Veterans Administration Research Service, White River Junction, VT 05009, USA; Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Cytokine. 2013 Oct;64(1):337-42. doi: 10.1016/j.cyto.2013.05.019. Epub 2013 Jun 14.
The macrophage is essential to the innate immune response, but also contributes to human disease by aggravating inflammation. Under severe inflammation, macrophages and other immune cells over-produce immune mediators, including vascular endothelial growth factor (VEGF). The VEGF protein stimulates macrophage activation and induces macrophage migration. A natural inhibitor of VEGF, the soluble VEGF receptor (sFlt-1) is also produced by macrophages and sFlt-1 has been used clinically to block VEGF. In macrophages, we have shown that the mRNA regulatory protein AUF1/hnRNP D represses VEGF gene expression by inhibiting translation of AURE-regulated VEGF mRNA. Peptides (AUF1-RGG peptides) that are modeled on the arginine-glycine-glycine (RGG) motif in AUF1 also block VEGF expression. This report shows that the AUF1-RGG peptides reduce two other AURE-regulated genes, TNF and GLUT1. Three alternative splice variants of sFlt-1 contain AURE in their 3'UTR, and in an apparent paradox, AUF1-RGG peptides stimulate expression of these three sFlt-1 Variants. The AUF1-RGG peptides likely act by distinct mechanisms with complimentary effects to repress VEGF gene expression and over-express the endogenous VEGF blocking agent, sFlt-1. The AUF1-RGG peptides are novel reagents that reduce VEGF and other inflammatory mediators, and may be useful tools to suppress severe inflammation.
巨噬细胞是先天免疫反应所必需的，但通过加剧炎症也会导致人类疾病。在严重的炎症中，巨噬细胞和其他免疫细胞会过度产生免疫介质，包括血管内皮生长因子 (VEGF)。VEGF 蛋白刺激巨噬细胞活化并诱导巨噬细胞迁移。VEGF 的一种天然抑制剂，可溶性 VEGF 受体 (sFlt-1) 也由巨噬细胞产生，并且 sFlt-1 已在临床上用于阻断 VEGF。在巨噬细胞中，我们已经表明，mRNA 调节蛋白 AUF1/hnRNP D 通过抑制 AURE 调节的 VEGF mRNA 的翻译来抑制 VEGF 基因表达。模拟 AUF1 中精氨酸-甘氨酸-甘氨酸 (RGG) 基序的肽 (AUF1-RGG 肽) 也可阻断 VEGF 表达。本报告表明，AUF1-RGG 肽减少了另外两个 AURE 调节的基因，TNF 和 GLUT1。sFlt-1 的三种替代剪接变体在其 3'UTR 中含有 AURE，这似乎是一个悖论，AUF1-RGG 肽刺激这三种 sFlt-1 变体的表达。AUF1-RGG 肽可能通过不同的机制发挥作用，具有互补的作用，可抑制 VEGF 基因表达并过度表达内源性 VEGF 阻断剂 sFlt-1。AUF1-RGG 肽是减少 VEGF 和其他炎症介质的新型试剂，可能是抑制严重炎症的有用工具。
