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

We hypothesize that adenosine and PGE₂ could have a complementary immunosuppressive effect that is mediated via common cAMP-PKA signaling.

To test this hypothesis, the effect of adenosine and PGE₂ on the cytotoxic activity and cytokine production of lymphokine activated killer (LAK) cells was investigated.

PGE₂ and adenosine inhibited LAK cells cytotoxic activity and production of INF-γ, GM-CSF and TNF-α. In combination they showed substantially higher inhibition than each modality used alone. Using agonists and antagonists specific for PGE₂ and adenosine receptors we found that cooperation of PGE₂ 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 PGE₂ 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 PGE₂. In contrast, Rp-8-Br-cAMPS, an inhibitor of PKA type I blocked their immunosuppressive effects, suggesting that the inhibitory effects of PGE₂ and adenosine are mediated via common pathway with activation of cAMP-PKA and inhibition of Akt.

In comparison to other immunosuppressive molecules (TGF-β and IL-10), adenosine and PGE₂ are unique in their ability to inhibit the executive function of highly cytotoxic cells. High intratumor levels of adenosine and PGE₂ could protect tumor from immune-mediated destruction by inactivation of the tumor infiltrating functionally active immune cells.