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

Cancer Immunol Immunother (2008) 57:16111623

DOI 10.1007/s00262-008-0494-5

ORIGINAL ARTICLE

Cooperation of adenosine and prostaglandin E2 (PGE2)in ampliWcation of cAMPPKA signaling and immunosuppression

Yunyun Su Xiaojun Huang Tatiana Raskovalova Lefteris Zacharia Anna Lokshin Edwin Jackson Elieser Gorelik

Received: 4 December 2007 / Accepted: 22 February 2008 / Published online: 8 March 2008 Springer-Verlag 2008

Abstract

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

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

Results PGE2 and adenosine inhibited LAK cells cytotoxic activity and production of INF-[afii9828], GM-CSF and TNF-[afii9825]. In combination they showed substantially higher inhibition than each modality used alone. Using agonists and antagonists speciWc for PGE2 and adenosine receptors we found that cooperation of PGE2 and adenosine in their inhibitory eVects are mediated via EP2 and A2A receptors, respectively. LAK cells have 35-fold higher expression of EP2 than A2A. Combined PGE2 and adenosine treatment resulted in augmentation of cAMP production, PKA activity, CREB phosphorylation and inhibition of Akt phosphor-ylation. Wortmannin and LY294002 enhanced the suppressive eVects of adenosine and PGE2. In contrast, Rp-8-Br-cAMPS, an inhibitor of PKA type I blocked their

immunosuppressive eVects, suggesting that the inhibitory eVects of PGE2 and adenosine are mediated via common pathway with activation of cAMP-PKA and inhibition of Akt.

Conclusion In comparison to other immunosuppressive molecules (TGF-[afii9826] 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 inWltrating functionally active immune cells.

Keywords PGE2 Adenosine Immunosuppression Cytotoxicity Cytokine production

Introduction

Prostaglandin E2 (PGE2 ) is a major product of cyclooxygenases (COX-1 and COX-2) and plays an important role in regulating inXammation, as well as various other biological processes. PGE2 exerts biological eVects by binding to four receptors, termed EP1, EP2, EP3 and EP4 that belong to the family of G protein-coupled receptors and are diVerentially expressed on divergent types of cells [1]. EP2 and EP4 receptors are coupled to Gs, and PGE2 binding to these receptors therefore results in stimulation...