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OBJECTIVE: A3 adenosine receptor (A3AR) upregulation has been found in cells of synovial tissue and in peripheral blood mononuclear cells (PBMC) of rats with adjuvant-induced arthritis. We investigated A3AR levels in PBMC of patients with rheumatoid arthritis (RA) and in mitogen-activated PBMC from healthy subjects. We examined the role of nuclear factor-kappaB (NF-kappaB), a transcription factor present in the A3AR promoter, in mediating receptor upregulation. METHODS: A3AR and NF-kappaB protein levels were evaluated in PBMC of RA patients (n = 23) and healthy subjects by Western blot. A3AR and NF-kappaB levels were also analyzed in phytohemagglutinin (PHA) and lipopolysaccharide (LPS)-stimulated PBMC in the presence and absence of antibodies against interleukin 2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha). Reverse transcription-polymerase chain reaction was performed in PHA-stimulated PBMC of healthy subjects to determine A3AR expression. RESULTS: A3AR was overexpressed in PBMC of RA patients compared to healthy subjects and was directly correlated to an increase in NF-kappaB. Similar findings were observed in PHA and LPS-stimulated PBMC from healthy subjects. Antibodies against IL-2 or TNF-alpha prevented the increase in A3AR and NF-kappaB expression. CONCLUSION: Overexpression of A3AR was found in PBMC of RA patients. Receptor upregulation was induced by inflammatory cytokines controlling the expression of the A3AR transcription factor NF-kappaB.