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

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Abstract

Introduction

The reduction of the inflammatory status represents one of the most important targets in rheumatoid arthritis (RA). A central role of A _2Aand A ₃adenosine receptors (ARs) in mechanisms of inflammation has been reported in different pathologies. The primary aim of this study was to investigate the A _2Aand A ₃ARs 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 A _2Aand A ₃AR 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 A _2Aand A ₃AR 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, A _2Aand A ₃ARs were up-regulated if compared with healthy controls. A _2Aand A ₃AR activation inhibited the NF-kB pathway and diminished inflammatory cytokines such as TNF-α, IL-1β and IL-6. A _2Aand A ₃AR agonists mediated a reduction of MMP-1 and MMP-3 release. A _2Aand A ₃AR 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 A _2Aand A ₃ARs and support the use of A _2Aand/or A ₃AR agonists as novel and effective pharmacological treatment in RA patients.

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The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.

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Author and article information

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Journal ID (iso-abbrev): Arthritis Res. Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Print): 2011

Publication date (Electronic): 6 December 2011

Volume: 13

Issue: 6

Page: R197

Affiliations

[1 ]Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara via Fossato di Mortara 17-19, 44121 Ferrara, Italy

[2 ]Department of Clinical and Experimental Medicine, Rheumatology Section, University of Ferrara via Fossato di Mortara 17-19, 44121 Ferrara, Italy

Article

Publisher ID: ar3527

DOI: 10.1186/ar3527

PMC ID: 3334647

PubMed ID: 22146575

SO-VID: 98fda13c-5223-488c-aac9-3d50dbcd37be

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 28 July 2011

Date revision received : 3 October 2011

Date accepted : 6 December 2011

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