
• [文献書誌] Ebihara Y.: "Synergistic action of Flt3 and gp130 signalings in human hematopoiesis." Blood. 90. 4363-4368 (1997)
• [文献書誌] Tsuji K.: "Role of soluble interleukin-6 receptor with interleukin-6 in human hematopoiesis." Hematology. 2. 143-149 (1997)
• [文献書誌] Suzuki H.: "An increase in periheral 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)
• [文献書誌] 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)
• [文献書誌] Suzuki H.: "Eary and late events in FcεRI signal transduction in human cultured mast cells." The Journal of Immunology. 159. 5881-5888 (1997)
• [文献書誌] Takahashi T.: "A novel molecular approach to ex vivo hematopoietic expansion with recombinant EGFR-expressing adenovirus vector." Blood. (in press.).
• [文献書誌] Toru H.: "IL-4 promotes the development of tryptase and chymase double positive human mast cells accompanied with cell maturation." Blood. (in press.).
• [文献書誌] Manabe A.: "Characterization of leukemic cells in CD2/CD19 double positive acute lymphoblastic leukemia." Int.J.Hematol.(in press.).
• [文献書誌] Sui X.: "Soluble IL-6 receptor with IL-6 stimulates megakaryopoiesis from human CD34+ cells through gp130 signaling." Blood. in press.
• [文献書誌] Nakahata T.: "Ex vivo expansion of human primitive hemopoietic progenitors." Stem Cells.in press.
• [文献書誌] Mukouyama Y.: "Induction of hematopoiesis by oncostatin M in the AGM region." Immunity. in press.
• [文献書誌] Nishijima I.: "Human granulocyte-macrophage colony stimulating factor (hGM-CSF) dependent in vitro and in vivo proliferation and differentiation of all hematopoietic progenitor cells in hGM-SCF receptor transgenic mice." Allergy and Clin.Immunol.in press.
• [文献書誌] Nishihata 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.
• [文献書誌] Tsuji K.: "Interferon-γ and human megakaryopoiesis." Leukemia and Lymphoma. in press.
• [文献書誌] Tajika K.: "IL-6 and SCF exart different effects on megakaryocyte maturation." Brit.J.Haematol.(in press.).
• [文献書誌] 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.).
• [文献書誌] Xu M.: "Stimulation of human primitive hematopoiesis by murine AGM-derived stromal cells." Blood. (in press.).
• [文献書誌] Ishiguro A.: "Elevation of serum thrombopoietin precedes the thrombocytopoiesis in Kawasaki disease." Thromb.Haemostasis. (in press.).
• [文献書誌] Tajika K.: "A novel aspect of the maturation step of megakaryocytes in thrombopoiesis:bundle formation of microtubules in megakaryocytes" Exp.Hematol.24. 291-298 (1996)
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• [文献書誌] Sui X.: "Erythropoietin-independent erythrocyte production:signals through gp130 and c-Kit dramatically promote erythropoiesis from human CD34^+ cells" J.Exp.Med.183(3). 837-845 (1996)
• [文献書誌] Yoshida K.: "Targeted disruption of gp130,a common signal transducer for the interleukin 6 family of cytokines,leads to myocardial and hematological disorders" Proc.Natl.Acad.Sci.USA. 93. 407-411 (1996)
• [文献書誌] Saito H.: "Selective growth of human mast cell induced by steel factor,IL-6,and prostaglandin E_2 fromcord blood mononuclear cells" J.Immunol.157. 343-350 (1996)
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