title: A2A and A3 adenosine receptor expression in rheumatoid arthritis: upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release.
abstract: BACKGROUND
  The reduction of the inflammatory status represents one of the most important targets in rheumatoid arthritis (RA). A central role of A2A and A3 adenosine receptors (ARs) in mechanisms of inflammation has been reported in different pathologies. The primary aim of this study was to investigate the A2A and A3ARs and their involvement in RA progression measured by Disease Activity Score in 28 or 44 joints (DAS28 or DAS).
  
  
  METHODS
  ARs were analyzed by saturation binding assays, mRNA and Western blotting analysis in lymphocytes from early and established RA patients. The effect of A2A and A3AR agonists in nuclear factor kB (NF-kB) pathway was evaluated. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) release was carried out by A2A and A3AR activation. AR pharmacological regulation in matrix metalloproteinase-1 (MMP-1) and metalloproteinase-3 (MMP-3) release was also studied.
  
  
  RESULTS
  In lymphocytes obtained from RA patients, A2A and A3ARs were up-regulated if compared with healthy controls. A2A and A3AR activation inhibited the NF-kB pathway and diminished inflammatory cytokines such as TNF-α, IL-1β and IL-6. A2A and A3AR agonists mediated a reduction of MMP-1 and MMP-3 release. A2A and A3AR density inversely correlated with DAS28 and DAS suggesting a direct role of the endogenous activation of these receptors in the control of RA joint inflammation.
  
  
  CONCLUSIONS
  Taken together these data demonstrate that the inflammatory and clinical responses in RA are regulated by A2A and A3ARs and support the use of A2A and/or A3AR agonists as novel and effective pharmacological treatment in RA patients.
authors.affiliation: Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara via Fossato di Mortara 17-19, 44121 Ferrara, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Melissa
authors.initials: M
authors.lastname: Padovan
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.forename: Martina
authors.initials: M
authors.lastname: Targa
authors.forename: Francesco
authors.initials: F
authors.lastname: Trotta
authors.forename: Marcello
authors.initials: M
authors.lastname: Govoni
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016014:Linear Models; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A / Q000235:genetics* / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D058908:Adenosine A2 Receptor Agonists; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D045726:Metalloproteases; D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide