Cooperation of adenosine and prostaglandin E2 (PGE2) in amplification of cAMP-PKA signaling and immunosuppression

Introduction We hypothesize that adenosine and PGE(2) could have a complementary immunosuppressive effect that is mediated via common cAMP-PKA signaling. Materials and methods To test this hypothesis, the effect of adenosine and PGE(2) on the cytotoxic activity and cytokine production of lymphokine activated killer (LAK) cells was investigated. Results PGE(2) and adenosine inhibited LAK cells cytotoxic activity and production of INF-gamma, GM-CSF and TNF-alpha. In combination they showed substantially higher inhibition than each modality used alone. Using agonists and antagonists specific for PGE(2) and adenosine receptors we found that cooperation of PGE(2) and adenosine in their inhibitory effects are mediated via EP2 and A(2A) receptors, respectively. LAK cells have 35-fold higher expression of EP2 than A(2A). Combined PGE(2) and adenosine treatment resulted in augmentation of cAMP production, PKA activity, CREB phosphorylation and inhibition of Akt phosphorylation. Wortmannin and LY294002 enhanced the suppressive effects of adenosine and PGE(2). In contrast, Rp-8-Br-cAMPS, an inhibitor of PKA type I blocked their immunosuppressive effects, suggesting that the inhibitory effects of PGE(2) and adenosine are mediated via common pathway with activation of cAMP-PKA and inhibition of Akt. Conclusion In comparison to other immunosuppressive molecules (TGF-beta and IL-10), adenosine and PGE(2) are unique in their ability to inhibit the executive function of highly cytotoxic cells. High intratumor levels of adenosine and PGE(2) could protect tumor from immune-mediated destruction by inactivation of the tumor infiltrating functionally active immune cells.