2001 Fiscal Year Final Research Report Summary
The intracellular signal transduction of granulopoiesis
| 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 School of Medicine, University Hospital, Kyushu University, Associate Professor, 医学部・附属病院, 助手 (90311844)
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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)
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| Project Period (FY) |
1999 – 2001
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| Keywords | Tyk2 / G-CSF / TPO / IL-12 / IL-18 / Jak kinase |
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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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