サイトカインのシグナル制御と免疫制御の分子機構

• 研究課題/領域番号: 18109005
• 研究種目: 基盤研究(S)
• 配分区分: 補助金
• 研究分野: 免疫学
• 研究機関: 慶應義塾大学 (2008-2009); 九州大学 (2006-2007)
• 研究代表者: 吉村 昭彦 慶應義塾大学, 医学部, 教授 (90182815)
• 研究期間 (年度): 2006 – 2009
• 研究課題ステータス: 完了 (2009年度)
• 配分額: 107,250千円 (直接経費: 82,500千円、間接経費: 24,750千円); 2009年度: 11,050千円 (直接経費: 8,500千円、間接経費: 2,550千円); 2008年度: 27,690千円 (直接経費: 21,300千円、間接経費: 6,390千円); 2007年度: 33,150千円 (直接経費: 25,500千円、間接経費: 7,650千円); 2006年度: 35,360千円 (直接経費: 27,200千円、間接経費: 8,160千円)
• キーワード: サイトカイン / シグナル伝達 / チロシンキナーゼ / 転写因子 / ヘルパーT / 細胞 / 樹状細胞 / Ras c-fos / ヘルパーT細胞 / インターフェロン / SOCS / 炎症 / アレルギー / 自己免疫疾患 / STAT / 負の制御 / 免疫制御 / アレルギー自己免疫疾患 / TGFβ / 抑制性T細胞

研究概要

サイトカインはマクロファージや樹状細胞などの自然免疫系の細胞やT 細胞などの獲得免疫系の細胞を制御する。我々はサイトカインシグナルを制御するSOCSファミリーとSpred/Sproutyファミリーを中心に主に遺伝子改変マウスを用いて個体レベルでの解析を行って来た。その結果SOCS1やSOCS3は転写因子STATを制御することで、ヘルパーT細胞(Th17やTreg)の分化を調節することを見いだした。またSpred1が神経芽細胞腫の原因遺伝子であることなどを明らかにした。さらに新規のシグナル制御機構としてcAMPによるTLRシグナルの抑制にc-fosが関与することを見いだした。またSmad2/3がTGFβによる免疫抑制に必須であることも見いだした。

研究成果

• [雑誌論文] (2011)
  • 著者名/発表者名: Chinen T, Komai K, Muto G, Morita R, Inoue N, Yoshida H, Sekiya T, Yoshida R, Nakamura K, Takayanagi R, Yoshimura A
  • 雑誌名: Nature Commun. 2 ページ: 190-190
• [雑誌論文] Smad2 and Smad3 are redundantly essential for the TGF-beta-mediated regulation of regulatory T plasticity and Th1 development. (2010)
  • 著者名/発表者名: Takimoto T, Wakabayashi Y, Sekiya T, Inoue N, Morita R, Ichiyama K, Takahashi R, Asakawa M, Muto G, Mori T, Hasegawa E, Shizuya S, Hara T, Nomura M, Yoshimura A
  • 雑誌名: J Immunol. 185(2) ページ: 842-55
• [雑誌論文] Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. (2010)
  • 著者名/発表者名: Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, Yoshimura A, Baltimore D, Rudensky AY
  • 雑誌名: Cell. 142(6) ページ: 914-29
• [雑誌論文] Pivotalrole of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. (2009)
  • 著者名/発表者名: Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A
  • 雑誌名: Nature Med. 15(8) ページ: 946-50
• [雑誌論文] SOCS3 in T and NKT cells negatively regulates cytokine production and ameliorates ConA-induced hepatitis. (2009)
  • 著者名/発表者名: Nakaya M, Hashimoto M, Nakagawa R, Wakabayashi Y, Ishizaki T, Takada I, Komai K, Yoshida H, Yoshimura A
  • 雑誌名: J Immunol. 183(11) ページ: 7047-53
• [雑誌論文] Clinical and mutational spectrum of Legius syndrome (2009)
  • 著者名/発表者名: Messiaen L, Yao S, 他, Taniguchi K, Ayada T, Okamoto F, Yoshimura A, Parret A, Korf B, Legius E
  • 雑誌名: JAMA. 302(19) ページ: 2111-8
• [雑誌論文] Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. (2009)
  • 著者名/発表者名: Taleb S, Romain M, Ramkhelawon B, Uyttenhove C, Pasterkamp G, Herbin O, Esposito B, Perez N, Yasukawa H, Van Snick J, Yoshimura A, Tedgui A, Mallat Z
  • 雑誌名: J Exp Med. 206(10) ページ: 2067-77
• [雑誌論文] Suppression of Sproutys has a therapeutic effect for a mouse model of ischemia by enhancing angiogenesis. (2009)
  • 著者名/発表者名: Taniguchi K, Sasaki K, Watari K, Yasukawa H, Imaizumi T, Ayada T, Okamoto F, Ishizaki T, Kato R, Kohno R, Kimura H, Sato Y, Ono M, Yonemitsu Y, Yoshimura A
  • 雑誌名: PLoS ONE. 4(5)
• [雑誌論文] Cyclic adenosine monophosphate suppresses the transcription of proinflammatory cytokines via the c-Fos protein phosphorylated by IKKbeta (2009)
  • 著者名/発表者名: Koga K, Takaesu G, Yoshida R, Nakaya M, Kobayashi T, Kinjyo I, Yoshimura A
  • 雑誌名: Immunity. 30(3) ページ: 372-383
• [雑誌論文] Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. (2009)
  • 著者名/発表者名: Lu LF, Thai TH, Calado DP, ChaudhryA, Kubo M, Tanaka K, Loeb GB, Lee H, Yoshimura A, Rajewsky K, Rudensky AY
  • 雑誌名: Immunity. 30(1) ページ: 80-91
• [雑誌論文] major lipid raft protein raftlin modulates T cell receptor signaling and enhances Th17-mediated autoimmune responses (2009)
  • 著者名/発表者名: Saeki K, Fukuyama S, Ayada T, et al.
  • 雑誌名: J Immunol. 182(10) ページ: 5929-5937
  • 査読あり
• [雑誌論文] Signal-Transducing Adaptor Protein-2 Regulates Stromal Cell-Derived Factor-1{alpha}-Induced Chemotaxis in T Cells. (2009)
  • 著者名/発表者名: Sekine Y, Ikeda O, Tsuji S, et al.
  • 雑誌名: J Immunol. 183(12) ページ: 7966-7974
  • 査読あり
• [雑誌論文] Clinical and mutational spectrum of Legius syndrome (2009)
  • 著者名/発表者名: Messiaen L, Yao S, Brems H, et al.
  • 雑誌名: JAMA 206(10) ページ: 2067-2077
  • 査読あり
• [雑誌論文] Cyclic adenosine monophosphate suppresses the transcription of proinflammatory cytokines via the c-Fos protein phosphorylated by IKKbeta (2009)
  • 著者名/発表者名: Koga K, Takaesu G, Yoshida R, Nakaya M, Kobayashi T, Kinjyo I, Yoshimura A
  • 雑誌名: Immunity 30(3) ページ: 372-383
• [雑誌論文] Rajewsky K, Rudensky AY. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein (2009)
  • 著者名/発表者名: Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K, Loeb GB, Lee H, Yoshimura A
  • 雑誌名: Immunity 30(1) ページ: 80-91
• [雑誌論文] STAT6 inhibits TGF-beta 1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. (2008)
  • 著者名/発表者名: Takaki H, Ichiyama K, Koga K, Chinen T, Takaesu G, Sugiyama Y, Kato S, Yoshimura A, Kobayashi T
  • 雑誌名: J Biol Chem. 283(22) ページ: 14955-62
• [雑誌論文] Loss of Suppressor of Cytokine Signaling 1 in Helper T Cells Leads to Defective Th17 Differentiation by Enhancing Antagonistic Effects of IFN-{gamma} on STAT3 and Smads. (2008)
  • 著者名/発表者名: Tanaka K, Ichiyama K, Hashimoto M, Yoshida H, Takimoto T, Takaesu G, Torisu T, Hanada T, Yasukawa H, Fukuyama S, Inoue H, Nakanishi Y, Kobayashi T, Yoshimura A
  • 雑誌名: J Immunol. 180(6) ページ: 3746-56
• [雑誌論文] STAT6 inhibits TGF-beta 1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor (2008)
  • 著者名/発表者名: Takaki H, Ichiyama K, Koga K, Chinen T, Takaesu G, Sugiyama Y, Kato S, Yoshimur a A, Kobayashi T
  • 雑誌名: J Biol Chem 283(22) ページ: 14955-14962
• [雑誌論文] Loss of Suppressor of Cytokine Signaling 1 in Helper T Cells Leads to Defective Th17 Differentiation by Enhancing Antagonistic Effects of IFN-{gamma} on STAT3 and Smads (2008)
  • 著者名/発表者名: Tanaka K, Ichiyama K, Hashimoto M, Yoshida H, Takimoto T, Takaesu G, Torisu T, Hanada T, Yasukawa H, Fukuyama S, Inoue H, Nakanishi Y, Kobayashi T, Yoshimur a A
  • 雑誌名: J Immunol 180(6) ページ: 3746-3756
• [雑誌論文] Loss of Suppressor of Cytokine Signaling 1 in Helper T Cells Leads to Defective Th17 Differentiation by Enhancing Antagonistic Effects of IFN{gamma} on STAT3 and Smads. (2008)
  • 著者名/発表者名: Tanaka K, Kobayashi T, Yoshimura A, et. al.
  • 雑誌名: J Immunol. 180 ページ: 1-1
  • 査読あり
• [雑誌論文] SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellular trafficking and stability of HIV-1 Gag (2008)
  • 著者名/発表者名: Ryo A, Yoshimura A, Aoki I, Morikawa Y, Yamamoto N., et. al.
  • 雑誌名: Proc Natl Acad Sci U S A. 105 ページ: 294-9
  • 査読あり
• [雑誌論文] SOCS proteins, cytokine signalling and immune regulation. (2007)
  • 著者名/発表者名: Yoshimura A, Naka T, Kubo M
  • 雑誌名: Nat Rev Immunol. 7(6) ページ: 454-65
• [雑誌論文] Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. (2007)
  • 著者名/発表者名: Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E
  • 雑誌名: Nature Genet. 39(9) ページ: 1120-6
• [雑誌論文] SOCS proteins, cytokine signalling and immune regulation (2007)
  • 著者名/発表者名: Yoshimur a A, Naka T, Kubo M
  • 雑誌名: Nat Rev Immunol 7(6) ページ: 454-465
• [雑誌論文] Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype (2007)
  • 著者名/発表者名: Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimur a A, Legius E
  • 雑誌名: Nature Genet 39(9) ページ: 1120-1126
• [雑誌論文] Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. (2007)
  • 著者名/発表者名: Brems H, Marunen P, Thomas G, Yoshimura A, Legius E, et. al.
  • 雑誌名: Nature Genet. 39 ページ: 1120-6
  • 査読あり
• [雑誌論文] Selective expansion of fox3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient demdritic cells (2007)
  • 著者名/発表者名: Matsumura Y, Wyss-Coray T, Sato K, Yoshimura A, et. al.
  • 雑誌名: J Imunol. 179 ページ: 2170-9
  • 査読あり
• [雑誌論文] SOCS3 Protein Developmentally Regulates the Chemokine Receptoe CXC R4-FAK Signaling Pathway during B Lymphopoiesis (2007)
  • 著者名/発表者名: Le Y, Yoshimura A, Silberstein LE, et. al.
  • 雑誌名: Immunity. 27 ページ: 811-823
  • 査読あり
• [雑誌論文] SOCS proteins, cytokine signalling and immune regulation (2007)
  • 著者名/発表者名: Yoshimura A, Naka T, Kubo M.
  • 雑誌名: Nat Rev Immunol. 7 ページ: 454-65
  • 査読あり
• [雑誌論文] Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor recrptor 3 signaling. (2007)
  • 著者名/発表者名: Taniguchi K, Maehara Y, Yoshimura A, et. al.
  • 雑誌名: Mol Cell Biol. 27 ページ: 4541-50
  • 査読あり
• [雑誌論文] IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice (2006)
  • 著者名/発表者名: Hanada T, Kobayashi T, Chinen T, Saeki K, Takaki H, Koga K, Minoda Y, Sanada T, Yoshioka T, Mimata H, Kato S, Yoshimura A
  • 雑誌名: J Exp Med 203(6) ページ: 1391-1397
• [雑誌論文] Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-beta 1 (2006)
  • 著者名/発表者名: Kinjyo I, Inoue H, Hamano S, Fukuyama S, Yoshimura T, Koga K, Takaki H, Himeno K, Takaesu G, Kobayashi T, Yoshimura A
  • 雑誌名: J Exp Med 203(4) ページ: 1021-1031
• [雑誌論文] Two-sided roles of IL-27 : induction of Th1 differentiation on naive CD4+ T cells versus suppression of proinflammatory cytokine production including IL-23-induced IL-17 on activated CD4+ T cells partially through STAT3-dependent mechanism. (2006)
  • 著者名/発表者名: Yoshimura T, Takeda A, Yoshimura A, Yoshida H, et al.
  • 雑誌名: J Immunol. 177(8) ページ: 5277-85
• [雑誌論文] Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. (2006)
  • 著者名/発表者名: Stumhofer JS, Laurence A, Yoshimura A, Hunter CA, et al.
  • 雑誌名: Nat Immunol. 7(9) ページ: 937-45
• [雑誌論文] IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. (2006)
  • 著者名/発表者名: Hanada T, Kobayashi T, Chinen T, Saeki K, Yoshimura A, et al.
  • 雑誌名: J Exp Med. 203(6) ページ: 1391-7
• [雑誌論文] Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-beta 1. (2006)
  • 著者名/発表者名: Kinjyo I, Inoue H, Hamano S, Yoshimura A, et al.
  • 雑誌名: J Exp Med. 203(4) ページ: 1021-31
• [雑誌論文] Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. (2006)
  • 著者名/発表者名: Chen Z, Laurence A, Kanno Y, Yoshimura A, O'Shea JJ, et al.
  • 雑誌名: Proc Natl Acad Sci USA. 103(21) ページ: 8137-42
• [雑誌論文] Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling. (2006)
  • 著者名/発表者名: Yajima T, Yoshimura A, Knowlton KU, et al.
  • 雑誌名: Circulation. 114(22) ページ: 2364-73
• [学会発表] SOCS is a molecular link between inflammation and cancer development. (2010)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: International symposium of infection-associated cancers
  • 発表場所: Conference Hall of Hokkaido University in Sapporo, Hokkaido, Japan
• [学会発表] Role of SOCS1 in innate and adaptive immune tolerance World (2010)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: Immune Regulation Meeting IV
  • 発表場所: Davos Switzerland
• [学会発表] Molecular basis for immune suppression by TGFb/Smad2/3 5th Leukocyte Signal Transduction Workshop (2009)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: sponsored by Aegean Conferences Aldeamar Knossos Royal Village in Hersonissos
  • 発表場所: Crete, Greece
• [学会発表] SOCS1 and SOCS3 are Critical Regulators of Cytokine Signaling (2007)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: Implication for Helper T Cell Differentiation and Tumor Development.
  • 発表場所: KEYSTONE SYMPOSIA on Molecular and Cellular BiologyKeystone USA
• [学会発表] SOCS1 is a link between inflammation and inflammationmediated carcinogenesis. (2007)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: 5th International Aachen Symposium on Cytokine Signalling
  • 発表場所: Aachen Germany
• [学会発表] SOCS1 is a link between inflammation and inflammation-mediated carcinogenesis (2007)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: 5th International Aachen Symposium on Cytokine Signalling
  • 発表場所: Aachen, Germany
• [学会発表] SOCS1 and SOCS3 are Critical Regulators of Cytokine Signaling ; Implication for Helper T Cell Differentiation and Tumor Development (2007)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: KEYSTONE SYMPOSIA on Molecular and Cellular Biology
  • 発表場所: Keystone, USA
• [学会発表] Physiological functions of the Sprouty/Spred family proteins,negative regulators for the Ras/ERK pathway (2006)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: BEATSON INTERNATIONAL CANCER CONFERENCE
  • 発表場所: Glasgow, UK
• [学会発表] Regulation of osteoclastgenesis by inflammatory cytokines and SOCS (2006)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: 1st International Conference on Osteoimmunology Ist International meeting of osteoimmunology
  • 発表場所: Crete ,Greek
• [備考] ホームページ等
• [備考]
  • URL: http://www.immunoreg.jp/