Adenosine and IFN-α synergistically increase IFN-γ production of human NK cells

Prevention of overwhelming immune reactions is essential for an organism to survive. Adenosine, a ribonucleoside produced by various cell types during inflammatory processes, has been shown to inhibit effector functions of different immune cells. Here, we show that the adenosine A(3) receptor agonist iodobenzyl methylcarboxamidoadenosine potently inhibited proliferation, IFN-gamma production, and cytotoxicity of activated human lymphoid cells. Stimulation of the A(3) receptor also caused apoptosis of activated PBMC. However, when PBMC were stimulated with IFN-alpha, adenosine did not decrease, but synergistically increased, the IFN-gamma production of NK cells. This effect was also mediated mainly via the A(3) receptor. Thus, our data suggest that adenosine differentially contributes to the regulation of immune responses during inflammatory processes: It may increase effector functions of NK cells in combination with IFN-alpha but also prevents overwhelming immune responses by inhibiting proliferation and induction of apoptosis of activated lymphoid cells. Future studies need to define the role of the different adenosine receptors in more detail. J. Leukoc. Biol. 85: 452-461; 2009.