Open AccessAdenosine A 1 receptor promotion of multinucleated giant cell formation by human monocytes. A mechanism for methotrexate‐induced nodulosis in rheumatoid arthritis
Author(s) -
Merrill Joan T.,
Shen Christine,
Schreibman David,
Coffey Dan,
Zakharenko Olga,
Fisher Robert,
Lahita Robert G.,
Salmon Jane,
Cronstein Bruce N.
Publication year - 1997
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.1780400716
Subject(s) - adenosine , methotrexate , rheumatoid arthritis , giant cell , adenosine receptor , chemistry , pharmacology , agonist , synovial membrane , synovitis , inflammation , receptor , endocrinology , medicine , in vitro , immunology , biochemistry , pathology
Objective . To determine why methotrexate (MTX) exacerbates rheumatoid nodules in some patients, despite the effective suppression of synovial inflammation. Methods . Phorbol myristate acetate (PMA)‐induced differentiation of monocytes into multinucleated giant cells was used as an in vitro model to study the effects of adenosine on nodulosis. Results. MTX at 200‐2,000 n M or the adenosine A 1 agonist N 5 ‐cyclopentyl adenosine (CPA) (10 −12 to 10 ‐9 M ) or the A 2 antagonist 3,7‐dimethyl‐1‐propargylxanthine markedly enhanced giant cell formation, whereas the adenosine A 1 antagonist 8‐cyclopentyl‐dipropylxanthine completely reversed these effects. PMA, CPA, and MTX induced adenosine release by cultured monocytes at concentrations consistent with those associated with predominantly A 1 effects. Furthermore, surface expression of A 1 receptors was found to remain unchanged on the differentiating cells throughout the culture period. Conclusion . Agents that inhibit adenosine A 1 receptors might be useful in the treatment of MTX‐induced rheumatoid nodulosis, while still potentiating the A 2 ‐mediated antiinflammatory effects of MTX on synovitis.