Molecular mechanism for adenosine regulation of dendritic cells

Abstract

Abstract Extracellular adenosine concentrations and expression adenosine receptors are elevated after cell death, injury and inflammation. Antigen presenting cells are one of the primary targets for adenosine to suppress T and NK cell responses. However, molecular mechanisms for adenosine regulation of dendritic cells are poorly understood. Here we show that adenosine receptor stimulation strongly suppresses dendritic cell activation. Adenosine did not affect phosphoactivation of inflammatory signaling pathways such as MAPKs, NF-κB and IRF3. Adenosine receptor signaling increased intracellular cAMP accumulation. Specific cAMP analogs for EPAC and PKA pathways phenocopied the effects of adenosine on dendritic cells especially when used together. Adenosine-mediated suppression of inflammatory/effector cytokines is associated with increased expression of anti-inflammatory c-Fos and NR4A receptors. NR4A and cFos expression were also increased by EPAC and PKA-specific cAMP analogs. Addition of conditioned mediums from dendritic cells prestimulated with stable adenosine analog or PKA and EPAC specific cAMP analogs together inhibited the IFNγ production by activated T cells. Overall our data suggest that adenosine can potentially target both PKA and EPAC pathways and increase the expression of NR4A nuclear orphan receptors and cFos to regulate dendritic cell responses. Our findings have important implications for the development of novel therapies for immune related diseases such as cancer by targeting adenosine receptors.