Interleukin-13 is a potent activator of JAK3 and STAT6 in cells expressing interleukin-2 receptor-γ and interleukin-4 receptor-α
Interleukin-13 is a potent activator of JAK3 and STAT6 in cells expressing interleukin-2 receptor-γ and interleukin-4 receptor-α
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Interleukin-13 是表达 IL-2 受体-γ 和 IL-4 受体-α 的细胞中 JAK3 和 STAT6 的有效激活剂
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发表时间：
1996
期刊：
影响因子：
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通讯作者：
R. Kirken
中科院分区：
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作者：
M. G. Malabarba;H. Rui;H. Deutsch;Johanna Chung;F. Kalthoff;W. Farrar;R. Kirken
淋巴细胞生长因子白介素-2 （IL2）、IL4、IL7、IL9和IL15利用共同的IL2受体-γ (IL2Rγ)激活IL2Rγ相关酪氨酸激酶JAK3 （Janus激酶3）。IL13在结构上与IL4相关，与IL4竞争结合到细胞表面受体，并表现出许多类似的生物学效应。IL4和IL13之间这种功能重叠的分子基础主要归因于共同使用140 kDa的IL4Rα，因为这些细胞因子似乎有独特的不同，根据最近的几篇报道，IL13不招募IL2Rγ或JAK3。在某些缺乏IL2Rγ的IL13应答细胞系中发现了一种新的70 kDa的IL13受体，这一观点得到了支持。本研究首次证明，在同时表达IL2Rγ和IL4Rα的细胞中，IL13可以模拟IL4诱导的IL2Rγ和IL4Rα的异源二聚化，从而显著激活JAK3和转录因子STAT6 (IL4- stat)，从而为IL13和IL4之间的功能重叠问题提供了新的视角。BA/F3细胞的重组实验表明，这两种细胞因子需要同时存在IL4Rα和IL2Rγ来介导JAK3和增殖反应，对12种IL4Rα变异的分析表明，IL4和IL13信号同样受到细胞质结构域突变的影响。我们得出结论，IL13在适当的细胞类型中激活il2r γ相关的JAK3酪氨酸激酶，并提出IL13能够以细胞依赖性和组合方式与多个受体亚基相互作用。因此，我们预测IL13信号转导的部分中断也有助于与IL2Rγ或JAK3基因失活相关的严重联合免疫缺陷综合征。
The lymphocyte growth factors interleukin-2 (IL2), IL4, IL7, IL9 and IL15 use the common IL2 receptor-γ (IL2Rγ) and activate the IL2Rγ-associated tyrosine kinase JAK3 (Janus kinase 3). IL13 is structurally related to IL4, competes with IL4 for binding to cell surface receptors and exhibits many similar biological effects. The molecular basis for this functional overlap between IL4 and IL13 has been attributed mainly to a shared use of the 140 kDa IL4Rα, since these cytokines appear to be uniquely different in that, according to several recent reports, IL13 does not recruit the IL2Rγ or JAK3. This notion has been supported by the identification of a novel 70 kDa IL13 receptor in certain IL13-responsive cell lines that lack IL2Rγ. The present study sheds new light on the issue of functional overlap between IL13 and IL4, by demonstrating for the first time that, in cells that express both IL2Rγ and IL4Rα, IL13 can mimic IL4-induced heterodimerization of IL2Rγ and IL4Rα, with consequent marked activation of JAK3 and the transcription factor STAT6 (IL4-STAT). Reconstitution experiments in BA/F3 cells showed that both cytokines require the simultaneous presence of IL4Rα and IL2Rγ to mediate JAK3 and proliferative responses, and analysis of 12 IL4Rα variants showed that IL4 and IL13 signals were equally affected by mutations of the cytoplasmic domain. We conclude that IL13 activates the IL2Rγ-associated JAK3 tyrosine kinase in appropriate cell types, and propose that IL13 is capable of interacting with multiple receptor subunits in a cell-dependent and combinatorial manner. Consequently, we predict that partial disruption of IL13 signal transduction also contributes to the severe combined immunodeficiency syndromes associated with inactivation of the IL2Rγ or JAK3 genes.