1995 年度実績報告書

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

研究課題/領域番号	07407023
研究種目	一般研究(A)
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)
キーワード	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)
研究概要	(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。

研究成果

(20件)

すべてその他

すべて文献書誌 (20件)

[文献書誌] 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)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] 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)
[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.(in press).
[文献書誌] Kojima S.: "Measurement of endogeneous plasma granulocyte colony-stimulating factor in patients with acquired aplastic anemia by a sensitive chemiluminescent immunoassay." Blood. (in press).
[文献書誌] 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).
[文献書誌] Nakahata T.: "Role of gp130 and c-Kit signaling in proliferation and differentiation of human hemopoietic progenitor cells." Cancer Chemother.Pharmacol.(in press).
[文献書誌] 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).
[文献書誌] 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).
[文献書誌] Ishiguro A.: "Reference intervals for serum granulocyte colony-stimulating factor level in children." J.Pediatr.(in press).
[文献書誌] Igarashi A.: "Characteristics of histamine release from cultured human mast cells." Clin.Exp.Allergy. (in press).
[文献書誌] Tajika K.: "Anovel aspect of the maturation step of megakaryocytes in theombopoiesis:bundle formation of microtubules in magakaryocytes." Exp.Hematol.(in press).
[文献書誌] Sawai N.: "Aberrant growth of granulocyte-macrophage progenitors in Juvenile chronic myelogenous Ieukemia in serum-free culture." Exp.Hematol.(in press).
[文献書誌] Okamura N.: "Chemotactic and chemokinetic activity of stem cell factor on murine hematopoietic progenitors." Blood. (in press).
[文献書誌] 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).
[文献書誌] Nakahata T.: "Biological and Molecular Aspects of Mast Cell and Basophil Differentiation and Function." Elsevier Science Publishers, 13-24 (1995)
[文献書誌] Ra C.: "Biological and Molecular Aspects of Mast Cell and Basophil Differentiation and Function." Elsevier Science Publishers, 239-248 (1995)

1995 年度 実績報告書

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

研究代表者

中畑 龍俊 東京大学, 医科学研究所, 教授 (20110744)

研究成果

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] 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)

[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.(in press).

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

[文献書誌] 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).

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

[文献書誌] 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).

[文献書誌] 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).

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

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

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

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

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

[文献書誌] 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).

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

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

1995 年度実績報告書

中畑龍俊東京大学, 医科学研究所, 教授 (20110744)