Activation of Nuclear Orphan Receptor NURR1 Transcription by NF-κB and Cyclic Adenosine 5′-Monophosphate Response Element-Binding Protein in Rheumatoid Arthritis Synovial Tissue

• Published in: The Journal of immunology (1950) Vol. 168; no. 6; pp. 2979 - 2987
• Main Authors: McEvoy, Alice N., Murphy, Eithne A., Ponnio, Tiia, Conneely, Orla M., Bresnihan, Barry, FitzGerald, Oliver, Murphy, Evelyn P.
• Format: Journal Article
• Language: English
• Published: United States 15.03.2002
• Subjects: Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Cells, Cultured; CREB-1 protein; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP Response Element-Binding Protein - physiology; Dinoprostone - pharmacology; DNA - metabolism; DNA-Binding Proteins; Humans; Inflammation Mediators - pharmacology; interleukin 1^b; Interleukin-1 - pharmacology; NF-kappa B - metabolism; NF-kappa B - physiology; Nuclear Receptor Subfamily 4, Group A, Member 2; NURR1 protein; Promoter Regions, Genetic - drug effects; Protein Binding - drug effects; Protein Binding - genetics; Receptors, Cytoplasmic and Nuclear - biosynthesis; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Synovial Membrane - drug effects; Synovial Membrane - metabolism; Synovial Membrane - pathology; Transcription Factors - biosynthesis; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.168.6.2979

Modulation of the NURR subfamily of nuclear receptors may be an important mechanism regulating pathways associated with inflammatory joint disease. We examined the signaling mechanisms through which inflammatory mediators, produced by rheumatoid arthritis (RA) synovial tissue, contribute to the regulation of the NURR subfamily. Markedly enhanced expression of NURR1 is observed in synovial tissue of patients with RA compared with normal subjects. Modulation by proinflammatory mediators in primary RA and normal synoviocytes shows that PGE2, IL-1β, and TNF-α markedly enhance NURR1 mRNA and protein levels in contrast to other subfamily members, NUR77 and NOR-1. We have established that transcriptional activation of the NURR1 gene by IL-1β and TNF-α requires a proximal promoter region that contains a consensus NF-κB DNA-binding motif. IL-1β- and TNF-α-induced NF-κB binding to this site is due predominantly to p65-p50 heterodimer and p50 homodimer subunit protein complexes. We further demonstrate a direct CREB-1-dependent regulation by PGE2 situated at promoter region −171/−163. Moreover, analyses confirm the presence of CREB-1 and NF-κB p50 and p65 subunit binding to the NURR1 promoter under basal conditions in freshly explanted RA synovial tissue. In summary, enhanced NF-κB- and CREB-1-binding activity on the NURR1 promoter by inflammatory mediators delineates novel mechanisms in the regulation of NURR1 transcription. PGE2-, TNF-α-, and IL-1β-dependent stimulation of the NURR1 gene implies that NURR1 induction represents a point of convergence of at least two distinct signaling pathways, suggesting an important common role for this transcription factor in mediating multiple inflammatory signals.