Down-modulation of type 1 interferon responses by receptor cross-competition for a shared Jak kinase
Down-modulation of type 1 interferon responses by receptor cross-competition for a shared Jak kinase
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DOI：
10.1074/jbc.m104316200
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发表时间：
2001-12-14
影响因子：
4.8
通讯作者：
Tavernier, J
中科院分区：
文献类型：
--
作者：
Dondi, E;Pattyn, E;Tavernier, J
与大量的I类和II类细胞因子受体相反，只有四种Janus激酶（Jak）蛋白在哺乳动物细胞中表达，这意味着许多不同的受体复合物共同使用这些激酶。因此，如果受体数量超过可用Jak的量，则可以预期交叉干扰模式。我们设计了两个模型细胞系统，表达两种不同的外源Tyk 2相互作用受体。产生受体嵌合体，其中干扰素-α/β受体的干扰素1型受体（Ifnar 1）组分的细胞外部分被促红细胞生成素受体的等同结构域取代。尽管Tyk 2激活，促红细胞生成素治疗表达这种促红细胞生成素受体/Ifnar 1嵌合体的细胞没有引起任何可检测的IFN-型反应。然而，通过内源性Ifnar复合物对信号转导的剂量依赖性干扰被发现用于STAT 1、STAT 2、STAT 3、Tyk 2和Jak 1活化、基因诱导和抗病毒活性。在类似的方法中，表达白细胞介素-12受体β 1链的细胞显示出对IFN-α的转录应答降低以及STAT和激酶活化降低。在这两个模型系统中，Tyk 2激酶滴定远离Ifnar 1受体链解释了观察到的交叉干扰。
In contrast to the large number of class I and II cytokine receptors, only four Janus kinase (Jak) proteins are expressed in mammalian cells, implying the shared use of these kinases by many different receptor complexes. Consequently, if receptor numbers exceed the amount of available Jak, cross-interference patterns can be expected. We have engineered two model cellular systems expressing two different exogenous Tyk2-interacting receptors. A receptor chimera was generated wherein the extracellular part of the interferon type 1 receptor (Ifnar1) component of the interferon-alpha/beta receptor is replaced by the equivalent domain of the erythropoietin receptor. Despite Tyk2 activation, erythropoietin treatment of cells expressing this erythropoietin receptor/Ifnar1 chimera did not evoke any detectable IFN-type response. However, a dose-dependent interference with signal transduction via the endogenous Ifnar complex was found for STAT1, STAT2, STAT3, Tyk2, and Jak1 activation, for gene induction, and for antiviral activity. In a similar approach, cells expressing the beta1 chain of the interleukin-12 receptor showed a reduced transcriptional response to IFN-alpha as well as reduced STAT and kinase activation. In both model systems, titration of the Tyk2 kinase away from the Ifnar1 receptor chain accounts for the observed cross-interference.