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

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• 作者：Nesrine Kamal Bassal ; Bernard P Hughes ; Maurizio Costabile ; ^{maurizio.costabile@unisa.edu.au" class="auth_mail" title="E-mail the corresponding author}
• 关键词：IDO ; Indoleamine 2 ; 3-dioxygenase ; Kyn ; Kynurenine ; IFNγ ; Interferon-γ ; PKA ; Protein kinase A ; DP1 ; Prostanoid DP receptor ; CRTH2 ; Chemoattractant receptor homologous molecule expressed on Th2 cells
• 刊名：Prostaglandins, Leukotrienes and Essential Fatty Acids
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：110
• 期：Complete
• 页码：48-54
• 全文大小：475 K

文摘

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 7.2 µM in THP-1 cells and 5.2 µM 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 N⁶-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.