The Endocannabinoid Metabolite Prostaglandin E2 (PGE2)-Glycerol Inhibits Human Neutrophil Functions: Involvement of Its Hydrolysis into PGE2 and EP Receptors
2017
The endocannabinoids 2-arachidonoyl-glycerol and N -arachidonoyl-ethanolamine mediate an array of pro- and anti-inflammatory effects. These effects are related, in part, to their metabolism by eicosanoid biosynthetic enzymes. For example, N -arachidonoyl-ethanolamine and 2-arachidonoyl-glycerol can be metabolized by cyclooxygenase-2 into PG-ethanolamide (PG-EA) and PG-glycerol (PG-G), respectively. Although PGE 2 is a recognized suppressor of neutrophil functions, the impact of cyclooxygenase-derived endocannabinoids such as PGE 2 -EA or PGE 2 -G on neutrophils is unknown. This study’s aim was to define the effects of these mediators on neutrophil functions and the underlying cellular mechanisms involved. We show that PGE 2 -G, but not PGE 2 -EA, inhibits leukotriene B 4 biosynthesis, superoxide production, migration, and antimicrobial peptide release. The effects of PGE 2 -G were prevented by EP 1 /EP 2 receptor antagonist AH-6809 but not the EP 4 antagonist ONO-AE2-227. The effects of PGE 2 -G required its hydrolysis into PGE 2 , were not observed with the non-hydrolyzable PGE 2 -serinol amide, and were completely prevented by methyl-arachidonoyl-fluorophosphate and palmostatin B, and partially prevented by JZL184 and WWL113. Although we could detect six of the documented PG-G hydrolases in neutrophils by quantitative PCR, only ABHD12 and ABHD16A were detected by immunoblot. Our pharmacological data, combined with our protein expression data, did not allow us to pinpoint one PGE 2 -G lipase, and rather support the involvement of an uncharacterized lipase and/or of multiple hydrolases. In conclusion, we show that PGE 2 -G inhibits human neutrophil functions through its hydrolysis into PGE 2 , and by activating the EP 2 receptor. This also indicates that neutrophils could regulate inflammation by altering the balance between PG-G and PG levels in vivo.
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