Molecular mechanism for adenosine regulation of dendritic cells

Cell death, inflammation or other cellular stress factors cause accumulation of adenosine in the extracellular space. Adenosine has immunosuppressive effects on antigen presenting cells. However, molecular mechanisms for adenosine regulation of dendritic cells are poorly understood. Here we showed that adenosine receptor signaling promotes an antiinflammatory dendritic cell phenotype. While adenosine receptor signaling increased intracellular cAMP levels, phosphoactivation of major inflammatory pathways such as MAPKs, NF-κB and IRF3 were not affected. Adenosine’s effects were phenocopied by cAMP. Specific cAMP analogs for EPAC and PKA pathways indicated that adenosine activates both intracellular cAMP receptors to inhibit dendritic cell activation. Antiinflammatory cFOS and NR4A receptor family expressions were increased by adenosine or EPAC and PKA specific cAMP analogs. Furthermore, T cells incubated with the medium of dendritic cells, which prestimulated with adenosine receptor agonist and PKAEPAC specific cAMP analogs, produced less IFNγ. Overall our data suggest that dendritic cells are regulated by adenosine through both PKA and EPAC pathways and increased the expression of NR4A nuclear orphan receptors and cFOS. Our findings suggest that for effective targeting of adenosine or other cAMP-inducing receptors both PKA and EPAC are important to modulate immune responses