Figure 3.

cAMP mediated intracellular signaling of A2 AdoR. A2A and A2B AdoR activate adenylyl cyclase and elevate cAMP levels. The A2B AdoR can concomitantly activate Phospholipase C (PLC), thereby triggering elevated levels of free Calcium (Ca²⁺). PKC mediated activation of NF-κB related gene expression follows. cAMP can suppress AKT activation leading to reduced mTORC activity either directly or via PRAS40. Without proper mTORC activity 4E-BP1 complex will terminate translation of proteins widely necessary for activation of cells. Additionally cAMP can signal via PKA, leading to hyper phosphorylation of Salt induced kinase (SIK) 2, allowing the phosphorylated transcription factor CRTC3 to cluster with CREB and to initiate translation of IL-10. Besides, further interaction of PKA with transcription factors such as NF-κB, HIF and CREB can induce “inhibitory” gene expression. A PKA independent pathway is mediated by EPAC, an enzyme that activates RAP via GTP binding, leading to profound changes in cytoskeleton and migration of DCs. As a result inhibitory DC:Treg clusters are formed and the immunological synapse may be changed in a tolerogenic fashion.