title: Prostaglandin D2 is a novel repressor of IFNγ induced indoleamine-2,3-dioxygenase via the DP1 receptor and cAMP pathway.
abstract: 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 PGD2 displayed significant repressor activity. PGD2 inhibited IDO activity with an IC50 of 7.2µM in THP-1 cells and 5.2µM in monocytes. PGD2 caused a significant decrease in both IDO mRNA and protein. Using receptor specific agonists, PGD2 was found to act via the DP1 receptor, while the CRTH2 receptor was not involved. A DP1 antagonist significantly reduced the activity of PGD2, while CRTH2 agonists were ineffective. PGD2 increased intracellular cAMP levels and exogenous N(6)-cAMP was also found to be highly inhibitory. The effects of PGD2 via cAMP were blocked by Rp-cAMP indicating involvement of PKA. PGD2 also stimulated CREB phosphorylation, a PKA dependent transcription factor. This is the first report demonstrating that PGD2, a prostanoid typically associated with allergy, can inhibit IDO activity via the DP1/cAMP/PKA/CREB pathway. Our findings suggest that PGD2 and its derivatives may form the basis of novel repressors of IFNγ-mediated IDO expression.
authors.affiliation: University of South Australia, School of Pharmacy and Medical Sciences, North Terrace, Adelaide, South Australia, 5000, Australia.
authors.forename: Nesrine Kamal
authors.initials: NK
authors.lastname: Bassal
authors.affiliation: University of South Australia, School of Pharmacy and Medical Sciences, North Terrace, Adelaide, South Australia, 5000, Australia.
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Hughes
authors.affiliation: University of South Australia, School of Pharmacy and Medical Sciences, North Terrace, Adelaide, South Australia, 5000, Australia. Electronic address: maurizio.costabile@unisa.edu.au.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Costabile
mesh_terms: D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000074084:THP-1 Cells
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011982:Receptors, Prostaglandin; C501562:prostanoid D receptor 1, human; D007371:Interferon-gamma; D000242:Cyclic AMP; D015230:Prostaglandin D2
keywords: Cyclic-AMP; DP1; Indoleamine 2,3-Dioxygenase; PKA; Prostaglandin D(2)