The cell-to-cell interaction through binding of intercellular adhesion molecule (ICAM)-1 on monocytes to their ligands lymphocyte function-associated antigen (LFA)-1 on T-cells plays important roles in cytokine production and T-cell proliferation. Interleukin (IL)-18, which plasma levels are elevated in patients during acute rejection following organ transplantation, induces the expression of ICAM-1 on monocytes, production of interferon (IFN)-γ and IL-12 and lymphocyte proliferation during human mixed lymphocyte reaction. Activation of the adenosine A2A receptor on during reperfusion of various tissues has been found to markedly reduce ischemia-reperfusion injury. In the present study, we examined the effect of adenosine at increasing concentrations ranging from 0.1 to 100 μM on the IL-18-enhanced expression of ICAM-1, production of IFN-γ and IL-12 and lymphocyte proliferation during human mixed lymphocyte reaction. Adenosine inhibited the IL-18-initiated immune responses. The IC50 values of adenosine for inhibition of the IL-18-enhanced ICAM-1 expression, IFN-γ production and lymphocyte proliferation were 20 μM, respectively. The actions of adenosine depended on the stimulation of adenosine A2A receptor. An inhibitor of protein kinase A (PKA) at 100 μM inhibited the actions of adenosine, suggesting that PKA might be involved in the actions of adenosine. On the other hand, the stimulation of adenosine A1 and A3 receptor blocked the actions of adenosine A2A receptor stimulation. These results suggest that adenosine inhibits the immune responses during mixed lymphocyte reaction via adenosine A2A receptor.
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