title: Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli.
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-kappaB 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-kappaB 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-kappaB 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.
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Pei
authors.forename: Antonio
authors.initials: A
authors.lastname: Castrillo
authors.forename: Mingyi
authors.initials: M
authors.lastname: Chen
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D000818:Animals; D001161:Arteriosclerosis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D017124:Conserved Sequence; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008024:Ligands; D050356:Lipid Metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D057093:Orphan Nuclear Receptors; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000096:biosynthesis*; D020218:Response Elements; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D016328:NF-kappa B; C539821:NR4A1 protein, human; C539882:NR4A2 protein, human; C490412:NR4A3 protein, human; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C539883:Nr4a2 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors; D012313:RNA; D010100:Oxygen