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

Abstract

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.

Modulation of Orphan Nuclear Receptor NURR1 Expression by Methotrexate in Human Inflammatory Joint Disease Involves Adenosine A2A Receptor-Mediated Responses

“…The NOR-1 gene was identified originally through its involvement in the chromosomal rearrangement associated with extraskeletal myxoid chondrosarcoma (42). Recent studies identify the NURR subfamily as effector proteins of cytokine action (32,39,43,44). Data from our laboratory and others (39,(45)(46)(47) propose that the NURR subfamily could serve as novel targets in the treatment of inflammatory arthritis, atherosclerosis, and lung cancer.…”

Cyclooxygenase 2–derived prostaglandin E2 production by corticotropin‐releasing hormone contributes to the activated cAMP response element binding protein content in rheumatoid arthritis synovial tissue

“…We and others have shown that NF-B p50/p65 heterodimers and homodimers are intimately involved in transcriptional activation of many inflammatory genes in response to proinflammatory cytokines (5,39,40). CRH and PGE 2 failed to induce subunit binding to this sequence in both cell types (data not shown), demonstrating the specificity of the CREB/ATF family in mediating CRH and PGE 2 signaling downstream of cAMP/PKA activation.…”

Synergistic Induction of NR4A Orphan Nuclear Receptors by LPS and cAMP in Murine Macrophage Cells

“…Whereas Nurr1 mRNA had very little response to LPS, it was strongly induced by 8-bromo-cAMP, peaking around 2 h, and the mRNA levels remained elevated for at least 20 h (Figure 2). As an example of the potential relevance of these results to inflammatory disease, Nurr1 in human synoviocytes was found previously to be strongly induced by the cAMP-elevating agents prostaglandin E2 or forskolin, acting via a CRE sequence in the Nurr1 promoter [19].…”

“…By 4 h, the relative mRNA levels for Nur77 and [7-12, 20, 21], there has been increased interest in regulation of their expression by various inflammatory stimuli, including LPS [10]. Several studies have shown that NR4A expression can be induced by cAMP [13][14][15][16]19], whose intracellular levels can be increased in response to mediators of inflammation or stress such as prostaglandins or catecholamines. However, potential interactions between LPS and cAMP analogs or cAMP-elevating agents in regulating NR4A expression have not been reported previously.…”