ADENOSINE A(1) RECEPTOR PROMOTION OF MULTINUCLEATED GIANT-CELL FORMATION BY HUMAN MONOCYTES - A MECHANISM FOR METHOTREXATE-INDUCED NODULOSIS IN RHEUMATOID-ARTHRITIS

Objective. To determine why methotrexate (MTX) exacerbates rheumatoid nodules in some patients, despite the effective suppression of synovia l inflammation. Methods. Phorbol myristate acetate (PMA)induced differ entiation 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 nM or the adenosine A(1) agonist N-5-cyclopentyl ad enosine (CPA) (10(-12) to 10(-9) M) or the A(2) antagonist 3,7-dimethy l-1-propargylxanthine markedly enhanced giant cell formation, whereas the adenosine A(1) antagonist 8-cyclopentyl-dipropylxanthine completel y reversed these effects. PMA, CPA, and MTX induced adenosine release by cultured monocytes at concentrations consistent with those associat ed with predominantly A(1) effects. Furthermore, surface expression of A(1) receptors was found to remain unchanged on the differentiating c ells throughout the culture period. Conclusion. Agents that inhibit ad enosine A(1) receptors might be useful in the treatment of MTX-induced rheumatoid nodulosis, while still potentiating the A(2)-mediated anti inflammatory effects of MTX on synovitis.