title: Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis.
abstract: 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 nM or the adenosine A1 agonist N5-cyclopentyl adenosine (CPA) (10(-12) to 10(-9) M) or the A2 antagonist 3,7-dimethyl-1-propargylxanthine markedly enhanced giant cell formation, whereas the adenosine A1 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 A1 effects. Furthermore, surface expression of A1 receptors was found to remain unchanged on the differentiating cells throughout the culture period.
  
  
  CONCLUSIONS
  Agents that inhibit adenosine A1 receptors might be useful in the treatment of MTX-induced rheumatoid nodulosis, while still potentiating the A2-mediated antiinflammatory effects of MTX on synovitis.
authors.affiliation: St. Luke's/Roosevelt Hospital Center, New York, New York 10019, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Merrill
authors.forename: C
authors.initials: C
authors.lastname: Shen
authors.forename: D
authors.initials: D
authors.lastname: Schreibman
authors.forename: D
authors.initials: D
authors.lastname: Coffey
authors.forename: O
authors.initials: O
authors.lastname: Zakharenko
authors.forename: R
authors.initials: R
authors.lastname: Fisher
authors.forename: R G
authors.initials: RG
authors.lastname: Lahita
authors.forename: J
authors.initials: J
authors.lastname: Salmon
authors.forename: B N
authors.initials: BN
authors.lastname: Cronstein
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002478:Cells, Cultured; D006801:Humans; D008727:Methotrexate / Q000009:adverse effects*; D009000:Monocytes / Q000187:drug effects / Q000473:pathology*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D012218:Rheumatoid Nodule / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013805:Theobromine / Q000031:analogs & derivatives / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
chemical_list: D018501:Antirheumatic Agents; D018047:Receptors, Purinergic P1; D014970:Xanthines; C048599:N(6)-cyclopentyladenosine; C057837:3,7-dimethyl-1-propargylxanthine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D013755:Tetradecanoylphorbol Acetate; D013805:Theobromine; D008727:Methotrexate