Molecular Mechanism of Regulation of the Cytokine Signal and Immunity

2008 Fiscal Year Self-evaluation Report

• 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
• Keywords: シグナル伝達 / 負の制御 / 免疫制御 / アレルギー自己免疫疾患 / 炎症

Research Abstract

サイトカインは免疫応答のみならず造血、炎症、癌など広範な疾患とも関連が深い。サイトカインはネットワークをつくり特に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。これらの作用を細胞内のシグナル伝達の観点から理解し、新たな免疫調節の方法論を開発することが求められている。さらにTh17やiTregなどの新たな細胞集団も発見されこれらの発生、分化、機能制御を理解する上でも、サイトカインのシグナル制御についての理解が求められている。
申請者らは世界にさきがけてサイトカインによって誘導されそのシグナルを負に制御する分子群CIS/SOCSファミリーとpred/Sprouty ファミリーを発見した。本研究ではこれらの分子を各種臓器において特異的に欠失したマウス(cKOマウス)を作製し解析を行い、サイトカインシグナルの制御による免疫ホメオスターシス維持の分子機構とその破綻による免疫関連疾患の発症機構を解明することを目的とする。また未解明の免疫制御機構、例えばcAMP やTGFβによる免疫抑制の分子機構を解明し、炎症性疾患や自己免疫疾患との関係を明らかにする。

Research Products

• [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, 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] 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] 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
• [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
  • Year and Date: 20070329-31
• [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
  • Year and Date: 20070105-10
• [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
  • Year and Date: 20060618-21
• [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
  • Year and Date: 20060528-0602
• [Remarks]
  • URL: http://www.immunoreg.jp/