Cooperation of adenosine and prostaglandin E2 (PGE2) in amplification of cAMP-PKA signaling and immunosuppression.
BACKGROUND
We hypothesize that adenosine and PGE2 could have a complementary immunosuppressive effect that is mediated via common cAMP-PKA signaling.


METHODS
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.


RESULTS
PGE2 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 PGE2 and adenosine receptors we found that cooperation of PGE2 and adenosine in their inhibitory effects 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 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.


CONCLUSIONS
In comparison to other immunosuppressive molecules (TGF-beta 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.
Su
Yunyun
Y
Department of Pathology, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA.
Huang
Xiaojun
X
Raskovalova
Tatiana
T
Zacharia
Lefteris
L
Lokshin
Anna
A
Jackson
Edwin
E
Gorelik
Elieser
E
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000276:immunology / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010120:Oxytocics / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D010120:Oxytocics; C545644:PTGER2 protein, human; C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D018047:Receptors, Purinergic P1; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine; D015232:Dinoprostone