Molecular Mechanism of Regulation of the Cytokine Signal and Immunity

• Project/Area Number: 18109005
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: Keio University (2008-2009); Kyushu University (2006-2007)
• Principal Investigator: YOSHIMURA Akihiko Keio University, 医学部, 教授 (90182815)
• Project Period (FY): 2006 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥107,250,000 (Direct Cost: ¥82,500,000、Indirect Cost: ¥24,750,000); Fiscal Year 2009: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000); Fiscal Year 2008: ¥27,690,000 (Direct Cost: ¥21,300,000、Indirect Cost: ¥6,390,000); Fiscal Year 2007: ¥33,150,000 (Direct Cost: ¥25,500,000、Indirect Cost: ¥7,650,000); Fiscal Year 2006: ¥35,360,000 (Direct Cost: ¥27,200,000、Indirect Cost: ¥8,160,000)
• Keywords: 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

Research Abstract

Cytokines play essential roles in regulation of innate and adaptive immunity. We have investigated the function of SOCS family and Spred/Sprouty family proteins which regulate cytokine signaling, by using genetically engineered mice. We found that SOCS1 and SOCS3 regulate helper T cell differentiation incuding Th17 and Tregs by modulating STAT transcription factors. We also found that human SPRED1 is responsible for neurofibromatosis type I like disease. Furthermore we discovered a novel mechanism of cAMP-mediated TLR signaling suppression through c-fos. We also found that Smad2/3 is essential for immunosuppression by TGF-beta.

Research Products

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