The endogenous bioactive lipid prostaglandin D ₂ ‐glycerol ester reduces murine colitis via DP1 and PPARγ receptors

Abstract

Cyclooxygenase-2 (COX-2) has long been implicated in the pathogenesis of inflammatory bowel diseases (IBDs). COX-2 is mostly known for the production of prostaglandins (PGs) from arachidonic acid. However, it also metabolizes the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide into the less well-studied bioactive lipids PG-glycerol esters (PG-Gs) and PG-ethanolamides (PG-EAs or prostamides). We previously showed that PGD-G, a product of 2-AG oxygenation by COX-2, has anti-inflammatory effects. Therefore, we used the dextran sulfate sodium (DSS)-induced model of colitis in mice to explore the role of PGD-G in murine models of IBD. Colon inflammation was assessed using macroscopic and histologic scores, myeloperoxidase activity, and expression of inflammatory mediators by real-time quantitative PCR and ELISA. We also compared the effects of PGD-G with those of PGD and PGD-EA. Finally, we used receptor antagonists to gain mechanistic insight into the receptors responsible for the observed effects. PGD-G reduced DSS-induced colitis, but PGD and PGD-EA did not have the same effect. Furthermore, we showed that PGD-G is an agonist of the PGD receptor 1 (DP1) and that some of the effects of PGD-G were blocked by antagonism of peroxisome proliferator-activated receptor γ and DP1. Therefore, PGD-G could be one of the products from the COX-2/prostaglandin D synthase axis to exert beneficial effects in colitis.-Alhouayek, M., Buisseret, B., Paquot, A., Guillemot-Legris, O., Muccioli, G. G. The endogenous bioactive lipid prostaglandin D-glycerol ester reduces murine colitis via DP1 and PPARγ receptors.

Peroxisome Proliferator-Activated Receptors: Experimental Targeting for the Treatment of Inflammatory Bowel Diseases

“…Such a relationship between endocannabinoids and PGs is also found between cannabinoids and PPAR agonists (Sun and Bennett, 2007). Thus, Alhouayek et al (2018) studied the effect of a bioactive prostaglandin derived from the oxygenation of 2-AG to PGD2-G by COX2 and a hematopoietic PGD synthase (PGDS). They reported the first dual activation of PGD2 receptor (DP1) and PPARg by PGD2-G and its anti-inflammatory properties in a murine model of colitis.…”

Effects of R‐flurbiprofen and the oxygenated metabolites of endocannabinoids in inflammatory pain mice models

“…Sample analysis was based on previously described methods 12,26 . Briefly, we used a Xevo TQ‐S mass spectrometer (Waters) coupled to an Acquity UPLC class H (Waters) for sample analysis.…”

The role of n-3 PUFA-derived fatty acid derivatives and their oxygenated metabolites in the modulation of inflammation

“…Studies towards the biological activity of some of these other secondary ARA metabolites showed that PGD2-G, for example, has strong anti-inflammatory effects by reducing the formation of the proinflammatory cytokines in LPS administrated mice 100 , and by reducing DSS induced murine colitis 101 .…”