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Cancer Immunology, Immunotherapy

Published in:

01-11-2008 | Original Article

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

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

Published in: Cancer Immunology, Immunotherapy | Issue 11/2008

Abstract

Introduction

We hypothesize that adenosine and PGE₂ 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 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-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.

Conclusion

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.

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Title: Cooperation of adenosine and prostaglandin E2 (PGE2) in amplification of cAMP–PKA signaling and immunosuppression
Authors: Yunyun Su
Xiaojun Huang
Tatiana Raskovalova
Lefteris Zacharia
Anna Lokshin
Edwin Jackson
Elieser Gorelik
Publication date: 01-11-2008
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 11/2008
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-008-0494-5

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Abstract

Introduction

Materials and methods

Results

Conclusion

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