The intracellular signal transduction of granulopoiesis

Janus激酶（Jaks）在细胞因子受体的信号转导中起重要作用。Tyk2是一种Janus激酶，我们建立了Tyk2缺陷小鼠来研究体内对Tyk2的需求。tyk2缺陷小鼠没有表现出明显的发育异常，但是它们对少量IFNα缺乏反应性，尽管高浓度IFNα即使在缺乏tyk2的情况下也能完全转导其信号。此外，il -12诱导的T细胞功能在这些小鼠中存在缺陷。相比之下，这些小鼠对IL-6和IL-10的反应正常，这两种物质在体外激活tyk2。这些观察结果表明，tyk2在介导ifn α依赖性信号传导中只发挥有限的作用，而在介导IL-12依赖性生物反应中则是必需的。接下来，我们研究了IL-12诱导的NK细胞活性是否需要tyk2，因为IL-12是NK细胞介导的细胞毒性的刺激因子，与野生型小鼠的细胞相比，IL-12诱导的NK细胞活性在缺乏tyk2的小鼠细胞中急剧降低。IL-18与IL-12具有相同的生物学功能。然而，IL-18信号通路激活1L-1受体相关激酶和核因子_kB核易位的分子机制与IL-12不同。接下来，我们研究了IL-18诱导的生物学功能是否受到tyk2缺失的影响。缺乏tyk2可降低IL-18诱导的NK细胞活性和IFNγ的产生。此外，由于缺乏tyk2， IL-12和IL-18对IFNγ产生的协同作用也被取消了。这部分是由于IL-12处理后IL-18受体没有任何上调，这可能表明在细胞因子信号传导中存在Jak-Stat和MAP激酶途径之间的串扰。

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.