Abstract
Extracellular adenosine, produced from ATP secreted by neuronal or immune cells, may play a role in endogenous regulation of inflammatory responses. Studies show that adenosine induces hypersecretion of IL-17A by CD4+ T cells upon treatment with an A2aR agonist (PSB0777), and that adenosine-mediated IL-17A hypersecretion is suppressed by the A2aR antagonist (Istradefylline) in humans. However, it is unclear whether A2aR downstream signaling is involved in IL-17A hypersecretion. Here, we show that inhibitors of adenyl cyclase (AC), protein kinase A (PKA), and cAMP response element binding protein (CREB) (which are signaling molecules downstream of the Gs protein coupled to the A2aR), suppress IL-17A production, suggesting that activation of A2aR signaling induces IL-17A production by CD4+ T cells. Furthermore, immune subset studies revealed that adenosine induces hypersecretion of IL-17A by T-helper (Th)17 cells. These results indicate that adenosine is an endogenous modulator of neutrophilic inflammation. Administration of an A2aR antagonist to mice with experimental autoimmune encephalomyelitis led to marked amelioration of symptoms. Thus, inhibitors of the novel A2aR-AC-cAMP-PKA-CREB signaling pathway for IL-17A hypersecretion by TCR-activated Th17 cells suppresses adenosine-mediated IL-17A production, suggesting that it may be an effective treatment for Th17-related autoimmune diseases.