Inactivation of CES1 Blocks Prostaglandin D 2 Glyceryl Ester Catabolism in Monocytes/Macrophages and Enhances Its Anti-inflammatory Effects, Whereas the Pro-inflammatory Effects of Prostaglandin E 2 Glyceryl Ester Are Attenuated.

Autor: Scheaffer HL; Department of Biochemistry, Molecular Biology, Entomology, & Plant Pathology, College of Agriculture and Life Sciences, Mississippi State University, Mississippi State, Mississippi 39762, United States., Borazjani A; Center for Environmental Health Sciences, Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762, United States., Szafran BN; Center for Environmental Health Sciences, Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762, United States., Ross MK; Center for Environmental Health Sciences, Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762, United States.
Jazyk: angličtina
Zdroj: ACS omega [ACS Omega] 2020 Nov 03; Vol. 5 (45), pp. 29177-29188. Date of Electronic Publication: 2020 Nov 03 (Print Publication: 2020).
DOI: 10.1021/acsomega.0c03961
Abstrakt: Human monocytic cells in blood have important roles in host defense and express the enzyme carboxylesterase 1 (CES1). This metabolic serine hydrolase plays a critical role in the metabolism of many molecules, including lipid mediators called prostaglandin glyceryl esters (PG-Gs), which are formed during cyclooxygenase-mediated oxygenation of the endocannabinoid 2-arachidonoylglycerol. Some PG-Gs have been shown to exhibit anti-inflammatory effects; however, they are unstable compounds, and their hydrolytic breakdown generates pro-inflammatory prostaglandins. We hypothesized that by blocking the ability of CES1 to hydrolyze PG-Gs in monocytes/macrophages, the beneficial effects of anti-inflammatory prostaglandin D 2 -glyceryl ester (PGD 2 -G) could be augmented. The goals of this study were to determine whether PGD 2 -G is catabolized by CES1, evaluate the degree to which this metabolism is blocked by small-molecule inhibitors, and assess the immunomodulatory effects of PGD 2 -G in macrophages. A human monocytic cell line (THP-1 cells) was pretreated with increasing concentrations of known small-molecule inhibitors that block CES1 activity [chlorpyrifos oxon (CPO), WWL229, or WWL113], followed by incubation with PGD 2 -G (10 μM). Organic solvent extracts of the treated cells were analyzed by liquid chromatography with tandem mass spectrometry to assess levels of the hydrolysis product PGD 2 . Further, THP-1 monocytes with normal CES1 expression (control cells) and "knocked-down" CES1 expression (CES1KD cells) were employed to confirm CES1's role in PGD 2 -G catabolism. We found that CES1 has a prominent role in PGD 2 -G hydrolysis in this cell line, accounting for about 50% of its hydrolytic metabolism, and that PGD 2 -G could be stabilized by the inclusion of CES1 inhibitors. The inhibitor potency followed the rank order: CPO > WWL113 > WWL229. THP-1 macrophages co-treated with WWL113 and PGD 2 -G prior to stimulation with lipopolysaccharide exhibited a more pronounced attenuation of pro-inflammatory cytokine levels (interleukin-6 and TNFα) than by PGD 2 -G treatment alone. In contrast, prostaglandin E 2 -glyceryl ester (PGE 2 -G) had opposite effects compared to those of PGD 2 -G, which appeared to be dependent on the hydrolysis of PGE 2 -G to PGE 2 . These results suggest that the anti-inflammatory effects induced by PGD 2 -G can be further augmented by inactivating CES1 activity with specific small-molecule inhibitors, while pro-inflammatory effects of PGE 2 -G are attenuated. Furthermore, PGD 2 -G (and/or its downstream metabolites) was shown to activate the lipid-sensing receptor PPARγ, resulting in altered "alternative macrophage activation" response to the Th2 cytokine interleukin-4. These findings suggest that inhibition of CES1 and other enzymes that regulate the levels of pro-resolving mediators such as PGD 2 -G in specific cellular niches might be a novel anti-inflammatory approach.
Competing Interests: The authors declare no competing financial interest.
(© 2020 American Chemical Society.)
Databáze: MEDLINE
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