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The intracellular signal transduction of granulopoiesis

粒细胞生成的细胞内信号转导

基本信息

批准号：
11307015
负责人：
SHIMODA Kazuya
金额：
$ 24.33万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11307015/
关键词：
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

项目摘要

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.

Janus激酶（Jaks）在通过细胞因子受体的信号转导中起重要作用。Tyk 2是一种Janus激酶，我们开发了tyk 2缺陷小鼠来研究体内对tyk 2的需求。Tyk 2缺陷型小鼠未显示明显的发育异常，但它们对少量IFNα缺乏反应性，尽管即使在缺乏tyk 2的情况下，高浓度的IFNα也可以完全抑制其信号。此外，IL-12诱导的T细胞功能在这些小鼠中是有缺陷的。相比之下，这些小鼠对IL-6和IL-10的反应正常，这两种物质都在体外激活tyk 2。这些观察结果表明tyk 2在介导IFNα依赖性信号传导中仅起有限的作用，而在介导IL-12依赖性生物学应答中是必需的。与野生型小鼠的细胞相比，tyk 2缺陷小鼠的细胞中IL-12诱导的NK细胞活性显著降低。IL-18与IL-12具有相同的生物学功能。然而，IL-18信号转导的分子机制与IL-12不同，IL-18信号转导激活IL-1受体相关激酶和核因子_kB的核转位。我们接下来检查了由IL-18诱导的生物学功能是否受到tyk 2缺失的影响。由于tyk 2的缺失，IL-18诱导的NK细胞活性和IFNγ产生减少。此外，IL-12和IL-18对IFNγ产生的协同作用也因tyk 2的缺乏而消除。这部分是由于用IL-12处理的IL-18受体没有任何上调，并且这可能表明在细胞因子信号传导中Jak-Stat和MAP激酶途径之间存在串扰。