Abstract
BackgroundNur77 is an orphan nuclear receptor expressed in human atheroma. In vascular cells in vitro, Nur77 expression is induced by pro-inflammatory factors, such as oxidized LDL (oxLDL).MethodsWe analyze the role of Nur77 in the oxLDL-induced differentiation of macrophages into dendritic cells (DC). The murine RAW264.7 macrophage cell line was stably transfected with expression plasmids encoding either GFP or GFP fusions with either full-length Nur77 (GFP-Nur77), Nur77 lacking the DNA binding domain (GFP-Nur77-ΔDBD) or Nur77 lacking the transactivation domain (GFP-Nur77-ΔTAD).ResultsGFP-Nur77 overexpression significantly suppressed the effect of oxLDL treatment on DC morphologic changes, expression of DC maturation markers, endocytic activity, allogeneic activation of T cell proliferation, and the activity and secretion of pro-inflammatory cytokines. Analysis of GFP-Nur77-ΔTAD and GFP-Nur77-ΔDBD indicated that the Nur77 DNA binding and transactivation domains were both required for this effect. GFP-Nur77-ΔDBD consistently had the opposite effect to GFP-Nur77, increasing DC-type differentiation in all assays. Interestingly, GFP-Nur77-ΔDBD protein was cytosolic, whereas GFP-Nur77 and GFP-Nur77-ΔTAD were both nuclear.ConclusionsThese data show that GFP-Nur77 inhibited differentiation of oxLDL-treated macrophages into DC. The effects of Nur77 on the macrophage phenotype may involve changes in its subcellular distribution.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-014-0054-z) contains supplementary material, which is available to authorized users.
Highlights
Nur77 is an orphan nuclear receptor expressed in human atheroma
We show that overexpression of Nur77 significantly inhibited the differentiation into dendritic cells (DC) of the RAW264.7 macrophage cells exposed to oxidized LDL (oxLDL)
Establishment of stable RAW264.7 cell lines expressing GFP-Nur77 and GFP-Nur77 deletion mutants We have shown previously that macrophages exposed to oxLDL in vitro differentiate into mature DC
Summary
In vascular cells in vitro, Nur expression is induced by pro-inflammatory factors, such as oxidized LDL (oxLDL). Atherosclerosis is a chronic inflammatory disease of the arterial wall. The immune and inflammatory actions of monocytes/macrophages play an important role in this disease [1,2,3]. The orphan nuclear receptor Nur, known as NR4A1, NGFI-B or TR3, is a member of the steroid/thyroid hormone nuclear receptor superfamily, and was first identified as an early response gene to growth factor stimulation. These nuclear receptors are all transcription factors characterized by three main functional domains:
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