A2A and A3 adenosine receptor expression in rheumatoid arthritis: upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release.

Katia Varani,Fabrizio Vincenzi,Marcello Govoni,Pier Andrea Borea,Melissa Padovan,Francesco Trotta,Martina Targa

doi:10.1186/ar3527

Abstract

IntroductionThe 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).MethodsARs 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.ResultsIn 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.ConclusionsTaken 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.

Highlights

The reduction of the inflammatory status represents one of the most important targets in rheumatoid arthritis (RA)
Western blotting and densitometric analysis in lymphocytes indicate a significant increase in A2A and A3AR protein expression in RA patients compared to healthy subjects while no differences were found in A1 and A2BARs (Figure 1B, C)
A2A and A3AR density was significantly increased in early RA (ERA) and RA patients compared with healthy subjects (Figure 2)

Summary

Introduction

The reduction of the inflammatory status represents one of the most important targets in rheumatoid arthritis (RA). 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). Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by progressive joint destruction associated with synovial proliferation and secretion of high levels of pro-inflammatory mediators, including cytokines and growth factors [1,2]. Many proteinases are expressed in joint tissues of RA patients even if among them different matrix metalloproteinases (MMPs) are believed to have a key role in joint destruction [13]. MMP-1 and MMP-3 are important because they are produced by fibroblast-like synoviocytes and monocytes/macrophages in the synovium and are known to play a key role in tissue destruction [14,15]

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