IL-17 enhances chemokine gene expression through mRNA stabilization
IL-17 enhances chemokine gene expression through mRNA stabilization
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DOI：
10.4049/jimmunol.179.6.4135
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发表时间：
2007-09-15
影响因子：
4.4
通讯作者：
Hamilton, Thomas
中科院分区：
文献类型：
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作者：
Hartupee, Justin;Liu, Caini;Hamilton, Thomas
IL-17通过诱导促炎基因表达在宿主防御和自身免疫中起重要作用，特别是与TNF-α组合。IL-17调节这种表达的分子机制还不清楚。使用小鼠趋化因子CXCL 1（KC）基因作为模型，我们已经研究了IL-17单独或与TNF-α的组合对转录和转录后事件的影响。虽然单独用IL-17处理小鼠胚胎成纤维细胞仅适度增加KC表达，但IL-17与TNF-α的组合诱导协同反应。IL-17处理通过延长高度不稳定的TNF-α诱导的KC mRNA的t（1/2）来发挥强大的转录后效应。在HeLa细胞中使用四环素调节的转基因，我们确定了在TNF-α不存在的情况下单独的IL-17处理促进KC mRNA的稳定。IL-17处理对KC转录或NF-κ B活化几乎没有影响，表明它主要在转录后起作用。我们鉴定了许多其他mRNA，其t（1/2）响应于IL-17而延长，这表明这是IL-17促进增强的基因表达的常见机制。最后，NF-κ B1蛋白（Act 1）的激活剂（最近与IL-17信号传导有关的衔接蛋白）对于IL-17诱导的稳定是必需的，并且Act 1的过表达导致KC mRNA的稳定，这表明Act 1下游的事件足以启动这一过程。因此，TNF-α和IL-17之间的协同作用反映了它们对KC基因表达的独立作用; TNF-α通过激活NF-κ B作为启动转录的刺激物，而IL-17通过Act 1依赖性途径驱动mRNA稳定。
IL-17 plays an important role in host defense and autoimmunity via the induction of proinflammatory gene expression, particularly in combination with TNF-alpha. The molecular mechanisms by which IL-17 regulates such expression are not well understood. Using the mouse chemokine CXCL1 (KC) gene as a model, we have examined the effects of IL-17 alone or in combination with TNF-a on transcriptional and posttranscriptional events. Although treatment of mouse embryonic fibroblasts with IL-17 alone only modestly increased KC expression, the combination of IL-17 with TNF-a induced a synergistic response. IL-17 treatment exerted a strong posttranscriptional effect by extending the t(1/2) of the highly unstable, TNF-alpha-induced KC mRNA. Using a tetracycline-regulated transgene in HeLa cells, we determined that IL-17 treatment alone promoted stabilization of KC mRNA in the absence of TNF-a. IL-17 treatment exerted little effect on KC transcription or NF-kappa B activation, suggesting that it primarily acts posttranscriptionally. We identified a number of other mRNAs whose t(1/2) are prolonged in response to IL-17, suggesting that this is a common mechanism by which IL-17 promotes enhanced gene expression. Finally, activator of NF-kappa B1 protein (Act1), an adaptor protein recently implicated in IL-17 signaling, was necessary for IL-17-induced stabilization, and overexpression of Act1 resulted in stabilization of KC mRNA, indicating that events downstream of Act1 are sufficient to initiate this process. Thus, the synergy between TNF-a and IL-17 reflects their independent actions on KC gene expression; TNF-a serves as a stimulus to initiate transcription through activation of NF-kappa B, whereas IL-17 drives mRNA stabilization through an Act1-dependent pathway.