Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses
| Autor: | David Kane, Alice N. McEvoy, Evelyn P. Murphy, Jennifer A. Ralph, Barry Bresnihan, Oliver FitzGerald |
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| Rok vydání: | 2005 |
| Předmět: |
musculoskeletal diseases
DNA Complementary Receptor Adenosine A2A Immunology Cell Adenosine A2A receptor Gene Expression Biology Pharmacology Dinoprostone Proinflammatory cytokine Nuclear Receptor Subfamily 4 Group A Member 2 medicine Immunology and Allergy Humans RNA Messenger Transcription factor Cells Cultured Orphan receptor Base Sequence Dose-Response Relationship Drug Arthritis Psoriatic Synovial Membrane Adenosine Adenosine receptor DNA-Binding Proteins medicine.anatomical_structure Methotrexate Antirheumatic Agents Endothelium Vascular Signal transduction Immunosuppressive Agents medicine.drug Transcription Factors |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 175(1) |
| ISSN: | 0022-1767 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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