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

Abstract

Modulation by proinflammatory mediators indicate that NURR1 induction represents a point of convergence of distinct signaling pathways, suggesting an important common role for this transcription factor in mediating multiple inflammatory signals. The present study identifies NURR1 as a molecular target of methotrexate (MTX) action in human inflammatory joint disease and examines the mechanism through which MTX modulates NURR1 expression. MTX significantly suppresses expression of NURR1 in vivo in patients with active psoriatic arthritis (n = 10; p < 0.002) who were prescribed low-dose MTX for management of peripheral arthritis. Importantly, reduction in NURR1 levels correlate (n = 10; r = 0.57; p = 0.009) with changes in disease activity score (both clinical and laboratory parameters). MTX selectively modulates NURR1 levels induced by inflammatory stimuli and growth factors in resident cell populations of synovial tissue. In primary human synoviocytes and microvascular endothelial cells, we observe dose-dependent differential effects of MTX on steady-state and inducible NURR1 levels. Our data confirms that adenosine, and its stable analog 5′-N-ethylcarboxamideadenosine, can mimic the differential effects of MTX on NURR1 transcription. In addition, we verify that the inhibitory effect of low-dose MTX on NURR1 activation is mediated through the adenosine receptor A2. More specifically, our data distinguishes the selective involvement of the A2A receptor subtype in these responses. In summary, these findings establish the nuclear orphan receptor NURR1 as a molecular target of MTX action in human inflammatory joint disease and demonstrate that the immunomodulatory actions of MTX on NURR1 expression are mediated through adenosine release.

Adenosine Modulates NR4A Orphan Nuclear Receptors To Attenuate Hyperinflammatory Responses in Monocytic Cells

“…Adenosine modulates NR4A1-3 gene expression in human and murine monocyte cells Adenosine and its stable analog, NECA, have been shown to modulate expression of the NR4A family member, NR4A2, to elicit anti-inflammatory effects downstream of methotrexate treatment in primary synovial cells isolated from rheumatoid arthritis synovial tissue (19). In mast cells, NECA has been shown to potently modulate NR4A1-3 expression (20).…”

“…Thus, adenosine and NR4A receptors are known to control differentiation and inflammatory processes in cells of myeloid origin. We and others have shown that adenosine receptor stimulation can potently alter expression of NR4A family members in human synoviocyte, endothelial, mast, and monocyte cells (19)(20)(21). However, the transcriptional effects controlled by NR4A receptors downstream of adenosine signaling in myeloid cells remain unknown and are the object of this study.…”

Limited Role of Nuclear Receptor Nur77 in Escherichia coli-Induced Peritonitis

“…This nuclear receptor plays a role in chronic inflammation conditions such as atherosclerosis (10,16,17) and rheumatoid arthritis (32). Nurr1, another member of the NR4A subfamily, has also been implicated in several chronic inflammatory diseases, namely, psoriasis (33), inflammatory arthritis (34), and osteoarthritis (35). Furthermore, all three NR4A subfamily members have been implicated in atopic dermatitis (36).…”

Adenosine regulates thrombomodulin and endothelial protein C receptor expression in folliculostellate cells of the pituitary gland

“…In support of this is the expression of both NR4A1 and NR4A2 in human atherosclerotic lesion macrophages where they play a protective role by reducing inflammation [44]. Adenosine, acting in particular through the A2a receptor and NR4A2 has also been shown to mediate the antiinflammatory effects of methotrexate in rheumatoid arthritis [45]. NR4A2 also mediates the repression of matrix metalloproteinases during inflammation [46].…”