Role and Function of A2Aand A₃ Adenosine Receptors in Patients with Ankylosing Spondylitis, Psoriatic Arthritis and Rheumatoid Arthritis.
Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are chronic inflammatory rheumatic diseases that affect joints, causing debilitating pain and disability. Adenosine receptors (ARs) play a key role in the mechanism of inflammation, and the activation of A2Aand A₃AR subtypes is often associated with a reduction of the inflammatory status. The aim of this study was to investigate the involvement of ARs in patients suffering from early-RA (ERA), RA, AS and PsA. Messenger RNA (mRNA) analysis and saturation binding experiments indicated an upregulation of A2Aand A₃ARs in lymphocytes obtained from patients when compared with healthy subjects. A2Aand A₃AR agonists inhibited nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation and reduced inflammatory cytokines release, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6. Moreover, A2Aand A₃AR activation mediated a reduction of metalloproteinases (MMP)-1 and MMP-3. The effect of the agonists was abrogated by selective antagonists demonstrating the direct involvement of these receptor subtypes. Taken together, these data confirmed the involvement of ARs in chronic autoimmune rheumatic diseases highlighting the possibility to exploit A2Aand A₃ARs as therapeutic targets, with the aim to limit the inflammatory responses usually associated with RA, AS and PsA.
Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy. rvnnls@unife.it.
Annalisa
A
Ravani
Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy. vncfrz@unife.it.
Fabrizio
F
Vincenzi
Department of Medical Sciences, Section of Rheumatology, University of Ferrara and Azienda Ospedaliero Universitaria Sant'Anna, 44124 Cona, Ferrara, Italy. brtlsn@unife.it.
Alessandra
A
Bortoluzzi
Department of Medical Sciences, Section of Rheumatology, University of Ferrara and Azienda Ospedaliero Universitaria Sant'Anna, 44124 Cona, Ferrara, Italy. pdvmss@unife.it.
Melissa
M
Padovan
Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy. psqslv@unife.it.
Silvia
S
Pasquini
Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy. gss@unife.it.
Stefania
S
Gessi
Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy. mhs@unife.it.
Stefania
S
Merighi
Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy. bpa@unife.it.
Pier Andrea
PA
Borea
Department of Medical Sciences, Section of Rheumatology, University of Ferrara and Azienda Ospedaliero Universitaria Sant'Anna, 44124 Cona, Ferrara, Italy. gvl@unife.it.
Marcello
M
Govoni
Department of Medical Sciences, Pharmacology Unit, University of Ferrara, 44121 Ferrara, Italy. vrk@unife.it.
Katia
K
Varani
D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry / Q000378:metabolism; D058909:Adenosine A3 Receptor Agonists / Q000737:chemistry / Q000378:metabolism; D058918:Adenosine A3 Receptor Antagonists / Q000737:chemistry / Q000378:metabolism; D015535:Arthritis, Psoriatic / Q000378:metabolism / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010627:Phenethylamines / Q000737:chemistry / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism*; D013167:Spondylitis, Ankylosing / Q000378:metabolism / Q000473:pathology*
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D016207:Cytokines; D016328:NF-kappa B; D010627:Phenethylamines; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D000241:Adenosine; C416650:SCH 442416
adenosine receptors; ankylosing spondylitis; inflammation; psoriatic arthritis; rheumatoid arthritis