Fra-1 negatively regulates lipopolysaccharide-mediated inflammatory responses
Fra-1 negatively regulates lipopolysaccharide-mediated inflammatory responses
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DOI：
10.1093/intimm/dxp015
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发表时间：
2009-04-01
影响因子：
4.4
通讯作者：
Takeda, Kiyoshi
中科院分区：
文献类型：
--
作者：
Morishita, Hideaki;Saito, Fumiji;Takeda, Kiyoshi
巨噬细胞受到Toll样受体配体--脂多糖的刺激，促进了基因表达。激活蛋白-1(AP-1)转录因子家族介导这些反应。然而，作为AP-1家族的一员，c-Fos被证明能抑制内毒素诱导的巨噬细胞基因表达。在这项研究中，我们分析了转录因子AP-1家族的另一个成员Fos相关抗原-1(Fra-1)在脂多糖诱导RAW264.7巨噬细胞反应中的作用。与c-Fos相比，FRA-1在内毒素刺激的巨噬细胞中的诱导具有延迟的时间动力学。慢病毒导入Fra-1可在蛋白和mRNA水平阻断内毒素诱导的促炎介质的表达。缺少异源二聚体形成和DNA结合所需的基本亮氨酸拉链结构域的Fra-1突变体不抑制内毒素诱导的反应。在内毒素刺激的巨噬细胞中，c-Fos早期结合到AP-1结合部位，但后来被Fra-1取代。在内毒素刺激后的早期，Fra-1的过表达诱导其与Jun蛋白的结合和稳定的DNA结合。这些结果表明，Fra-1通过与AP-1结合部位来抑制内毒素诱导的mRNA表达。RNAi介导的RAW264.7巨噬细胞中Fra-1的敲除导致了内毒素诱导的一组基因表达的增强。因此，像c-Fos一样，Fra-1负性调节RAW264.7巨噬细胞的内毒素诱导的反应。
Stimulation of macrophages with a Toll-like receptor ligand, LPS, facilitates gene expression. The activator protein-1 (AP-1) family of transcription factors mediates these responses. However, c-Fos, a member of the AP-1 family, has been shown to inhibit LPS-induced gene expression in macrophages. In this study, we analyzed the role of Fos-related antigen-1 (Fra-1), another member of the AP-1 family of transcription factors, in LPS-induced responses in RAW264.7 macrophages. Fra-1 was induced in LPS-stimulated macrophages with delayed time kinetics compared with c-Fos. Lentiviral introduction of Fra-1 blocked LPS-induced expression of pro-inflammatory mediators at the protein and mRNA levels. A Fra-1 mutant, which lacks the basic leucine zipper domain required for heterodimer formation and DNA binding, did not inhibit LPS-induced responses. c-Fos bound to the AP-1-binding site early, but afterward it was replaced by Fra-1 in LPS-stimulated macrophages. Over-expression of Fra-1 induced its association with Jun proteins and stable DNA binding from an early time point following LPS stimulation. These findings indicate that Fra-1 suppresses LPS-induced mRNA expression by binding to the AP-1-binding site. RNAi-mediated knockdown of Fra-1 in RAW264.7 macrophages resulted in enhanced LPS-induced expression of a subset of genes. Thus, like c-Fos, Fra-1 negatively regulates LPS-induced responses in RAW264.7 macrophages.