Potent activity of prostaglandin J₂ on prostanoid DP receptors

Prostaglandin D₂ (PGD₂), an anti-inflammatory mediator, is acting through Gs-protein coupled D-type prostanoid (DP) receptors. DP receptors are not extensively distributed; in tissues, they are the least abundant among members of the prostanoid receptor family, whereas their primary ligand PGD₂ is the main prostanoid in most tissues. PGD₂ is dehydrated or isomerized to a number of metabolites enzymatically or nonenzymatically. To understand why many metabolites of PGD₂ are produced via different pathways, regular cell-based experiments, Black/Leff operational model calculations, and in silico simulations were utilized. Here we show that, among the five metabolites of PGD₂, prostaglandin J₂ (PGJ₂) was the most potent metabolite for DP receptors, particularly in the cAMP signaling pathway. This result was attributed to PGJ₂ forming an extra and/or stronger hydrogen bond by more negatively charged carbonyl in the cyclopentene ring with DP receptors than PGD₂. Therefore, when PGD₂ is released into the blood, it would activate DP receptors, which are then continuously activated by PGJ₂ to sustain the DP receptor/cAMP-mediated signaling pathway. Thus, the anti-inflammatory effects of PGD₂ may be taken over/out competed and/or even enhanced by PGJ₂. Here, PGJ₂ was found to be a standout mediator of cAMP-mediated signaling pathway, which induces more potent and prolonged DP receptor activities as a biased ligand, possibly for resolving the inflammatory reaction. Moreover, since each metabolite showed different properties, these results provide insight into why many metabolites of PGD₂ are produced and the miscellaneous physiological roles induced by the main prostanoid in most tissues through the least abundant DP receptors.