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Submitted on August 15, 2005
Accepted on November 30, 2005
Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095
* To whom correspondence should be addressed. E-mail: ptontonoz{at}mednet.ucla.edu.
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 PPAR and LXR inhibit NF-
B signaling and inflammatory gene expression. We recently identified the NR4A subfamily of orphan nuclear receptors (Nur77/NR4A1, Nurr1/NR4A2 and NOR1/NR4A3) as LPS- and NF-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 PPAR and LXR, the role of NR4A receptors in macrophages is pro-inflammatory. 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
, an important component of the NF-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 LPS. These results identify a new role for NR4A orphan nuclear receptors in the control of macrophage gene expression during inflammation.
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