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J. Biol. Chem., Vol. 280, Issue 32, 29256-29262, August 12, 2005

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Induction of NR4A Orphan Nuclear Receptor Expression in Macrophages in Response to Inflammatory Stimuli^*

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

From the Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095 and the Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093

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-B 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-B 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-B 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.

Received for publication, March 9, 2005 , and in revised form, May 24, 2005.

^* This work was supported by Grant HL3 0568 from the National Institutes of Health and a Bristol-Myers Squibb Freedom to Discover Award in Cardiovascular Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ An investigator of the Howard Hughes Medical Institute at UCLA. To whom correspondence should be addressed: Howard Hughes Medical Institute, UCLA School of Medicine, Box 951662, Los Angeles, CA 90095-1662. Tel.: 310-206-4546; Fax: 310-267-0382; E-mail: ptontonoz{at}mednet.ucla.edu.

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