Adenosine is a potent endogenous anti-inflammatory agent released by cells in metabolically unfavorable conditions, such as hypoxia or ischemia. Adenosine modulates different functional activities in macrophages. Some of these activities are believed to be induced through the uptake of adenosine into the macrophages, while others are due to the interaction with specific cell surface receptors. In murine bone marrow-derived macrophages, the use of different radioligands for adenosine receptors suggests the presence of A 2B and A 3 adenosine receptor subtypes. The presence of A 2B receptors was confirmed by flow cytometry using specific Abs. The A 2B receptor is functional in murine macrophages, as indicated by the fact that agonists of A 2B receptors, but not agonists for A 1, A 2A, or A 3, lead to an increase in cAMP levels. IFN-γ up-regulates the surface protein and gene expression of the A 2B adenosine receptor by induction of de novo synthesis. The up-regulation of A 2B receptors correlates with an increase in cAMP production in macrophages treated with adenosine receptor agonist. The stimulation of A 2B receptors by adenosine or its analogues inhibits the IFN-γ-induced expression of MHC class II genes and also the IFN-γ-induced expression of nitric oxide synthase and of proinflammatory cytokines. Therefore, the up-regulation of the A 2B adenosine receptor expression induced by IFN-γ could be a feedback mechanism for macrophage deactivation.