Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli

Liming Pei, Antonio Castrillo, Mingyi Chen, Alexander Hoffmann, Peter Tontonoz

Research output: Contribution to journalArticle

179 Citations (Scopus)

Abstract

Oxidized lipids and inflammatory cytokines are believed to play a causal role in atherosclerosis through the regulation of gene expression in macrophages and other cells. Previous work has implicated the nuclear receptors peroxisome proliferator-activated receptor and liver X receptor in the control of lipid-dependent gene expression and inflammation. Here we demonstrate that expression of a third group of nuclear receptors, the NR4A ligand-independent orphan receptors, is highly inducible in macrophages by diverse inflammatory stimuli. Treatment of macrophages with lipopolysaccharide (LPS), cytokines, or oxidized lipids triggers the transcriptional induction of Nur77 (NR4A1), Nurr1 (NR4A2), and NOR1 (NR4A3) expression. Several lines of evidence point to the NF-κB signaling pathway as a principal mediator of inducible NR4A expression in macrophages. Analysis of the murine and human Nur77 promoters revealed two highly conserved NF-κB response elements. Mutation of these elements inhibited LPS-dependent expression of the Nur77 promoter in transient transfection assays. Furthermore, induction of Nur77 expression by LPS was severely compromised in fibroblasts lacking the three NF-κB subunits, Nfkb1, c-Rel, and RelA. Consistent with its ability to be induced by oxidized lipids, Nur77 was expressed in macrophages within human atherosclerotic lesions. These results identified NR4A nuclear receptors as potential transcriptional mediators of inflammatory signals in activated macrophages.

Original languageEnglish (US)
Pages (from-to)29256-29262
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number32
DOIs
StatePublished - Aug 12 2005

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Orphan Nuclear Receptors
Macrophages
Cytoplasmic and Nuclear Receptors
Lipopolysaccharides
Lipids
Gene expression
Cytokines
Peroxisome Proliferator-Activated Receptors
Gene Expression Regulation
Response Elements
Fibroblasts
Liver
Transfection
Assays
Atherosclerosis
Ligands
Inflammation
Gene Expression
Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli. / Pei, Liming; Castrillo, Antonio; Chen, Mingyi; Hoffmann, Alexander; Tontonoz, Peter.

In: Journal of Biological Chemistry, Vol. 280, No. 32, 12.08.2005, p. 29256-29262.

Research output: Contribution to journalArticle

Pei, Liming ; Castrillo, Antonio ; Chen, Mingyi ; Hoffmann, Alexander ; Tontonoz, Peter. / Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 32. pp. 29256-29262.
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