2000 年度実績報告書

癌細胞浸潤及び血管新生におけるマクロファージ遊走阻止因子の機能に関する基礎的研究

研究課題

研究課題/領域番号	12213008
研究機関	北海道大学
研究代表者	西平順北海道大学, 医学研究科, 助教授 (30189302)
研究分担者	小山芳一北海道大学, 医学研究科, 助手 (90186841) 岩渕和也北海道大学, 遺伝子病制御研究所, 助教授 (20184898) 小林正伸北海道大学, 遺伝子病制御研究所, 助教授 (80241321)
キーワード	MIF / マクロファージ / エンドトキシンショック / サイトカイン
研究概要	申請者はラットMIFの遺伝子構造を決定し、そのタンパク質の高次構造を明らかにするなど、MIFに関して一貫した研究を行ってきた。MIFは、本来リンパ球のみで産生されマクロファージを活性化すると考えられてきたが、免疫担当細胞に限らず種々の組織でも産生され、多くの炎症性疾患に関与することを発表した。劇症肝炎やARDSモデル動物を作成し、抗MIF抗体投与により致死率や病理組織学的所見が顕著に改善すること、anti-CD3による刺激による解析からMIFがTリンパ球の活性化に必須であることを報告した。さらにアトピー性皮膚炎や膠原病などの免疫系の破綻による難治性疾患の病態に深く関与することや脂肪細胞におけるMIFの発現がinsulinやglucoseにより制御されることも示した。一方、MIFは細胞増殖因子として機能し腫瘍細胞増殖や血管新生に深く関与することやmatrix metalloproteinaseを誘導し組織破壊の重要な因子であることを明らかにした。本年度の補助金を活用し、MIFトランスジェニックマウスを作製し癌発症、増殖、転移との関連を検討し以下の結果を得ている。1.トランスジェニックマウスに皮下移植した腫瘍体積はコントロールマウスに比して有意に増加し、血管新生を強く誘導する。2.トランスジェニック由来の繊維芽細胞はMMP-13を有意に発現する。3.トランスジェニックマウスとコントロールマウスについてのDifferential Gene Array Systemから約100個の遺伝子を解析中である。またMIFの作用機序を分子レベルで解析するため細胞内でのMIF結合蛋白質の検索とシグナル伝達系についてYeast two-hybrid法によりSumo(proteosome関連タンパク質)を同定している。さらに、ヒト肺癌組織を用いた研究においてMIFが核内にも存在し、核内への存在が腫瘍の悪性度に密接に関与することを示した。

研究成果

(25件)

すべてその他

すべて文献書誌 (25件)

[文献書誌] Abe,R.: "Enhancement of macrophage migration inhibitory factor (MIF) expression in injured epidermis and cultured fibroblasts."Biochem.Biophys.Acta. 1500. 1-9 (2000)
[文献書誌] Koyama,N.: "Aneuploidy of sex chromosomes in basal cell carcinoma : its clonality and involvement in the development of carcinogenesis."Int.J.Oncol.. 16. 15-23 (2000)
[文献書誌] Kitaichi,N.: "Inhibition of experimental autoimmune uveoretinitis with anti-macrophage migration inhibitory factor antibodies."Curr.Eye Res.. 20. 109-114 (2000)
[文献書誌] Onodera,S.: "Macrophage migration inhibitory factor (MIF) up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis."J.Biol.Chem.. 7. 444-450 (2000)
[文献書誌] Yabunaka,N.: "Elevated serum content of macrophage migration inhibitory factor in patients with type 2 diabetes."Diabetes Care. 23. 256-258 (2000)
[文献書誌] Kitaichi,N.: "Different influence of macrophage migration inhibitory factor (MIF) in signal transduction pathway of various T cell subsets."Immunobiol.. 201. 356-367 (2000)
[文献書誌] Ishikawa,K.: "The crystal structure of human MRP8, a member of S100 calcium-binding protein family, by MAD phasing at 1.9 A resolution."Acta Crystallogr.D. 56. 559-566 (2000)
[文献書誌] Mizue,Y.: "Quantitation of macrophage migration inhibitory factor (MIF) using the one-step sandwich enzyme immunosorbent assay : Elevated serum MIF concentrations in patients with autoimmune diseases and identification of MIF in erythrocytes."Int.J.Mol.Med.. 5. 397-403 (2000)
[文献書誌] Ogawa,H.: "Combined treatment with TNP-47O and 5-fluorouracil effectively inhibits growth of murine colon cancer cells in vitro and liver metastasis in vivo."Oncol.Rep.. 7. 467-472 (2000)
[文献書誌] Mitamura,Y.: "Hepatocyte growth factor levels in the vitreous of patients with proliferative vitgreoretinopathy."Am.J.Ophthalmol.. 29. 678-680 (2000)
[文献書誌] Ogawa,H.: "An antibody for macrophage migration inhibitory factor suppresses tumor growth and inhibits tumor-associated angiogenesis."Cytokine. 12. 309-314 (2000)
[文献書誌] Mitamura,Y.: "Macrophage migration inhibitory factor levels in the vitreous of patients with proliferative diabeteic retinopathy."British J.Ophthalmol.. 84. 636-639 (2000)
[文献書誌] Morimoto,Y.: "Pentobarbital inhibits apoptosis in neuronal cells."Critical Care Med.. 28. 1899-1904 (2000)
[文献書誌] Kamimura,A.: "Intracellular distribution of macrophage migration inhibitory factor (MIF) predicts the prognosis of patients with adenocarcinoma of the lung."Cancer. 89. 334-341 (2000)
[文献書誌] Gando,S.: "An increase in macrophage migration inhibitory factor release in patients with cardiopulmonary bypass surgery."Surg.Today. 30. 689-694 (2000)
[文献書誌] Honda,K.: "Serum levels of macrophage migration inhibitory factor in various types of glomerulonephritis."Nephron. 86. 91-92 (2000)
[文献書誌] Yamaguchi,E.: "Macrophage migration inhibitory factor (MIF) in bronchial asthma."Clin.Exp.Allergy. 30. 1244-1249 (2000)
[文献書誌] Atsumi,T.: "Enhancement of oxidized low density lipoprotein uptake by macrophages in response to macrophage migration inhibitory factor."Cytokine. 12. 1553-1556 (2000)
[文献書誌] Kitaichi,N.: "Increase of macrophage migration inhibitory factor in sera of patients with iridocyclitis."British.J.Ophthalmol.. 84. 1423-1425 (2000)
[文献書誌] Niino,M.: "Macrophage migration inhibitory factor (MIF) in the cerebrospinal fluid of patients with conventional and optic-spinal forms of multiple sclerosis, and neuro-Behct's disease."J.Neurolog.Sci.. 179. 127-131 (2000)
[文献書誌] Suzuki,T.: "Japanese encephalitis virus up-regulates expression of macrophage migration inhibitory factor (MIF) mRNA in the mouse brain."Biochim.Biophys.Acta.. 1517. 100-106 (2000)
[文献書誌] Kitaichi,N.: "High-dose corticosteroid administration induces increase of serum macrophage migration inhibitory factor in patients with Vogt-Koyanagi-Harada's disease."Micobiol.Immunol.. 44. 1075-1077 (2000)
[文献書誌] Nishihira,J.: "Macrophage migration inhibitory factor (MIF): Its essential role in the immune system and cell growth."J.Interferon Cytokine Res.. 20. 751-762 (2000)
[文献書誌] 西平順: "肺損傷におけるMIFの機能と役割"呼吸. 19・11. 1094-1101 (2000)
[文献書誌] 西平順: "MIFの基礎と臨床"Annual Review免疫2001. 169-178 (2000)

2000 年度 実績報告書

癌細胞浸潤及び血管新生におけるマクロファージ遊走阻止因子の機能に関する基礎的研究

研究代表者

西平 順 北海道大学, 医学研究科, 助教授 (30189302)

研究成果

[文献書誌] Abe,R.: "Enhancement of macrophage migration inhibitory factor (MIF) expression in injured epidermis and cultured fibroblasts."Biochem.Biophys.Acta. 1500. 1-9 (2000)

[文献書誌] Koyama,N.: "Aneuploidy of sex chromosomes in basal cell carcinoma : its clonality and involvement in the development of carcinogenesis."Int.J.Oncol.. 16. 15-23 (2000)

[文献書誌] Kitaichi,N.: "Inhibition of experimental autoimmune uveoretinitis with anti-macrophage migration inhibitory factor antibodies."Curr.Eye Res.. 20. 109-114 (2000)

[文献書誌] Onodera,S.: "Macrophage migration inhibitory factor (MIF) up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis."J.Biol.Chem.. 7. 444-450 (2000)

[文献書誌] Yabunaka,N.: "Elevated serum content of macrophage migration inhibitory factor in patients with type 2 diabetes."Diabetes Care. 23. 256-258 (2000)

[文献書誌] Kitaichi,N.: "Different influence of macrophage migration inhibitory factor (MIF) in signal transduction pathway of various T cell subsets."Immunobiol.. 201. 356-367 (2000)

[文献書誌] Ishikawa,K.: "The crystal structure of human MRP8, a member of S100 calcium-binding protein family, by MAD phasing at 1.9 A resolution."Acta Crystallogr.D. 56. 559-566 (2000)

[文献書誌] Mizue,Y.: "Quantitation of macrophage migration inhibitory factor (MIF) using the one-step sandwich enzyme immunosorbent assay : Elevated serum MIF concentrations in patients with autoimmune diseases and identification of MIF in erythrocytes."Int.J.Mol.Med.. 5. 397-403 (2000)

[文献書誌] Ogawa,H.: "Combined treatment with TNP-47O and 5-fluorouracil effectively inhibits growth of murine colon cancer cells in vitro and liver metastasis in vivo."Oncol.Rep.. 7. 467-472 (2000)

[文献書誌] Mitamura,Y.: "Hepatocyte growth factor levels in the vitreous of patients with proliferative vitgreoretinopathy."Am.J.Ophthalmol.. 29. 678-680 (2000)

[文献書誌] Ogawa,H.: "An antibody for macrophage migration inhibitory factor suppresses tumor growth and inhibits tumor-associated angiogenesis."Cytokine. 12. 309-314 (2000)

[文献書誌] Mitamura,Y.: "Macrophage migration inhibitory factor levels in the vitreous of patients with proliferative diabeteic retinopathy."British J.Ophthalmol.. 84. 636-639 (2000)

[文献書誌] Morimoto,Y.: "Pentobarbital inhibits apoptosis in neuronal cells."Critical Care Med.. 28. 1899-1904 (2000)

[文献書誌] Kamimura,A.: "Intracellular distribution of macrophage migration inhibitory factor (MIF) predicts the prognosis of patients with adenocarcinoma of the lung."Cancer. 89. 334-341 (2000)

[文献書誌] Gando,S.: "An increase in macrophage migration inhibitory factor release in patients with cardiopulmonary bypass surgery."Surg.Today. 30. 689-694 (2000)

[文献書誌] Honda,K.: "Serum levels of macrophage migration inhibitory factor in various types of glomerulonephritis."Nephron. 86. 91-92 (2000)

[文献書誌] Yamaguchi,E.: "Macrophage migration inhibitory factor (MIF) in bronchial asthma."Clin.Exp.Allergy. 30. 1244-1249 (2000)

[文献書誌] Atsumi,T.: "Enhancement of oxidized low density lipoprotein uptake by macrophages in response to macrophage migration inhibitory factor."Cytokine. 12. 1553-1556 (2000)

[文献書誌] Kitaichi,N.: "Increase of macrophage migration inhibitory factor in sera of patients with iridocyclitis."British.J.Ophthalmol.. 84. 1423-1425 (2000)

[文献書誌] Niino,M.: "Macrophage migration inhibitory factor (MIF) in the cerebrospinal fluid of patients with conventional and optic-spinal forms of multiple sclerosis, and neuro-Behct's disease."J.Neurolog.Sci.. 179. 127-131 (2000)

[文献書誌] Suzuki,T.: "Japanese encephalitis virus up-regulates expression of macrophage migration inhibitory factor (MIF) mRNA in the mouse brain."Biochim.Biophys.Acta.. 1517. 100-106 (2000)

[文献書誌] Kitaichi,N.: "High-dose corticosteroid administration induces increase of serum macrophage migration inhibitory factor in patients with Vogt-Koyanagi-Harada's disease."Micobiol.Immunol.. 44. 1075-1077 (2000)

[文献書誌] Nishihira,J.: "Macrophage migration inhibitory factor (MIF): Its essential role in the immune system and cell growth."J.Interferon Cytokine Res.. 20. 751-762 (2000)

[文献書誌] 西平順: "肺損傷におけるMIFの機能と役割"呼吸. 19・11. 1094-1101 (2000)

[文献書誌] 西平順: "MIFの基礎と臨床"Annual Review免疫2001. 169-178 (2000)

2000 年度実績報告書

西平順北海道大学, 医学研究科, 助教授 (30189302)