Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77
Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77
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DOI：
10.1210/me.2005-0331
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发表时间：
2006-04-01
影响因子：
--
通讯作者：
Tontonoz, P
中科院分区：
文献类型：
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作者：
Pei, LM;Castrillo, A;Tontonoz, P
核激素受体超家族的成员已经成为炎症和疾病中巨噬细胞基因表达的重要调节因子。既往研究表明，脂质活化受体过氧化物酶体增殖物活化受体和肝脏X受体抑制核因子κ B （nf - κ B）信号传导和炎症基因表达。我们最近发现孤儿核受体NR4A亚家族（Nur77/ NR4A1， Nurr1/NR4A2和NOR1/NR4A3）在巨噬细胞中作为脂多糖和nf - κ b应答基因。然而，这些转录因子在巨噬细胞基因表达中的作用尚不清楚。我们在这里证明，与过氧化物酶体增殖激活受体和肝脏X受体相比，NR4A受体在巨噬细胞中的作用是促炎的。巨噬细胞中逆转录病毒Nur77的表达可导致多个参与炎症、凋亡和细胞周期控制的基因的转录激活。一个特别有趣的nur77应答基因是诱导激酶IKKi/IKK epsilon，它是NF-kappa B信号通路的重要组成部分。IKKi启动子包含一个功能性NR4A结合位点，并在瞬时转染试验中被所有三种NR4A受体激活。与IKKi的激活一致，巨噬细胞中Nur77的表达增强了脂多糖对炎症基因表达的诱导。这些结果确定了NR4A孤儿核受体在炎症过程中控制巨噬细胞基因表达的新作用。
Members of the nuclear hormone receptor superfamily have emerged as important regulators of macrophage gene expression in inflammation and disease. Previous studies have shown that the lipid-activated receptors peroxisomal proliferator-activated receptor and liver X receptor inhibit nuclear factor-kappa B (NF-kappa B) signaling and inflammatory gene expression. We recently identified the NR4A subfamily of orphan nuclear receptors ( Nur77/ NR4A1, Nurr1/NR4A2, and NOR1/NR4A3) as lipopolysaccharide- and NF-kappa B-responsive genes in macrophages. However, the role of these transcription factors in macrophage gene expression is unknown. We demonstrate here that, in contrast to peroxisomal proliferator-activated receptor and liver X receptor, the role of NR4A receptors in macrophages is proinflammatory. Retroviral expression of Nur77 in macrophages leads to the transcriptional activation of multiple genes involved in inflammation, apoptosis, and cell cycle control. One particularly interesting Nur77-responsive gene is the inducible kinase IKKi/IKK epsilon, an important component of the NF-kappa B signaling pathway. The IKKi promoter contains a functional NR4A binding site and is activated by all three NR4A receptors in transient transfection assays. Consistent with the activation of IKKi, expression of Nur77 in macrophages potentiates the induction of inflammatory gene expression in response to lipopolysaccharide. These results identify a new role for NR4A orphan nuclear receptors in the control of macrophage gene expression during inflammation.