2000 Fiscal Year Annual Research Report

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 (A)
Research Institution	Osaka University
Principal Investigator	平野俊夫大阪大学, 医学系研究科, 教授 (40136718)
Co-Investigator(Kenkyū-buntansha)	吉村昭彦久留米大学, 分子生命科学研究所, 教授 (90182815) 竹田潔大阪大学, 微生物病研究所, 助手 (20309446) 瀧伸介千葉大学, 医学系研究科, 助教授 (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)
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Gp130のSHP2結合サイトの点突然変異を導入した変異gp130を発現しているノッインマウス(平成11年度に作製)が、加齢とともに自己免疫性の関節炎を自然発症することを明らかにした。この関節炎は発症マウスの脾臓細胞を正常マウスに移入することにより発症させることが可能であることが明らかとなった。樹状細胞、T細胞に異常を認めており、なぜサイトカインのシグナル異常により、自己免疫疾患が発症するかを解明する非常に良いモデルになりうる。瀧は転写因子IRF-2欠損マウスに自然発症する炎症性皮膚疾の原因遺伝子の同定を目指しており、本年は、1〜数個の優性なBALB遺伝子が、IRF-2欠損マウスの皮膚炎の発症を抑制していることを明かにした。吉村はリウマチや慢性炎症性大腸疾患などの炎症性疾患でCIS3がJAK/STAT経路の抑制を介して炎症の終結をもたらす重要な役割を果たしていることを明らかにした。高津は、Lnkはシグナル伝達の抑制分子として働くアダプター蛋白質ファミリーの一員であることを明らかにした。またIL-5/CD38のシグナル伝達に必須である、Btk会合分子としてBAM11を単離同定するとともに、Btkがpro-Bからpre-B細胞への分化に必須であることを明らかにした。竹田はTLR9遺伝子欠損マウスを作製し、TLR9が、細菌に特有の非メチル化CpGモチーフを含むDNA(CpG DNA)の認識に必須であることを明らかにした。熊ノ郷はリンパ球セマフォリン分子CD100が神経系や腎臓においてはplexinB-1を、免疫系においてはCD72をレセプターとして用いていることを明かにした。さらに、CD100刺激がリンパ球上のレセプターであるCD72のネガティブシグナルを解除することにより免疫反応を増強することを示した。

Research Products

(18 results)

All Other

All Publications (18 results)

[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)

2000 Fiscal Year Annual Research Report

サイトカイン、接着分子の情報伝達制御

Principal Investigator

平野 俊夫 大阪大学, 医学系研究科, 教授 (40136718)

Research Products

[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)

平野俊夫大阪大学, 医学系研究科, 教授 (40136718)