サイトカイン、接着分子の情報伝達制御

• Project/Area Number: 12051225
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka 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: ¥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。

Research Products

• [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)
• [Publications] Nishida, K., T.Hirano, et al.: "Requirement of Gab2 for mast cell development and Kitl/c-Kit signaling"Blood. 99. 1866-1869 (2002)
• [Publications] Hirano, T.: "Revival of the autoantibody model in rheumatoid arthritis"Nature Immunology. 3. 342-344 (2002)
• [Publications] Kinjyo I, A.Yoshimura, et al.: "SOCS1/JAB Is a Negative Regulator of LPS-Induced Macrophage Activation"Immunity. 17. 583-591 (2002)
• [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)
• [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)
• [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)
• [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)
• [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)
• [Publications] Suzuki, H., T.Takatsu, et al.: "PI3K and Btk differentially regulate B cell antigen receptor-mediated signal transduction"Nature Immunology. (in press). (2003)
• [Publications] Takatsu, K., A.Kariyone: "Immunogenic peptide for the Th1 development"Int. Immunopharmacol.. (In press). (2003)
• [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)
• [Publications] Takaki S, K.Takatsu, et al.: "Enhanced hematopoiesis by hematopojetic stem cells lacking intracellular adapto protein"J. Exp. Med.. 195. 151-160 (2002)
• [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)
• [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)
• [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).
• [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)
• [Publications] Kumanogoh, A., et al.: "Class TV semaphoring Sema4A enhances T cell activation and interacts with Tim-2"Nature. 419. 629-633 (2002)
• [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)
• [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)
• [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)
• [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)
• [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).
• [Publications] Nishida, K., T.Hirano, et al.: "Requirement of Gab2 for mast cell development and Kitl/c-Kit signaling"Blood. 99. 1866-1869 (2002)
• [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)
• [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).
• [Publications] Wakioka.T., A.Yoshimura, et al.: "Spred, a Sprouty-related suppressor of Ras signaling"Nature. 412. 647-651 (2001)
• [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)
• [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)
• [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)
• [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)
• [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)
• [Publications] Schnare, M., K.Takeda, et al.: "Toll-like receptors control activation of adaptive immune responses"Natura Immunol.. 2. 947-950 (2001)
• [Publications] Kumanogoh, A., H.Kikutani: "The CD1OO-CD72 interactions : a novel mechanism of immune regulation"Trends Immunol.(formerly Immunology Today). 22. 670-676 (2001)
• [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)
• [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)
• [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).
• [Publications] Hirose, J., M.Miyasaka, et al.: "Versican interacts with chemokines and modulates cellular responses"J.Biol.Chem.. 276. 5228-5234 (2001)
• [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)
• [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)
• [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)
• [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)
• [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)
• [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)
• [Publications] Hemmi,H.,and Taki,S, et al.: "A novel Toll-like receptor that recognizes bacterial DNA."Nature. 408. 740-745 (2000)
• [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)
• [Publications] Hemmi,H.,and Takeda,K., et al.: "A novel Toll-like receptor that recognizes bacterial DNA."Nature. 408. 740-745 (2000)
• [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)
• [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)
• [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)
• [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)
• [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)
• [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)
• [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)
• [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)
• [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)
• [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)