1995 Fiscal Year Annual Research Report

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

Research Project

Project/Area Number	07407023
Research Category	Grant-in-Aid for General Scientific Research (A)
Research Institution	The University of Tokyo
Principal Investigator	中畑龍俊東京大学, 医科学研究所, 教授 (20110744)
Co-Investigator(Kenkyū-buntansha)	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)
Keywords	造血幹細胞 / 増殖・分化 / 赤芽球造血 / gp130 / soluble Il-6 receptor(sIL-6R) / stem cell factor(SCF)
Research Abstract	(1)FACSを用いた解析により、ヒトCD34^+細胞のほとんどにgp130が発現しているが、IL-6レセプターを発現している細胞は30-50%であることが明らかとなった(投稿中)。 (2)CD34^+細胞上のgp130を可溶性IL-6受容体(sIL-6R)とIL-6を用いて活性化することにより、stem cell factor(SCF)存在下に各種造血前駆細胞の増殖が誘導された(Proc.Natl.Acad.Sci.USA 92:2859,1995)。 (3)CD34^+細胞をsIL-6R、IL-6、SCF存在下に培養すると赤血球、巨核球、マクロファージ、顆粒球などの成熟血球が出現した。特に赤芽球の増殖・分化は顕著であった。 (4)従来、赤血球はEPO刺激、好中球はG-GSFにより誘導されると考えられてきたが、EPO非存在下(無血清培養)、G-CSF非存在下でも赤血球、好中球を産生しうることが示された。 (5)のgp130活性化による赤血球系細胞の産生は抗gp130抗体あるいは抗IL-6R抗体により完全にブロックされるが、抗EPO抗体の影響は全く受けないことからEPOと無関係に赤血球を作るシステムがあることが世界で初めて明らかとなった(J.Exp.Med.in press.)。 (6)CD34^+細胞のうちIL-6レセプターを発現している細胞と発現していない細胞の両者をソーテイングし、その増殖分化能を検討すると、赤芽球はIL-6レセプター陰性細胞のみから出現することが明らかとなった。 (7)CD34^+IL-6R^-細胞分画のみからsIL-6R、IL-6、SCF存在下で赤血球が産生された。以上の如くヒト未分化造血前駆細胞から、EPOなしでもgp130の活性化により赤血球まで誘導できることを確認することができたことの生物学的意義は極めて大きいと考えられる。しかし、EPO刺激で形成される赤血球とgp130の活性化で形成される赤血球の生物学的差異の詳細な検討は行うことができなかった。

Research Products

(20 results)

All Other

All Publications (20 results)

[Publications] Saito H.: "Characterization of cord blood-derived human mast cells cultured in the presence of Steel Factor and IL-6." Int.Arch.Allergy Immunol.107. 63-65 (1995)
[Publications] Tsuji K.: "Synergistic action of IL-10 with IL-3,IL-4 and stem cell factor on colony formation from murine mast cells in culuture." Int.J.Hematol.61. 51-60 (1995)
[Publications] Sui X.: "gp130 and c-Kit signalings synergize for ex vivo expansion of human primitive hemopoietic progenitor cells." Proc.Natl.Acad.Sci.USA. 92. 2859-2863 (1995)
[Publications] Nishijima I.: "A human GM-CSF receptor expressed in transgenic mice stimulates proliferation and differentiation of hemopoietic progenitors to all lineages in response to human GM-CSF." Mol.Biol.Cell.6. 497-508 (1995)
[Publications] Yanagida M.: "Effects T-helper 2-type cytokines,interleukin-3(IL-3),IL-4,IL-5,and IL-6 on the survival of cultured human mast cells." Blood. 86. 3705-3714 (1995)
[Publications] Yoshida Y.: "Effects of long-term treatment with recombinant human garanulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome." Leukemia and lymphoma. 18. 457-463 (1995)
[Publications] Sui X.: "Erythropoietin-independent erythrocyte production:signals through gp130 and c-Kit dramatically promote erythropoiesis from human CD34^+ cells." J.Exp.Med.(in press).
[Publications] Kojima S.: "Measurement of endogeneous plasma granulocyte colony-stimulating factor in patients with acquired aplastic anemia by a sensitive chemiluminescent immunoassay." Blood. (in press).
[Publications] Yoshida K.: "Targeted disruption of gh130,a common signal transducer for IL-6-family of cytokines,leads to myocardial and hematological disorders." Proc.Natl.Acad.Sci.USA. (in press).
[Publications] Nakahata T.: "Role of gp130 and c-Kit signaling in proliferation and differentiation of human hemopoietic progenitor cells." Cancer Chemother.Pharmacol.(in press).
[Publications] Nakahata T.: "Effects of long-term treatment with recombinant human garanulocyte-macrophage colony-stimulating factor in patients with aplastic anemia." Am.J.Hematol.(in press).
[Publications] Saito H.: "Selective growth of human mast cell induced by steel factor,interleukin-6 and prostaglandin E2 from cord blood mononuclear cells." J.Immunol.(in press).
[Publications] Ishiguro A.: "Reference intervals for serum granulocyte colony-stimulating factor level in children." J.Pediatr.(in press).
[Publications] Igarashi A.: "Characteristics of histamine release from cultured human mast cells." Clin.Exp.Allergy. (in press).
[Publications] Tajika K.: "Anovel aspect of the maturation step of megakaryocytes in theombopoiesis:bundle formation of microtubules in magakaryocytes." Exp.Hematol.(in press).
[Publications] Sawai N.: "Aberrant growth of granulocyte-macrophage progenitors in Juvenile chronic myelogenous Ieukemia in serum-free culture." Exp.Hematol.(in press).
[Publications] Okamura N.: "Chemotactic and chemokinetic activity of stem cell factor on murine hematopoietic progenitors." Blood. (in press).
[Publications] Tanaka R.: "Kinetics and Characteristics of Peripheral blood progenitor cells (PBPC) mobilized by Filgrastim(rHuG-CSF)in normal healthy volunteers." Brit.J.Haematol.(in press).
[Publications] Nakahata T.: "Biological and Molecular Aspects of Mast Cell and Basophil Differentiation and Function." Elsevier Science Publishers, 13-24 (1995)
[Publications] Ra C.: "Biological and Molecular Aspects of Mast Cell and Basophil Differentiation and Function." Elsevier Science Publishers, 239-248 (1995)

1995 Fiscal Year Annual Research Report

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

Principal Investigator

中畑 龍俊 東京大学, 医科学研究所, 教授 (20110744)

Research Products

[Publications] Saito H.: "Characterization of cord blood-derived human mast cells cultured in the presence of Steel Factor and IL-6." Int.Arch.Allergy Immunol.107. 63-65 (1995)

[Publications] Tsuji K.: "Synergistic action of IL-10 with IL-3,IL-4 and stem cell factor on colony formation from murine mast cells in culuture." Int.J.Hematol.61. 51-60 (1995)

[Publications] Sui X.: "gp130 and c-Kit signalings synergize for ex vivo expansion of human primitive hemopoietic progenitor cells." Proc.Natl.Acad.Sci.USA. 92. 2859-2863 (1995)

[Publications] Nishijima I.: "A human GM-CSF receptor expressed in transgenic mice stimulates proliferation and differentiation of hemopoietic progenitors to all lineages in response to human GM-CSF." Mol.Biol.Cell.6. 497-508 (1995)

[Publications] Yanagida M.: "Effects T-helper 2-type cytokines,interleukin-3(IL-3),IL-4,IL-5,and IL-6 on the survival of cultured human mast cells." Blood. 86. 3705-3714 (1995)

[Publications] Yoshida Y.: "Effects of long-term treatment with recombinant human garanulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome." Leukemia and lymphoma. 18. 457-463 (1995)

[Publications] Sui X.: "Erythropoietin-independent erythrocyte production:signals through gp130 and c-Kit dramatically promote erythropoiesis from human CD34^+ cells." J.Exp.Med.(in press).

[Publications] Kojima S.: "Measurement of endogeneous plasma granulocyte colony-stimulating factor in patients with acquired aplastic anemia by a sensitive chemiluminescent immunoassay." Blood. (in press).

[Publications] Yoshida K.: "Targeted disruption of gh130,a common signal transducer for IL-6-family of cytokines,leads to myocardial and hematological disorders." Proc.Natl.Acad.Sci.USA. (in press).

[Publications] Nakahata T.: "Role of gp130 and c-Kit signaling in proliferation and differentiation of human hemopoietic progenitor cells." Cancer Chemother.Pharmacol.(in press).

[Publications] Nakahata T.: "Effects of long-term treatment with recombinant human garanulocyte-macrophage colony-stimulating factor in patients with aplastic anemia." Am.J.Hematol.(in press).

[Publications] Saito H.: "Selective growth of human mast cell induced by steel factor,interleukin-6 and prostaglandin E2 from cord blood mononuclear cells." J.Immunol.(in press).

[Publications] Ishiguro A.: "Reference intervals for serum granulocyte colony-stimulating factor level in children." J.Pediatr.(in press).

[Publications] Igarashi A.: "Characteristics of histamine release from cultured human mast cells." Clin.Exp.Allergy. (in press).

[Publications] Tajika K.: "Anovel aspect of the maturation step of megakaryocytes in theombopoiesis:bundle formation of microtubules in magakaryocytes." Exp.Hematol.(in press).

[Publications] Sawai N.: "Aberrant growth of granulocyte-macrophage progenitors in Juvenile chronic myelogenous Ieukemia in serum-free culture." Exp.Hematol.(in press).

[Publications] Okamura N.: "Chemotactic and chemokinetic activity of stem cell factor on murine hematopoietic progenitors." Blood. (in press).

[Publications] Tanaka R.: "Kinetics and Characteristics of Peripheral blood progenitor cells (PBPC) mobilized by Filgrastim(rHuG-CSF)in normal healthy volunteers." Brit.J.Haematol.(in press).

[Publications] Nakahata T.: "Biological and Molecular Aspects of Mast Cell and Basophil Differentiation and Function." Elsevier Science Publishers, 13-24 (1995)

[Publications] Ra C.: "Biological and Molecular Aspects of Mast Cell and Basophil Differentiation and Function." Elsevier Science Publishers, 239-248 (1995)

中畑龍俊東京大学, 医科学研究所, 教授 (20110744)