PMID- 33225149
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201125
IS  - 2470-1343 (Electronic)
IS  - 2470-1343 (Linking)
VI  - 5
IP  - 45
DP  - 2020 Nov 17
TI  - 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.
PG  - 29177-29188
LID - 10.1021/acsomega.0c03961 [doi]
AB  - 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 muM). 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 TNFalpha) 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 PPARgamma, 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.
CI  - (c) 2020 American Chemical Society.
FAU - Scheaffer, Hannah L
AU  - Scheaffer HL
AD  - Department of Biochemistry, Molecular Biology, Entomology, & Plant Pathology, 
      College of Agriculture and Life Sciences, Mississippi State University, 
      Mississippi State, Mississippi 39762, United States.
FAU - Borazjani, Abdolsamad
AU  - Borazjani A
AD  - Center for Environmental Health Sciences, Department of Comparative Biomedical 
      Sciences, College of Veterinary Medicine, Mississippi State University, 
      Mississippi State, Mississippi 39762, United States.
FAU - Szafran, Brittany N
AU  - Szafran BN
AD  - Center for Environmental Health Sciences, Department of Comparative Biomedical 
      Sciences, College of Veterinary Medicine, Mississippi State University, 
      Mississippi State, Mississippi 39762, United States.
FAU - Ross, Matthew K
AU  - Ross MK
AD  - Center for Environmental Health Sciences, Department of Comparative Biomedical 
      Sciences, College of Veterinary Medicine, Mississippi State University, 
      Mississippi State, Mississippi 39762, United States.
LA  - eng
GR  - R15 GM128206/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20201103
PL  - United States
TA  - ACS Omega
JT  - ACS omega
JID - 101691658
PMC - PMC7675540
COIS- The authors declare no competing financial interest.
EDAT- 2020/11/24 06:00
MHDA- 2020/11/24 06:01
PMCR- 2020/11/03
CRDT- 2020/11/23 05:42
PHST- 2020/08/17 00:00 [received]
PHST- 2020/10/19 00:00 [accepted]
PHST- 2020/11/23 05:42 [entrez]
PHST- 2020/11/24 06:00 [pubmed]
PHST- 2020/11/24 06:01 [medline]
PHST- 2020/11/03 00:00 [pmc-release]
AID - 10.1021/acsomega.0c03961 [doi]
PST - epublish
SO  - ACS Omega. 2020 Nov 3;5(45):29177-29188. doi: 10.1021/acsomega.0c03961. 
      eCollection 2020 Nov 17.