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サイトカイン、接着分子の情報伝達制御

Research Project

Project/Area Number 12051225
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionOsaka University

Principal Investigator

平野 俊夫  大阪大学, 生命機能研究科, 教授 (40136718)

Co-Investigator(Kenkyū-buntansha) 吉村 昭彦  九州大学, 生体防御医学研究所, 教授 (90182815)
竹田 潔  大阪大学, 微生物病研究所, 助手 (20309446)
瀧 伸介  信州大学, 医学研究科, 教授 (50262027)
熊ノ郷 淳  大阪大学, 微生物病研究所, 助手 (10294125)
高津 聖志  東京大学, 医科学研究所, 教授 (10107055)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥230,200,000 (Direct Cost: ¥230,200,000)
Fiscal Year 2002: ¥81,000,000 (Direct Cost: ¥81,000,000)
Fiscal Year 2001: ¥82,800,000 (Direct Cost: ¥82,800,000)
Fiscal Year 2000: ¥66,400,000 (Direct Cost: ¥66,400,000)
Keywordsサイトカイン / 自己免疫疾患 / 免疫抑制 / シグナル伝達 / 自然免疫 / STAT / CIS / IRF
Research Abstract

平野は、IL-6サイトカインファミリーの共通の受容体であるgp130の点変異により関節リウマチ様の自己免疫疾患が自然発症することを明らかにした。さらにアダプター分子Gab2がマスト細胞の分化に必須であることを明らかにした。吉村はSOCS1がLPSによるマクロファージの活性化を抑制しTLRのシグナルを制御することや、SOCS1-/-樹状細胞は活性化されており自己抗体産生に寄与することを見い出した。SOCS3がマクロファージにおいてII-6/gp130のシグナルを抑制する働きがあることを示した。滝はIFN-α/β、リンパ球、炎症にそれぞれ依存的な遺伝子群を同定した。またIFN-α/β、リンパ球のそれぞれに依存的な二つの独立した異常が皮膚炎症の原因となっていることをしめした。高津はCD38刺激はB-2細胞にBtk, PI3キナーゼ,PLC-gamma依存的にNF-κBの活性化と胚細胞型C-gamma1の転写促進をすることを示した。IL-5は活性化B細胞にAIDとBlimp-1の発現を増強させ、クラススイッチ変換と抗体産生細胞への最終分化を惹起する。さらにLnkが造血幹細胞の増殖を負の調節因子であることを明らかにした。竹田はアダプター分子TIRAPが、TLR2,TLR4を介したMyD88依存性のシグナルに必須であることを明らかにした。TLRのシグナルに関与し、IFN-βプロモーターの活性化を誘導する新たなアダプター分子TRIFを同定した。熊之郷は、CD100欠損マウスがヒトの多発性硬化症のモデルとして知られる実験的自己免疫性脳脊髄炎の発症に対して抵抗性であることを示した。T細胞に発現するCD100が樹状細胞の活性化及び成熟化を促進する事によりT細胞の活性化に寄与している事を明らかにした。樹状細胞に発現するセマフォリン分子Sema4Aを新たに同定し、Sema4AがT細胞の活性化及び分化に関与している事、Sema4Aの受容体がTim-2である事を明らかにした。宮坂は、リンパ球ホーミングを媒介する血管HEV(high endothelial venule)において数種のケモカイン結合分子を同定し、それぞれがいずれもユニークなケモカイン結合能を持ち、リンパ球移動に関与することを明らかにした。SLC, IP-10などのケモカインは特定の糖鎖構造、すなわちGIcAβ1/IdoAα-1-3GaINAc(4,6-O-disulfate)に結合し、さらにこの構造にはホーミング関連分子であるL-セレクチン、CD44も結合することを明らかにした。BLCがHEV内腔に発現してHEVが媒介するB細胞移動(ホーミング)に重要な関与をすることを初めて明らかにした。

Report

(3 results)
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (57 results)

All Other

All Publications (57 results)

  • [Publications] Atsumi, T., T.Hirano, et al.: "A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis"J. Exp Med.. 196. 979-990 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nishida, K., T.Hirano, et al.: "Requirement of Gab2 for mast cell development and Kitl/c-Kit signaling"Blood. 99. 1866-1869 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hirano, T.: "Revival of the autoantibody model in rheumatoid arthritis"Nature Immunology. 3. 342-344 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kinjyo I, A.Yoshimura, et al.: "SOCS1/JAB Is a Negative Regulator of LPS-Induced Macrophage Activation"Immunity. 17. 583-591 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida T, A.Yoshimura, et al.: "Activation of STAT3 by the Hepatitis C virus core protein leads to cellular transformation"J. Exp. Med.. 196. 641-653 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Flodstrom M, A.Yoshimura, et al.: "Antiviral defenses expressed by the pancreatic beta cell govern the development of type 1 diabetes after Coxsackievirus B4 infection"Nature Immunology. 3. 373-382 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Miura-Shimura, Y., S.Taki, et al.: "Clq regulatory region polymorphism down-regulating murine Clq protein levels with linkage to lupus nephritis"J. Immunol.. 169. 1334-1339 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ichii, H., S.Taki, et al.: "Role for Bcl-6 in the generation and maintenance of memory CD8+ T cells"Nature Immunology. 3. 558-563 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Taki, S.: "Type I interferons and autoimmunity : lessons from the clinic and from IRF-2-deficient mice"Cytokine Growth Factor Rev.. 13. 379-391 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Suzuki, H., T.Takatsu, et al.: "PI3K and Btk differentially regulate B cell antigen receptor-mediated signal transduction"Nature Immunology. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takatsu, K., A.Kariyone: "Immunogenic peptide for the Th1 development"Int. Immunopharmacol.. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takaki, S., K.Takatsu, et al.: "Impaired lymphopoiesis and altered B cell subpopulations in mice overexpressing Lnk adaptor protein"J. Immunol.. 170. 703-710 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takaki S, K.Takatsu, et al.: "Enhanced hematopoiesis by hematopojetic stem cells lacking intracellular adapto protein"J. Exp. Med.. 195. 151-160 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamamoto, M., K.Takeda, et al.: "Essential role for TIRAP in activation of the signaling cascade shared by TLR2 an TLR4"Nature. 420. 324-329 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamamoto, M., K.Takeda, et al.: "A novel Toll/IL-1 receptor domain-containing adaptor that preferentially activates the IFN-β promoter in the Toll-like receptor signaling"J. Immunol.. 169. 6668-6672 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sanjo, H., K.Takeda, et al.: "TAB2 is essential for prevention of apoptosis in fetal liver but not for IL-1 signaling"Mol. Cell. Blol.. (In press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Suzuki, K., A.Kumanogoh, et al.: "CD100/Sema4D, a lymphocyte semaphorin involved in the regulation of humora and cellular immune responses"Cytokine Growth Factor Rev. 14. 17-23 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kumanogoh, A., et al.: "Class TV semaphoring Sema4A enhances T cell activation and interacts with Tim-2"Nature. 419. 629-633 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kumanogoh, A., et al.: "Requirement for the lymphocyte semaphoring CD100, in the induction of antigen-specific T cells and the matuation of dendritic cells"J. Immunol.. 169. 1175-1181 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Saito K, M.Miyasaka, et al.: "Gene expression profiling of mucosal addressin cell adhesion molecule-1^+ -high endothelial venule cells (HEV) and identification of a leucine-rich HEV glycoprotein as a HEV marker"J. Immunol.. 168. 1050-1059 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kawashima H, M.Miyasaka, et al.: "Oversulfated chondroitin/dermatan sulfate containing GlcAβ1/ IdoAα-1-3GalNAc(4,6-O-disulfate) interact with L-and P-selectin and chemokines"J.Biol.Chem.. 277. 12921-12930 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Usui T, M.Miyasaka, et al.: "Characterization of mac25/angiomodulin expression by high endothelial venule cells in lymphoid tissues and its identification as an inducible marker for activated endothelial cells"Int. Immunol.. 14. 1273-1282 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kamimura, D., T.Hirano, et al.: "Tyrosine 759 of the cytokine receptor gp13O is involved in Listeria monocytogenes susceptibility"Genes and Immunity. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Nishida, K., T.Hirano, et al.: "Requirement of Gab2 for mast cell development and Kitl/c-Kit signaling"Blood. 99. 1866-1869 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Narimatsu, M., T.Hirano, et al.: "Tissue-specific autoregulation of the stat3 gene and its role in interleukin 6-induced survival signals in T cells"Mol.Cell.Biol.. 21. 6615-6625 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Flodstrom.M., A.Yoshimura, et al.: "Antiviral defenses expressed by the pancreatic beta cell govern the development of type 1 diabetes after Coxsackievirus B4 infection"Nature Immunol.. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Wakioka.T., A.Yoshimura, et al.: "Spred, a Sprouty-related suppressor of Ras signaling"Nature. 412. 647-651 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shouda.T., A.Yoshimura, et al.: "Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis 2001"J.Clin.Invest.. 108. 1781-1782 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takaki, S., K.Takatsu, et al.: "Enhanced hematopoiesis by hematopoietic stem cells lacking intracellular adaptor protein, Lnk"J.Exp.Med.. 195. 151-160 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Horikawa, K., K.Takatsu, et al.: "Essential role of signal transducer and activator of transcription (Stat) 5 for interleukin-5-dependent IgH switch recombination in mouse B cells"J.Immunol.. 167. 5018-5026 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Moon, B-G., K.Takatsu, et al.: "Functional dissection of the cytoplasmic subregions of the IL-5 receptor a chain in growth and IgG1 switch recombination of B cells"J.Immunol.. 102. 289-300 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hemmi, H., K.Takeda, et al.: "Small anti-viral compounds activate immune cells via the TLR7-MyD88-dependen signaling pathway"Nature Immunol.. 3. 196-200 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Schnare, M., K.Takeda, et al.: "Toll-like receptors control activation of adaptive immune responses"Natura Immunol.. 2. 947-950 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kumanogoh, A., H.Kikutani: "The CD1OO-CD72 interactions : a novel mechanism of immune regulation"Trends Immunol.(formerly Immunology Today). 22. 670-676 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Watanabe, C., A.Kumanogoh, et al.: "Enhanced immune responses in transgenic mice expressing a truncated form of the lymphocyte semaphorin CD100/Sema4D"J.Immunol.. 167. 4321-4328 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Wang, X., A.Kumanogoh, et al.: "Functional Soluble CD1OO/Sema4D/Sema4D Released from Activated Lymphocytes : Possible Role in Normal and Pathological Immune Responses"Blood. 97. 3498-3504 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kawashima, H., M.Miyasaka, et al.: "Oversulfated chondroitin/dermatan sulfates containing GlcAb1/IdoAa 1-3GalNAc(4,6-O-disulfate) interact with L-and P-selectin and chemokines"J.Biol.Chem.. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Hirose, J., M.Miyasaka, et al.: "Versican interacts with chemokines and modulates cellular responses"J.Biol.Chem.. 276. 5228-5234 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Saito, K., M.Miyasaka, et al.: "Gene expresson profiling of MAdCAM-1+high endothelial venule (HEV) cells and identification of a leucine-rich HEV glycoprotein as an HEVmarker"J.Immunol.. 168. 1050-1059 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Itoh,M.,and Hirano,T., et al.: "A role of Gab1 for heart, placenta, and skin development, and growth factors-and cytokines-induced ERK MAP kinase activation."Mol.Cell.Biol.. 20. 3695-3704 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohtani,T.,and Hirano,T., et al.: "Dissection of signaling cascades through gp130 in vivo : Reciprocal roles for STAT3- and SHP2-mediated signals in immune responses."Immunity. 12. 95-105 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hirano,T., et al.: "Roles of STAT3 in mediating the cell growth, differentiation, and survival signals relayed through the IL-6 family of cytokine receptors."Oncogene. 19. 2548-2556 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hibi,M.,and Hirano,T.: "Gab-family adapter molecules in signal transduction of cytokine and growth factor receptors, and T and B cell antigen receptors."Leukemia and Lymphoma. 37. 299-307 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hida,S.,and Taki,S., et al.: "CD8+ T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-a/b signaling."Immunity. 13. 643-655 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hemmi,H.,and Taki,S, et al.: "A novel Toll-like receptor that recognizes bacterial DNA."Nature. 408. 740-745 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nomura,F.,and Takeda,K., et al.: "Endotoxin tolerance in mouse peritoneal macrophages correlates with downregulation of surface Toll-like receptor 4 expression."J.Immunol.. 164. 3476-3479 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hemmi,H.,and Takeda,K., et al.: "A novel Toll-like receptor that recognizes bacterial DNA."Nature. 408. 740-745 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sato,S.,and Takeda,K., et al.: "Synergy and cross-tolerance between Toll-like receptor (TLR) 2- and TLR4-mediated signaling pathways."J.Immunol.. 165. 7096-7101 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Suzuki,A.,and Yoshimura,A., et al.: "CIS3/SOCS3/SSI3 Plays a Negative Regulatory Role in STAT3 Activation and Intestinal Inflammation."J.Exp.Med.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kamizono S,and Yoshimura,A., et al.: "The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2"J.Biol.Chem.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sasaki A,and Yoshimura,A., et al.: "CIS3/SOCS3 suppresses erythropoietin signaling by binding the EPO receptor and JAK2."J.Biol.Chem.. 275. 29338-29347 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takaki,S.,and K.Takatsu, et al.: "Control of B cell production by the adaptor protein, Lnk, a negative regulator of tyrosinekinase."Immunity. 13. 599-609 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kikuchi,Y.,and K.Takatsu, et al.: "Identification and characterization of a molecule, BAM11, that associates with the PH-domain of mouse Btk."Int.Immunol.. 12. 1397-1408 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kouro,T.,and K.Takatsu, et al.: "Brutonls tyrosine kinase (Btk) is required for CD75beta-mediated differentiation signal of pro-B to pre-B transition."Int.Immunol.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kumanogoh,A, et al.: "Increased T Cell Autoreactivity in the Absence of CD40-CD40 Ligand Interactions : A Role of CD40 in Regulatory T Cell Development."J.Immunol.. 166. 353-360 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kumanogoh,A, et al.: "Identification of CD72 as a Lymphocyte Receptor for the Class IV Semaphorin CD100 : A Novel Mechanism for Regulating B Cell Signaling."Immunity. 13. 621-631 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kumanogoh,A, et al.: "The Class IV Semaphorin CD100 Plays Nonredundant Rolse in the Immune System : Defective B and T Cell Activation in CD100-Deficient Mice."Immunity. 13. 633-642 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2018-03-28  

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