2003 年度実績報告書

炎症・免疫応答におけたマクロファージ遊走阻止因子(MIF)の機能の解明

研究課題

研究課題/領域番号	15590430
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	岩渕和也北海道大学, 遺伝子病制御研究所, 助教授 (20184898)
キーワード	MIF / マクロファージ / エンドトキシン / 遺伝子改変動物 / 血管新生
研究概要	Macrophage migration inhibitory factor (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を明らかにしてきた。例えば,トランスジェニック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することを報告してきた.このことから、MIFが腫瘍細胞の増殖と血管新生を促進すると推測されたが、その詳細については明らかにされていない。本研究では、マウス大腸癌Colon26細胞を用いて、MIFが癌の浸潤、転移を促進することを発見し、そのメカニズムとしてGTP結合蛋白質Rhoの活性化に依存することを明らかにした。癌細胞の浸潤に関与するMMPの発現上昇のシグナル伝達系に関する研究では、MIF刺激によりMMP-13の顕著な発現の上昇が認められた。次に、MIF siRNAの導入により、MIFの機能解析を行った。siRNAの導入により、細胞内MIFは80%以上knockdownされた。その場合、細胞増殖速度は約50%に減少した。同時に細胞浸潤におけるMIFの関与を明らかにするため、siRNAを導入した細胞を用いて、Millipore Chamber法により検討した。siRNA導入により、細胞浸潤は有意に抑制された。また、細胞浸潤に密接に関連する分子として知られているFAK, Integrin beta-1の活性化も有意に抑制された。以上のin vitroの結果を踏まえ、in vivoにおける転移実験を行った。siRNAで処理したColon26細胞を門脈から導入し、肝臓の重量、癌の転移個数、組織学的検討を行った。肝重量、転移個数ともにsiRNA処理により有意に減少した。また、組織学的検討を行ったが、血管新生も有意に抑制された。ごれらの結果から、MIFは癌の浸潤、転移のメカニズムに密接に関与していると考えられた。

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] Sakamoto, W.: "Coffee increases levels of urinary 8-hydroxydeoxyguanosine in rats"Toxicology. 183. 255-263 (2003)
[文献書誌] Iwaki, T.: "Recombinant adenovirus vector bearing antisense macrophage migration inhibitory factor (MIF) cDNA prevents acute lipopolysaccharide-induced liver failure in mice"Lab Invest. 83. 561-570 (2003)
[文献書誌] Yamada, H.: "Decreased serum levels of macrophage migration inhibitory factor in miscarriages with normal chromosome karyotype"Human Reprod. 18. 616-620 (2003)
[文献書誌] Watari, M.: "Lipopolysaccharide induces interleukin-8 production by human cervical smooth muscle cells"J Soc Gynecol Invest. 10. 110-117 (2003)
[文献書誌] Sakai, Y.: "Macrophage migration inhibitory factor is a critical mediator of severe acute pancreatitis"Gastroenterology. 124. 725-736 (2003)
[文献書誌] Shimizu, T.: "Impaired contact hypersensitivity in macrophage migration inhibitory factor (MIF)-deficient mice"Eur J Immunol. 33. 1478-1487 (2003)
[文献書誌] Sun, B.: "Induction of macrophage migration inhibitory factor by lysophosphatidic acid : Relevance to tumor growth and angiogenesis"Int J Mol Med. 12. 633-641 (2003)
[文献書誌] Morimoto, T.: "Immunohistochemical localization of macrophage migration inhibitory factor (MIF) in human gingival tissue and its pathophysiological functions"Histochem Cell Biol. 120. 293-298 (2003)
[文献書誌] Itoh, a.: "Effects of IL-1beta, TNF-alpha, and macrophage migration inhibitory factor on prostacyclin synthesis in rat pulmonary artery smooth muscle cells"Respirology. 8. 467-472 (2003)
[文献書誌] Igarashi, M.: "Energetics of catalytic reaction of acetylcholinesterase (AchE) with acetylcholine (Ach) : Role of the oxyanion hole"Internet Electron J Mol Des. 2. 712-722 (2003)
[文献書誌] Hori, Y.: "Immunohistochemical study of macrophage migration inhibitory factor in rat liver fibrosis induced by thioacetamide"Eur J Histochem. 47. 317-324 (2003)
[文献書誌] Sasaki, S.: "Transgene of macrophage migration inhibitory factor induces podocyte injury and progressive mesangial sclerosis"Kidney Int. 65. 469-481 (2004)
[文献書誌] Shimizu, T.: "Cetirizine, an H1-receptor antagonist, suppresses the expression of macrophage migration inhibitory factor (MIF) : Its potential anti-inflammatory action"Clin Exp Allergy. 34. 103-109 (2004)
[文献書誌] Watanabe, H.: "Ultraviolet A-induced production of matrix metalloproteinase-1 is mediated by macrophage migration inhibitory factor (MIF) in human dermal fibroblasts"J Biol Chem. 279. 1676-1683 (2004)
[文献書誌] Nakamaru, Y.: "Macrophage migration inhibitory factor (MIF) in allergic rhinitis : Identification of MIF in eosinophils and the site of allergic inflammation"Ann Otol Rhinol Laryngol. (in press). (2004)
[文献書誌] Tashimo, A.: "Aqueous levels of macrophage migration inhibitory factor and monocyte chemotactic protein-1 in patients with diabetic retinopathy"Diabet Med. (in press). (2004)
[文献書誌] Isomura, H.: "Bone metabolism and oxidative stress in postmenopausal rats with iron overload"Toxicology. (in press). (2004)
[文献書誌] Onodera, S.: "Increased expression of macrophage migration inhibitory factor during fracture healing in rats"Histochem Cell Biol. (in press). (2004)
[文献書誌] Onodera, S.: "Macrophage migration inhibitory factor (MIF) up-regulates expression of interleukin (IL)-8 mRNA in synovial fibroblasts of rheumatoid arthritis. common transcriptional regulatory mechanism between IL-8 and IL-1β"Arthritis Rheum. (in press). (2004)
[文献書誌] Shimizu, T.: "Macrophage Migration Inhibitory Factor (MIF) Is Induced by Thrombin and Factor Xa in Endothelial Cells"J Biol Chem. (in press). (2004)

2003 年度 実績報告書

炎症・免疫応答におけたマクロファージ遊走阻止因子(MIF)の機能の解明

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] Sakamoto, W.: "Coffee increases levels of urinary 8-hydroxydeoxyguanosine in rats"Toxicology. 183. 255-263 (2003)

[文献書誌] Iwaki, T.: "Recombinant adenovirus vector bearing antisense macrophage migration inhibitory factor (MIF) cDNA prevents acute lipopolysaccharide-induced liver failure in mice"Lab Invest. 83. 561-570 (2003)

[文献書誌] Yamada, H.: "Decreased serum levels of macrophage migration inhibitory factor in miscarriages with normal chromosome karyotype"Human Reprod. 18. 616-620 (2003)

[文献書誌] Watari, M.: "Lipopolysaccharide induces interleukin-8 production by human cervical smooth muscle cells"J Soc Gynecol Invest. 10. 110-117 (2003)

[文献書誌] Sakai, Y.: "Macrophage migration inhibitory factor is a critical mediator of severe acute pancreatitis"Gastroenterology. 124. 725-736 (2003)

[文献書誌] Shimizu, T.: "Impaired contact hypersensitivity in macrophage migration inhibitory factor (MIF)-deficient mice"Eur J Immunol. 33. 1478-1487 (2003)

[文献書誌] Sun, B.: "Induction of macrophage migration inhibitory factor by lysophosphatidic acid : Relevance to tumor growth and angiogenesis"Int J Mol Med. 12. 633-641 (2003)

[文献書誌] Morimoto, T.: "Immunohistochemical localization of macrophage migration inhibitory factor (MIF) in human gingival tissue and its pathophysiological functions"Histochem Cell Biol. 120. 293-298 (2003)

[文献書誌] Itoh, a.: "Effects of IL-1beta, TNF-alpha, and macrophage migration inhibitory factor on prostacyclin synthesis in rat pulmonary artery smooth muscle cells"Respirology. 8. 467-472 (2003)

[文献書誌] Igarashi, M.: "Energetics of catalytic reaction of acetylcholinesterase (AchE) with acetylcholine (Ach) : Role of the oxyanion hole"Internet Electron J Mol Des. 2. 712-722 (2003)

[文献書誌] Hori, Y.: "Immunohistochemical study of macrophage migration inhibitory factor in rat liver fibrosis induced by thioacetamide"Eur J Histochem. 47. 317-324 (2003)

[文献書誌] Sasaki, S.: "Transgene of macrophage migration inhibitory factor induces podocyte injury and progressive mesangial sclerosis"Kidney Int. 65. 469-481 (2004)

[文献書誌] Shimizu, T.: "Cetirizine, an H1-receptor antagonist, suppresses the expression of macrophage migration inhibitory factor (MIF) : Its potential anti-inflammatory action"Clin Exp Allergy. 34. 103-109 (2004)

[文献書誌] Watanabe, H.: "Ultraviolet A-induced production of matrix metalloproteinase-1 is mediated by macrophage migration inhibitory factor (MIF) in human dermal fibroblasts"J Biol Chem. 279. 1676-1683 (2004)

[文献書誌] Nakamaru, Y.: "Macrophage migration inhibitory factor (MIF) in allergic rhinitis : Identification of MIF in eosinophils and the site of allergic inflammation"Ann Otol Rhinol Laryngol. (in press). (2004)

[文献書誌] Tashimo, A.: "Aqueous levels of macrophage migration inhibitory factor and monocyte chemotactic protein-1 in patients with diabetic retinopathy"Diabet Med. (in press). (2004)

[文献書誌] Isomura, H.: "Bone metabolism and oxidative stress in postmenopausal rats with iron overload"Toxicology. (in press). (2004)

[文献書誌] Onodera, S.: "Increased expression of macrophage migration inhibitory factor during fracture healing in rats"Histochem Cell Biol. (in press). (2004)

[文献書誌] Onodera, S.: "Macrophage migration inhibitory factor (MIF) up-regulates expression of interleukin (IL)-8 mRNA in synovial fibroblasts of rheumatoid arthritis. common transcriptional regulatory mechanism between IL-8 and IL-1β"Arthritis Rheum. (in press). (2004)

[文献書誌] Shimizu, T.: "Macrophage Migration Inhibitory Factor (MIF) Is Induced by Thrombin and Factor Xa in Endothelial Cells"J Biol Chem. (in press). (2004)

2003 年度実績報告書

西平順北海道大学, 医学研究科, 助教授 (30189302)