| Project/Area Number |
11307015
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
SHIMODA Kazuya (2001) School of Medicine, University Hospital, Kyushu University, Associate Professor, 医学部・附属病院, 助手 (90311844)
岡村 孝 (2000) 九州大学, 医学部・附属病院, 講師 (30136436)
仁保 喜之 (1999) 九州大学, 大学院・医学系研究科, 教授 (60091287)
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| Co-Investigator(Kenkyū-buntansha) |
OKAMURA Takashi Kurume University, Faculty of Medicine, Assist Professor, 医学部, 助教授 (30136436)
GONDO Hisashi School of Medicine, University Hospital, Kyushu University, Associate Professor, 医学部・附属病院, 助手 (10253428)
下田 和哉 九州大学, 医学部・附属病院, 助手 (90311844)
浅野 嘉延 九州大学, 医学部・附属病院, 助手 (60271110)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥38,010,000 (Direct Cost: ¥36,000,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2001: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2000: ¥10,100,000 (Direct Cost: ¥10,100,000)
Fiscal Year 1999: ¥19,200,000 (Direct Cost: ¥19,200,000)
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| Keywords | Tyk2 / G-CSF / TPO / IL-12 / IL-18 / Jak kinase / Jakキナ-ゼ / IFN α / 好中球 / 細胞内情報伝達 / 分化 / Stat |
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| Research Abstract |
Janus kinases (Jaks) play an important role in signal transduction via cytokine receptors. Tyk2 is a Janus kinase, and we developed tyk2-deficient mice to study the requirement for tyk2 in vivo. Tyk2-deficient mice show no overt developmental abnormalities, however they display a lack of responsiveness to a small amount of IFNα, although a high concentration of IFNα can fully transduce its signal even in the absence of tyk2. Furthermore, IL-12-induced T cell function is defective in these mice. In contrast, these mice respond normally to IL-6 and IL-10 both of which activate tyk2 in vitro. These observations demonstrate that tyk2 plays only a restricted role in mediating IFNα-dependent signaling, whilst being required in mediating IL-12- dependent biological responses.
Next we examined whether tyk2 is required for IL-12-induced NK cell activity, as IL-12 is a stimulatory factor for NK cell-mediated cytotoxicity, IL-12-induced NK cell activity in cells from tyk2-deficient mice was drastically reduced compared to that in cells from wild-type mice. IL-18 shares its biological functions with IL-12. However, the molecular mechanism of IL-18 signaling, which activates an 1L-1 receptor-associated kinase and nuclear translocation of nuclear factor _kB, is different from that of IL-12. We next examined whether biological functions induced by IL-18 are affected by the absence of tyk2. NK cell activity and IFNγ production induced by IL-18 were reduced by the absence of tyk2. Moreover the synergistic effect of IL-12 and IL-18 for the production of IFNγ was also abrogated by the absence of tyk2. This was partially due to the absence of any up-regulation of the IL-18 receptor treated with IL-12, and it might suggest the presence of the cross-talk between Jak-Stat and MAP kinase pathways in cytokine signaling.
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