Normalization of A2A and A3 Adenosine Receptor Up-Regulation in Rheumatoid Arthritis Patients by Treatment With Anti-Tumor Necrosis Factor α but Not Methotrexate

Objective. To investigate A(1), A(2A), A(2B), and A(3) adenosine receptors in lymphocytes and neutrophils from patients with early rheumatoid arthritis (ERA) as well as from RA patients treated with methotrexate (MTX) or anti-tumor necrosis factor alpha (anti-TNF alpha), as compared with those in age-matched healthy controls, and to examine correlations between the status and functionality of adenosine receptors and TNF alpha release and NF-kappa B activation. Methods. Adenosine receptors were analyzed by saturation binding assays and Western blot analyses. We investigated the potency of typical A(2A) and A(3) agonists in the production of cAMP in control subjects, ERA patients, and RA patients treated with MTX or anti-TNF alpha. In a separate cohort of RA patients, TNF alpha release and NF-kappa B activation were evaluated in plasma and nuclear extracts, respectively. Results. In ERA patients, we found a high density and altered functionality of A(2A) and A(3) receptors. The binding and functional parameters of A(2A) and A(3) receptors normalized after anti-TNF alpha, but not MTX, treatment. TNF alpha release was increased in ERA patients and in MTX-treated RA patients, whereas in anti-TNF alpha-treated RA patients, release was comparable to that in the controls. NF-kappa B activation was elevated in ERA patients and in MTX-treated RA patients. Anti-TNF alpha treatment mediated decreased levels of NF-kappa B activation. Conclusion. A(2A) and A(3) receptor up-regulation in ERA patients and in MTX-treated RA patients was associated with high levels of TNF alpha and NF-kappa B activation. Treatment with anti-TNF alpha normalized A(2A) and A(3) receptor expression and functionality. This new evidence of A(2A) and A(3) receptor involvement opens the possibility of exploiting their potential role in human diseases characterized by a marked inflammatory component.