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Regulation of Macrophage Inflammatory Gene Expression by the Orphan Nuclear Receptor Nur77
- Source :
- Molecular Endocrinology. 20:786-794
- Publication Year :
- 2006
- Publisher :
- The Endocrine Society, 2006.
-
Abstract
- 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 peroxisomal proliferator-activated receptor and liver X receptor inhibit nuclear factor-κB (NF-κB) signaling and inflammatory gene expression. We recently identified the NR4A subfamily of orphan nuclear receptors (Nur77/NR4A1, Nurr1/NR4A2, and NOR1/NR4A3) as lipopolysaccharide- and NF-κB-responsive genes in macrophages. However, the role of these transcription factors in macrophage gene expression is unknown. We demonstrate here that, in contrast to peroxisomal proliferator-activated receptor and liver X receptor, the role of NR4A receptors in macrophages is proinflammatory. 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/IKKε, an important component of the NF-κB 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 lipopolysaccharide. These results identify a new role for NR4A orphan nuclear receptors in the control of macrophage gene expression during inflammation.
- Subjects :
- Receptors, Steroid
Nerve growth factor IB
Receptors, Cytoplasmic and Nuclear
Protein Serine-Threonine Kinases
Biology
Transfection
Cell Line
Mice
Liver X receptor beta
Endocrinology
Nuclear Receptor Subfamily 4, Group A, Member 1
Animals
Promoter Regions, Genetic
Molecular Biology
Nuclear receptor co-repressor 1
Oligonucleotide Array Sequence Analysis
Inflammation
Gene Expression Profiling
Macrophages
Liver receptor homolog-1
Liver X receptor alpha
General Medicine
Recombinant Proteins
I-kappa B Kinase
Neuron-derived orphan receptor 1
DNA-Binding Proteins
Gene Expression Regulation
ROR1
Cancer research
Estrogen-related receptor gamma
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 19449917 and 08888809
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Molecular Endocrinology
- Accession number :
- edsair.doi.dedup.....f59f8f353bdf6b6346c7c6a0c3675d5d