The orphan nuclear receptor ROR alpha is a negative regulator of the inflammatory response.
Retinoid-related orphan receptor alpha (ROR alpha) (NR1F1) is a member of the nuclear receptor superfamily whose biological functions are largely unknown. Since staggerer mice, which carry a deletion in the ROR alpha gene, suffer from immune abnormalities, we generated an adenovirus encoding ROR alpha1 to investigate its potential role in control of the inflammatory response. We demonstrated that ROR alpha is expressed in human primary smooth-muscle cells and that ectopic expression of ROR alpha1 inhibits TNFalpha-induced IL-6, IL-8 and COX-2 expression in these cells. ROR alpha1 negatively interferes with the NF-kappaB signalling pathway by reducing p65 translocation as demonstrated by western blotting, immunostaining and electrophoretic mobility shift assays. This action of ROR alpha1 on NF-kappaB is associated with the induction of IkappaB alpha, the major inhibitory protein of the NF-kappaB signalling pathway, whose expression was found to be transcriptionally upregulated by ROR alpha1 via a ROR response element in the IkappaB alpha promoter. Taken together, these data identify ROR alpha1 as a potential target in the treatment of chronic inflammatory diseases, including atherosclerosis and rheumatoid arthritis.
Delerive
P
P
INSERM U325, Département d'Athérosclérose, Institut Pasteur de Lille, France.
Monté
D
D
Dubois
G
G
Trottein
F
F
Fruchart-Najib
J
J
Mariani
J
J
Fruchart
J C
JC
Staels
B
B
D000256:Adenoviridae / Q000235:genetics; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050863:Synaptotagmin I; D050857:Synaptotagmins; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D002135:Calcium-Binding Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009419:Nerve Tissue Proteins; C000606205:Nfkbia protein, mouse; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; C539739:Rora protein, mouse; D050863:Synaptotagmin I; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D050857:Synaptotagmins; D000072000:NF-KappaB Inhibitor alpha; D012313:RNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases