紫外線による脳免疫統合系の制御機構とその生物学的意義の解明

• Project/Area Number: 15659082
• Research Category: Grant-in-Aid for Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Osaka City University
• Principal Investigator: 井上 正康 大阪市立大学, 大学院医学研究科, 教授 (80040278)
• Co-Investigator(Kenkyū-buntansha): 佐藤 英介 大阪市立大学, 大学院医学研究科, 講師 (60211942)
• Project Period (FY): 2003 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
• Keywords: 紫外線 / 一酸化窒素 / 光脳免疫統合系 / IgA / 誘導型一酸化窒素合成酵素 / 視床下部 / アレルギー / 三叉神経 / 疲労 / ランゲルハンス細胞 / TGF-β / コルチゾール / 雌雄 / 運動負荷 / 活性酸素 / ノックアウトマウス / iNOS / 酸素環境 / 脳免疫統合系 / ストレス

Research Abstract

本申請者は紫外線で眼を局所照射すると三叉神経・視床下部・下垂体プロオピオメラノコルチン系を介して全身のメラニン合成が亢進すると同時に、皮膚や腸粘膜の免疫活性が著変すること、iNOS^<-/->マウスでは両現象が起こらないこと、及び特定の可視光線で同時照射すると両現象が著しく増強して皮膚や腸管粘膜のアレルギー病態が増悪することを発見した。本研究は、(A)光脳免疫統合系の分子機構、(B)脳を介する皮膚・消化管粘膜の免疫応答変化の医学的意義、及び(C)本統合系制御による皮膚・消化管粘膜アレルギー病態の軽減法の開発を目指して行われた。
解析の結果、目を紫外線照射すると視床下部・下垂体系と自律神経系を介して全身の免疫系が制御される事、この経路にNOが関与すること、皮膚と消化管粘膜でTh1係が抑制されると同時にTh2系が活性化されて粘膜でIgAやIgEの産生分泌が亢進すること、および応答反応により皮膚や粘膜のアレルギー病態が大きく修飾されることが判明した。
目の表層組織から三叉神経・視床下部を介するシグナルにより皮膚と消化管粘膜でのアレルギー病態が著明に変化することが判明した。その臨床的意義の解明と制御法の開発を目指して現在様々な実験を行っている。解析の結果、ダニ感作性アトピー性皮膚炎、Th1型アレルギー反応、およびTh2型のアレルギー病態が味覚や嗅覚の刺激により大きく影響される事が明らかになった。この所見を基に粘膜アレルギー病態の予防治療法の開発を試みている。

Research Products

• [Journal Article] A possible cooperation of SOD1 and cytochrome c in mitochondria-dependent apoptosis. (2006)
  • Author(s): Q.Li
  • Journal Title: Free Radic Biol Med. 40・1 Pages: 173-181
• [Journal Article] 1-Carnitine suppresses the onset of neuromuscular degeneration and increases the life span of mice with familial amyotrophic lateral sclerosis. (2006)
  • Author(s): Y.Kira
  • Journal Title: Brain Research 1070・1 Pages: 206-214
• [Journal Article] Enhanced oxidative stress in neutrophils from hyperlipidemic guinea pig (2005)
  • Author(s): K.Maeda
  • Journal Title: Atherosclerosis 181・1 Pages: 87-92
• [Journal Article] Mechanism and Characteristics of Stimuli-Dependent ROS Generation in Undifferentiated HL-60 Cells (2005)
  • Author(s): S.Muranaka
  • Journal Title: ANTIOXIDANTS & REDOX SIGNALING 7・9-10 Pages: 1367-1376
• [Journal Article] Interferon reduces somatic mutation of mitochondrial DNA in liver tissues from chronic viral hepatitis patients (2005)
  • Author(s): M.Nishikawa
  • Journal Title: J Viral Hepat. 12・5 Pages: 494-498
• [Journal Article] Mitochondrial density determines the cellular sensitivity to cisplatin-induced cell death. (2005)
  • Author(s): W.Qian
  • Journal Title: Am J Physiol Cell Physiol. 289・6
• [Journal Article] Accumulation of mitochondrial DNA mutation with colorectal carcinogenesis in ulcerative colitis. (2005)
  • Author(s): M.Nishikawa
  • Journal Title: Br J Cancer 93・3 Pages: 331-337
• [Journal Article] L-carnitine inhibits hepatocarcinogenesis via protection of mitochondria (2005)
  • Author(s): B.Chang
  • Journal Title: Int J Cancer 113・5 Pages: 19-29
• [Journal Article] L-Carnitine inhibits hypoglycemia-induced brain damage in the rat (2005)
  • Author(s): K.Hino
  • Journal Title: Brain Research 1053・1-2 Pages: 77-87
• [Journal Article] Role of alpha-tocopherol in the regulation of mitochondrial membrane permeability transition. (2004)
  • Author(s): T.Kanno, M.Yorimitsu, S.Muranaka, EF.Sato, M.Nagano, A.Inoue, M.Inoue, K.Utsumi
  • Journal Title: J.Clin.Biochem.Nutr. 35 Pages: 7-15
• [Journal Article] Oxidative stress underlies the mechanism for Ca 2+-induced permeability transition of mitochondria. (2004)
  • Author(s): T.Kanno, EF.Sato, T.Utsumi, S.Muranaka, H.Fujita, T.Fujiwara, T.Utsumi, M.Inoue, K.Utsumi
  • Journal Title: Free Radic Res. 38・1 Pages: 27-35
• [Journal Article] Enhancing effect of an endocrine disruptor para-nonylphenol on the generation of reactive oxygen species in human blood cells. (2004)
  • Author(s): Y.Okai, EF.Sato, K.Higashi-Okai, M.Inoue
  • Journal Title: Environ Health Persp. 112・5 Pages: 553-556
• [Journal Article] Edaravone inhibits aute injury and cisplatin-induced cyst formation in rat kidney. (2004)
  • Author(s): T.Iguchi, M.Nishikawa, O.Muroya, EF.Sato, S.Nakatani, M.Inoue
  • Journal Title: Free Radic Res. 38・4 Pages: 333-341
• [Journal Article] Effect of 17b-estradiol on immunosuppression induced by ultraviolet B irradiation. (2004)
  • Author(s): K.Hiramoto, H.Tanaka, N.Yanagihara, EF.Sato, M.Inoue
  • Journal Title: Archives of Dermatological Research 295・8-9 Pages: 307-311
• [Journal Article] Oxidative stress promotes the regression of fetal liver hemopoiesis. (2004)
  • Author(s): EF.Sato, E.Nakagawa, K.Hiramoto, S.Yamamasu, I.Moriyama-Shimamoto, M.Inoue
  • Journal Title: Biochemistry (Moscow) 69・1 Pages: 18-22
• [Journal Article] Oxygen tension regulates reactive oxygen generation and mutation of helicobacter pylori. (2004)
  • Author(s): AM.Park, Q.Li, K.Nagata, T.Tamura, K.Shimano, EF.Sato, M.Inoue
  • Journal Title: Free Radical Biology & Medicine 36・9 Pages: 1126-1133
• [Journal Article] Free radical theory of mitochondria-dependent apoptosis and metamorphosis. (2004)
  • Author(s): M.Inoue, EF.Sato, M.Nishikawa, K.Hiramoto, A.Kashiwagi, K.Utsumi
  • Journal Title: Redox Report 9・5 Pages: 237-247
• [Journal Article] Effect of endocrine disruptor para-nonylphenol on the cell growth and oxygen radical generation in esherichia coli mutant cells (2004)
  • Author(s): Y.Okai, E.F.Sato, K.Higashi-Okai, M.Inoue
  • Journal Title: Free Radical Biology & Medicine 37・9 Pages: 1412-1418
• [Journal Article] Correlation between clinical characteristics and mitochondrial D-loop DNA mutations in hepatocellular carcinoma. (2004)
  • Author(s): M.Nishikawa, B.Chang, M.Inoue
  • Journal Title: Carcinogenesis 25・11 Pages: 2101-2105
  • NAID: 10014116216
• [Journal Article] Correlation between clinical characteristics and mitochondrial D-loop DNA mutations in hepatocellular carcinoma. (2004)
  • Author(s): Tamori, A., Nishiguchi, S., Nishikawa, M., Kubo, S., Koh, N., Hirohashi, K., Shiomi, S., Inoue, M.
  • Journal Title: Journal of Gastroenterology 39・11 Pages: 1063-1068
  • NAID: 10014116216
• [Book] 危ない!「慢性疲労」 (2004)
  • Author(s): 倉恒弘彦, 井上正康, 渡辺恭良
  • Total Pages: 209
  • Publisher: NHK出版
• [Publications] K.Hiramoto, Y.Yanagihara, EF.Sato, M.Inoue: "Activation of a nitric oxide-dependent neuroendocrinological pathway by the eye protects against ultraviolet B toxicity in the skin"J.Invest.Dermatol.. 120・1. 123-127 (2003)
• [Publications] M.Miyoshi, Y.Minamiyama, T.S.Taketani, K.Hiramoto, E.Kasahara, EF.: "Dietary nitrate inhibits stress-induced gastric mucosal injury in the rat"Free Radical Research. 37・1. 85-90 (2003)
• [Publications] AM Park, K Nagata, EF Sato, T Tamura, M Inoue: "Different sensitivity to nitric oxide in Helicobactor pylori and Eschelichia coli is due to the subtype of cytochrome c oxidase"Aech.Biochem.Biophys.. 411・1. 129-135 (2003)
• [Publications] Sato, E.F., Higashino, M., Ikeda, K., Wake, R., Matsuo, M., Utsumi, K., Inoue, M.: "Oxidative stress-induced cell death in oral neutrophils"Am.J.Phyiol.-Cell Physiol.. 284. C1048-C1053 (2003)
• [Publications] Bandoh T, Sato EF, Mitani H, Nakashima A, Hoshi K, Inoue M: "Antioxidative potential of fluvastatin via the inhibition of NADPH oxidase activity"Biological & Pharmaceutical Bulletin. 26・6. 818-822 (2003)
• [Publications] K.Maeda, K.Yasunari, EF Sato, J.Yoshikawa, M.Inoue: "Activation of protein kinase C and NADPH oxidase in leukocytes of spontaneously hypertensive rats"Hypertension Research. 26・12. 999-1006 (2003)
• [Publications] Chang BJ, Nishikawa M, Sato EF, Inoue M: "Mice lacking inducible nitric oxide synthase show strong resistance to anti-Fas antibody-induced fulminant hepatitis"Arch.Biochem.Biophys.. 411・1. 63-72 (2003)
• [Publications] Tsuchiya M, Asada A, Ryo K, Noda K, Hashino T, Sato Y, Sato EF, Inoue M: "Relaxing intraoperative natural sound blunts haemodynamic change at the emergence from propfol general anesthesia and increases the acceptability of anaesthesia to the patient"Acta Anaesthesiologica Scandinavica. 47・8. 939-943 (2003)
• [Publications] H.Hanada, K.Katsu, T.Kanno, E.F.Sato, A.Kashiwagi, J.Sasaki, M.Inoue, K.Utsumi: "Cyclosporin A inhibits thyroid hormone-induced shortening of the tadpole tail through membrane permeability transition"Comparative Biochemistry & Physiology. 135. 473-483 (2003)
• [Publications] Inoue M, Sato EF, Nishikawa M, Park AM, Kira Y, Imada I, Utsumi K.: "Cross talk of nitric oxide, oxygen radicals, and superoxide dismutase regulates the energy metabolism and cell death and determines the fates of aerobic life."Antioxid Redox Signal. 5・4. 475-484 (2003)
• [Publications] Inoue M, Sato EF, Nishikawa M, Park AM, Kira Y, Imada I, Utsumi K: "Mitochondrial generation of reactive oxygen species and its role in aerobic life."Curr Med Chem.. 23・10. 2495-2505 (2003)