2001 Fiscal Year Annual Research Report

トランスジェニックマウスを用いたマクロファージ遊走阻止因子の機能の解明

Research Project

Project/Area Number	13670311
Research Institution	Hokkaido University
Principal Investigator	西平順北海道大学, 医学研究科, 助教授 (30189302)
Co-Investigator(Kenkyū-buntansha)	岩渕和也北海道大学, 遺伝子病制御研究所, 助教授 (20184898) 西村正治北海道大学, 医学研究科, 教授 (00208224)
Keywords	MIF / マクロファージ / サイトカイン / 遺伝子改変動物 / 新生血管
Research Abstract	申請者は,MIFが多くの炎症性疾患及び細胞の分化・増殖に関与し,特に腫瘍細胞増殖や血管新生に深く関与することを明らかにしてきた.最近の研究では,MIF Tg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.ICRマウス由来の癌細胞(Sarcoma S180)をマウスの背部皮下に移植し,移植後隔日に腫瘍体積の推移を測定した.Tgマウスに皮下移植した腫瘍体積はcontrolマウスに比して有意に増加した.このことから,MIFの上昇は腫瘍細胞の増殖を促すと考えられた.また,腫瘍血管新生誘導試験ではSarcoma S180細胞を注入したMillipore chamberをマウスの背部皮下に移植し,移植後6日目に腫瘍血管の占有面積を定量的に測定した.TgマウスにおけるMIFの発現の上昇は癌細胞由来の可溶性因子による血管新生作用を増強することから,MIFが腫瘍細胞の増殖と血管新生を促進する作用を有すると考えられた. MIF結合タンパク質の検索については,Histidine6残基をカルボキシ末端に付加した融合recombinant MIF(His-tagged MIF)を発現するplasmidを細胞(melanoma G361)に遺伝子導入し,stable cloneを単離後,細胞内MIF結合タンパク質の検索を行った.MIFに結合するタンパク質のペプチドアミノ酸配列の解析からMIFはpre-mRNA splicing factor(PSF)と結合する結果を得た.MIF刺激による細胞内シグナル伝達系についても解析を進め,MIF刺激によりsrcの自己リン酸化,MAPKK(Mek)及びMAPK(Erk1/2)の活性化が認められた.また種々のタンパク質リン酸化阻害剤の実験結果から,MIFの作用はsrc-Mek-MAPKのシグナル伝達系を介すると考えられた.

Research Products

(18 results)

All Other

All Publications (18 results)

[Publications] Takahashi, M.: "De novo expression of macrophage migration inhibitory factor in atherogenesis"Circ. Res.. 88. 31 (2001)
[Publications] Sakamoto, W.: "Effect of coffee consumption on bone metabolism"Bone. 28. 332-336 (2001)
[Publications] Asakura, T.: "Suppression of GST-P by treatment with glutathione-doxorubicin conjugate induces potent apoptosis in rat hepatoma cells"Int. J. Cancer. 171-177 (2001)
[Publications] Shimizu, T.: "High macrophage migration inhibitory factor (MIF) associated with extended psoriasis"J. Invest. Dermatol.. 116. 989-990 (2001)
[Publications] Ohwatari, R.: "Serum level of macrophage migration inhibitory factor as a useful parameter of clinical course in patients with Wegner's granulomatosis and relapsing polychondritis"Ann. Otol. Rhionol. Laryngol.. 110. 1035-1040 (2001)
[Publications] Takahashi, M.: "Macrophage migration inhibitory factor as a redox-sensitive cytokine incardiac myocytes"Cardiovasc. Res.. 52. 438-445 (2001)
[Publications] Ito, H.: "Expression , purification, crystallization, and preliminary X-ray diffraction analysis of human calcium-binding protein MRP-14"Acta Crystallogr. D. 57. 1174-1176 (2001)
[Publications] Mitamura, Y.: "Monocyte chemotactic protein-1 in the vitreous of patients with proliferative diabetic retinopathy"Ophthalmologica. 215. 415-418 (2001)
[Publications] Gando, S.: "Systemic macrophage migration inhibitory factor release following hepatic resection"Surg Today. 31. 605-609 (2001)
[Publications] Taguchi, C.: "Macrophage Migration Inhibitory Factor in Ocular Fluids of Patients with Uveitis"British J. Ophthalmol.. 85. 1367-1371 (2001)
[Publications] Gando, S.: "Macrophage migration inhibitory factor is a critical mediator of systemic inflammatory response syndrome"Intensive Care Med.. 27. 1187-1193 (2001)
[Publications] Takahashi, M.: "Elevation of plasma level of macrophage migration inhibitory factor in patients with acute myocardial infarction"Am. J. Cardiol.. 89. 248-249 (2002)
[Publications] Itou, H.: "The crystal structure of human MRP14 (S100A9), a Ca2+-dependent regulator protein in inflammatory process"J. Mol. Biol.. 316. 265-276 (2002)
[Publications] Onodera, S.: "Macrophage migration inhibitory factor up-regulates matrix metalloproteinase-9 and -13 in rat osteoblasts. Relevance to intracellular signaling pathways"J. Biol. Chem.. (in press).
[Publications] Mitamura, Y.: "Monocyte chemotactic protein-1 levels in the vitreous of patients with proliferative vitreoretinopathy"Jap. J. Opthalmol.. (in press).
[Publications] Shimizu, T.: "Increased macrophage migration inhibitory factor (MIF) in the sera of patients with extensive alopecia areata"J. Invest. Dermatol.. (in press).
[Publications] Tanino, Y.: "Role of macrophage migration inhibitory factor in bleomycin-induced lung injury and fibrosis in mice"Am. J. Physiol.. (in press).
[Publications] Nishihira, J.: "Macrophage migration inhibitory factor (MIF) : Its potential role in tumor growth and tumor-associated angiogenesis"Ann. New York Acad. Sci.. (in press).

2001 Fiscal Year Annual Research Report

トランスジェニックマウスを用いたマクロファージ遊走阻止因子の機能の解明

Principal Investigator

西平 順 北海道大学, 医学研究科, 助教授 (30189302)

Research Products

[Publications] Takahashi, M.: "De novo expression of macrophage migration inhibitory factor in atherogenesis"Circ. Res.. 88. 31 (2001)

[Publications] Sakamoto, W.: "Effect of coffee consumption on bone metabolism"Bone. 28. 332-336 (2001)

[Publications] Asakura, T.: "Suppression of GST-P by treatment with glutathione-doxorubicin conjugate induces potent apoptosis in rat hepatoma cells"Int. J. Cancer. 171-177 (2001)

[Publications] Shimizu, T.: "High macrophage migration inhibitory factor (MIF) associated with extended psoriasis"J. Invest. Dermatol.. 116. 989-990 (2001)

[Publications] Ohwatari, R.: "Serum level of macrophage migration inhibitory factor as a useful parameter of clinical course in patients with Wegner's granulomatosis and relapsing polychondritis"Ann. Otol. Rhionol. Laryngol.. 110. 1035-1040 (2001)

[Publications] Takahashi, M.: "Macrophage migration inhibitory factor as a redox-sensitive cytokine incardiac myocytes"Cardiovasc. Res.. 52. 438-445 (2001)

[Publications] Ito, H.: "Expression , purification, crystallization, and preliminary X-ray diffraction analysis of human calcium-binding protein MRP-14"Acta Crystallogr. D. 57. 1174-1176 (2001)

[Publications] Mitamura, Y.: "Monocyte chemotactic protein-1 in the vitreous of patients with proliferative diabetic retinopathy"Ophthalmologica. 215. 415-418 (2001)

[Publications] Gando, S.: "Systemic macrophage migration inhibitory factor release following hepatic resection"Surg Today. 31. 605-609 (2001)

[Publications] Taguchi, C.: "Macrophage Migration Inhibitory Factor in Ocular Fluids of Patients with Uveitis"British J. Ophthalmol.. 85. 1367-1371 (2001)

[Publications] Gando, S.: "Macrophage migration inhibitory factor is a critical mediator of systemic inflammatory response syndrome"Intensive Care Med.. 27. 1187-1193 (2001)

[Publications] Takahashi, M.: "Elevation of plasma level of macrophage migration inhibitory factor in patients with acute myocardial infarction"Am. J. Cardiol.. 89. 248-249 (2002)

[Publications] Itou, H.: "The crystal structure of human MRP14 (S100A9), a Ca2+-dependent regulator protein in inflammatory process"J. Mol. Biol.. 316. 265-276 (2002)

[Publications] Onodera, S.: "Macrophage migration inhibitory factor up-regulates matrix metalloproteinase-9 and -13 in rat osteoblasts. Relevance to intracellular signaling pathways"J. Biol. Chem.. (in press).

[Publications] Mitamura, Y.: "Monocyte chemotactic protein-1 levels in the vitreous of patients with proliferative vitreoretinopathy"Jap. J. Opthalmol.. (in press).

[Publications] Shimizu, T.: "Increased macrophage migration inhibitory factor (MIF) in the sera of patients with extensive alopecia areata"J. Invest. Dermatol.. (in press).

[Publications] Tanino, Y.: "Role of macrophage migration inhibitory factor in bleomycin-induced lung injury and fibrosis in mice"Am. J. Physiol.. (in press).

[Publications] Nishihira, J.: "Macrophage migration inhibitory factor (MIF) : Its potential role in tumor growth and tumor-associated angiogenesis"Ann. New York Acad. Sci.. (in press).

西平順北海道大学, 医学研究科, 助教授 (30189302)