Prostaglandin D2 is a novel repressor of IFNγ induced indoleamine-2,3-dioxygenase via the DP1 receptor and cAMP pathway

Expression of elevated levels of Indoleamine 2,3-dioxygenase (IDO) is well established as a mechanism of cancer induced immunosuppression. Pharmacological inhibition of IDO activity is thus a promising alternative in the treatment of cancer. Previously we demonstrated that cyclooxygenase derived metabolites of arachidonic acid inhibited the interferon-gamma mediated induction of IDO in both THP-1 cells and human monocytes. Here we identified that of the five primary prostanoids produced by COX-1/COX-2, only PGD(2) displayed significant repressor activity. PGD(2) inhibited IDO activity with an IC50 of 7.2 mu M in THP-1 cells and 5.2 mu M in monocytes. PGD(2) caused a significant decrease in both IDO mRNA and protein. Using receptor specific agonists, PGD(2) was found to act via the DP1 receptor, while the CRTH2 receptor was not involved. A DP1 antagonist significantly reduced the activity of PGD(2), while CRTH2 agonists were ineffective. PGD(2) increased intracellular cAMP levels and exogenous N-6-cAMP was also found to be highly inhibitory. The effects of PGD(2) via cAMP were blocked by Rp-cAMP indicating involvement of PKA. PGD(2) also stimulated CREB phosphorylation, a PKA dependent transcription factor. This is the first report demonstrating that PGD(2), a prostanoid typically associated with allergy, can inhibit IDO activity via the DP1/cAMP/PKA/CREB pathway. Our findings suggest that PGD(2) and its derivatives may form the basis of novel repressors of IFN gamma-mediated IDO expression. (C) 2016 Elsevier Ltd. All rights reserved.