| Project/Area Number |
01065005
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| Research Category |
Grant-in-Aid for Specially Promoted Research
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| Allocation Type | Single-year Grants |
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| Research Institution | Osaka University |
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Principal Investigator |
KISHIMOTO Tadamitsu Osaka Univ. Med. Sch., Prof., 医学部, 教授 (10093402)
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| Co-Investigator(Kenkyū-buntansha) |
TAGA Tetsuya Inst. Molec. Cell. Biol., Osaka Univ., Ass. Prof., 細胞生体工学センター, 助手 (40192629)
AKIRA Shizuo Inst. Molec. Cell. Biol., Osaka Univ., Ass. Prof., 細胞生体工学センター, 助手 (50192919)
KIKUTANI Hitoshi Inst. Molec. Cell. Biol., Osaka Univ., Ass. Prof., 細胞生体工学センター, 助教授 (80161412)
平野 俊夫 大阪大学, 医学部, 教授 (40136718)
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| Project Period (FY) |
1989 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥213,000,000 (Direct Cost: ¥213,000,000)
Fiscal Year 1992: ¥46,000,000 (Direct Cost: ¥46,000,000)
Fiscal Year 1991: ¥45,000,000 (Direct Cost: ¥45,000,000)
Fiscal Year 1990: ¥45,000,000 (Direct Cost: ¥45,000,000)
Fiscal Year 1989: ¥77,000,000 (Direct Cost: ¥77,000,000)
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| Keywords | autoimmune disease / myeloma / acute phase reactions / cytokine / interleukin 6 / receptor / signal transduction / nuclear factor / タイロシンカイネース / MAPカイネース / ras / NF-IL6 / インタ-ロイキン6(ILー6) / ILー6レセプタ- / ILー6シグナル伝達分子(gp130) / NFーIL6 / NFーIL6β, / プラスマサイト-マ / 自己β細胞特異Tリンパ球 / FcεRIIaとFcεRIIb / インタ-ロイキン6レセプタ-(ILー6R) / シグナル伝達分子(gp130) / ILー6転写調節因子(NFーILー6) / 急性期蛋白 / ILー6トランスジェニックマウス / I型糖尿病 / plasmacytoma / インターロイキン6(ILー6) / ILー6レセプター / シグナルトランスデューサー(gp130) / ILー6トランスゲニックマウス / NFーILー6 / FcεRII / NODマウス |
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| Research Abstract |
Our research project supported by this special grant has aimed to molecularly dissect the immune system, especially focusing on interleukin-6(IL-6). One of the major achievements was finding of IL-6- signal transducer,gp130. We demonstrated that gp130 is utilized as a signal transducer also for several other cytokines functioning in immune, hematopoietic, neuronal, and developmental systems. Presence of the shared signal transducer like gp130 clearly explains functional redundancy of the cytokines.
From our paraclinical work, it becomes clear that dysregulated overexpression of IL-6 is involved in the pathogenesis of various diseases, e.g. multiple myeloma, Castleman's disease, and AIDS-related Kaposi's sarcoma. Furthermore, we generated monoclonal plasmacytoma with (12;15) chromosomal translocation in the IL-6 transgenic mice of Balb/c strain. To understand how overexpression of IL-6 in the IL-6-related diseases occurrs, regulation of IL-6 gene expression has been studied. We cloned th
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e nuclear factors NF-IL6 and its relative, NF-IL6beta,that are involved in the IL-6 gene expression. We found that these two molecules are able to form heterodimers, functionally synergizing one another. Interactions between NF-IL6 and NF-kappaB as well as Tax of HTLV-1 were shown to synergistically. contribute to the activation of the IL-6 promoter. We also demonstrated interaction between NF-IL6 and glucocorticoid receptor. These results have provided a clue for intervention of IL-6-related diseases.
Since NF-IL6 is responsible also for the regulation of IL-6-inducible acute phase protein genes, we have studied signaling processes of IL-6 in hepatocytes. We have found that IL-6-stimulation induces homodimerization of gp130 and associated tyrosine kinase activation which is followed by initiation of Ras-MAP kinase signaling cascades. This eventually results in the MAP kinase-dependent phosphorylation of Thr^<235> in NF-IL6,the critical step for its transcriptional activation.
In view of the molecular dissection of autoimmune diseases, we generated multiple sclerosis (MS)- like pathology in mice by transferring mononuclear cells from the MS patient's cerebrospinal fluid into brains of SCID mice. This achievement will provide an animal model for the study of MS.
From the above results together with our other achievements documented in the attached detailed report,it can be concluded that our research activities supported by this special grant are fruitful and have provided a basis for closer understanding of, and also future clinical approach to, the immune disorders. Less
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