Effects of adenosine on adhesion molecule expression and cytokine production in human PBMC depend on the receptor subtype activated

Background and purpose: Adenosine suppresses immune responses through adenosine _2A (A _2A) receptors, by raising intracellular cAMP. Interleukin (IL)-18 up-regulates the expression of intercellular adhesion molecule (ICAM)-1 on monocytes, leading to production of pro-inflammatory cytokines such as IL-12, interferon (IFN)-γ and tumor necrosis factor (TNF)-α by human peripheral blood mononuclear cells (PBMC). We have previously demonstrated that elevation of cAMP inhibits this IL-18-induced expression of adhesion molecules. In the present study, we examined the effect of adenosine on the IL-18-induced up-regulation of ICAM-1 on human monocytes and production of IL-12, IFN-γ and TNF-α by PBMC. Experimental approach: The expression of ICAM-1 was examined by flow cytometry. IL-12, IFN-γ and TNF-α were determined by ELISA ass1ay. Key results: Adenosine inhibited the IL-18-induced up-regulation of ICAM-1 on human monocytes and it abolished the IL-18-enhanced production of IL-12, IFN-γ and TNF-α. While an A _2A receptor antagonist reversed the action of adenosine, an A ₁ or A ₃ receptor antagonist enhanced them. An A _2A receptor agonist, CGS21680, mimicked the effects of adenosine and its effects were abolished not only by the A _2A receptor antagonist but also by A ₁ or A ₃ receptor agonists. Activation via A _2A receptors resulted in elevation of cAMP in monocytes, whereas the stimulation of A ₁ or A ₃ receptors inhibited it, suggesting that intracellular signal transduction following ligation of A _2A receptors might be blocked by activation of A ₁ or A ₃ receptors. Conclusions and Implications: Adenosine differentially regulates IL-18-induced adhesion molecule expression and cytokine production through several subtypes of its receptors.