Human leukocytes differentially express endocannabinoid‐glycerol lipases and hydrolyze 2‐arachidonoyl‐glycerol and its metabolites from the 15‐lipoxygenase and cyclooxygenase pathways
Abstract2‐Arachidonoyl‐glycerol (2‐AG) is an endocannabinoid with anti‐inflammatory properties. Blocking 2‐AG hydrolysis to enhance CB2 signaling has proven effective in mouse models of inflammation. However, the expression of 2‐AG lipases has never been thoroughly investigated in human leukocytes. Herein, we investigated the expression of seven 2‐AG hydrolases by human blood leukocytes and alveolar macrophages (AMs) and found the following protein expression pattern: monoacylglycerol (MAG lipase; eosinophils, AMs, monocytes), carboxylesterase (CES1; monocytes, AMs), palmitoyl‐protein thioesterase (PPT1; AMs), α/β‐hydrolase domain (ABHD6; mainly AMs), ABHD12 (all), ABHD16A (all), and LYPLA2 (lysophospholipase 2; monocytes, lymphocytes, AMs). We next found that all leukocytes could hydrolyze 2‐AG and its metabolites derived from cyclooxygenase‐2 (prostaglandin E2‐glycerol [PGE2‐G]) and the 15‐lipoxygenase (15‐hydroxy‐eicosatetraenoyl‐glycerol [15‐HETE‐G]). Neutrophils and eosinophils were consistently better at hydrolyzing 2‐AG and its metabolites than monocytes and lymphocytes. Moreover, the efficacy of leukocytes to hydrolyze 2‐AG and its metabolites was 2‐AG ≥ 15‐HETE‐G >> PGE2‐G for each leukocyte. Using the inhibitors methylarachidonoyl‐fluorophosphonate (MAFP), 4‐nitrophenyl‐4‐(dibenzo[d][1,3]dioxol‐5‐yl(hydroxy)methyl)piperidine‐1‐carboxylate (JZL184), Palmostatin B, 4′‐carbamoylbiphenyl‐4‐yl methyl(3‐(pyridin‐4‐yl)benzyl)carbamate, N‐methyl‐N‐[[3‐(4‐pyridinyl)phenyl]methyl]‐4′‐(aminocarbonyl)[1,1′‐biphenyl]‐4‐yl ester carbamic acid (WWL70), 4′‐[[[methyl[[3‐(4‐pyridinyl)phenyl]methyl]amino]carbonyl]oxy]‐[1,1′‐biphenyl]‐4‐carboxylic acid, ethyl ester (WWL113), tetrahydrolipstatin, and ML349, we could not pinpoint a specific hydrolase responsible for the hydrolysis of 2‐AG, PGE2‐G, and 15‐HETE‐G by these leukocytes. Furthermore, JZL184, a selective MAG lipase inhibitor, blocked the hydrolysis of 2‐AG, PGE2‐G, and 15‐HETE‐G by neutrophils and the hydrolysis of PGE2‐G and 15‐HETE‐G by lymphocytes, two cell types with limited/no MAG lipase. Using an activity‐based protein profiling (ABPP) probe to label hydrolases in leukocytes, we found that they express many MAFP‐sensitive hydrolases and an unknown JZL184‐sensitive hydrolase of ∼52 kDa. Altogether, our results indicate that human leukocytes are experts at hydrolyzing 2‐AG and its metabolites via multiple lipases and probably via a yet‐to‐be characterized 52 kDa hydrolase. Blocking 2‐AG hydrolysis in humans will likely abrogate the ability of human leukocytes to degrade 2‐AG and its metabolites and increase their anti‐inflammatory effects in vivo..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:106 |
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| Enthalten in: |
Journal of leukocyte biology - 106(2019), 6, Seite 1337-1347 |
| Beteiligte Personen: |
Turcotte, Caroline [VerfasserIn] |
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| BKL: |
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| Anmerkungen: |
©2019 Society for Leukocyte Biology |
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| Umfang: |
11 |
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| doi: |
10.1002/JLB.3A0919-049RRR |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Turcotte, Caroline |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Human leukocytes differentially express endocannabinoid‐glycerol lipases and hydrolyze 2‐arachidonoyl‐glycerol and its metabolites from the 15‐lipoxygenase and cyclooxygenase pathways |
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| 520 | |a Abstract2‐Arachidonoyl‐glycerol (2‐AG) is an endocannabinoid with anti‐inflammatory properties. Blocking 2‐AG hydrolysis to enhance CB2 signaling has proven effective in mouse models of inflammation. However, the expression of 2‐AG lipases has never been thoroughly investigated in human leukocytes. Herein, we investigated the expression of seven 2‐AG hydrolases by human blood leukocytes and alveolar macrophages (AMs) and found the following protein expression pattern: monoacylglycerol (MAG lipase; eosinophils, AMs, monocytes), carboxylesterase (CES1; monocytes, AMs), palmitoyl‐protein thioesterase (PPT1; AMs), α/β‐hydrolase domain (ABHD6; mainly AMs), ABHD12 (all), ABHD16A (all), and LYPLA2 (lysophospholipase 2; monocytes, lymphocytes, AMs). We next found that all leukocytes could hydrolyze 2‐AG and its metabolites derived from cyclooxygenase‐2 (prostaglandin E2‐glycerol [PGE2‐G]) and the 15‐lipoxygenase (15‐hydroxy‐eicosatetraenoyl‐glycerol [15‐HETE‐G]). Neutrophils and eosinophils were consistently better at hydrolyzing 2‐AG and its metabolites than monocytes and lymphocytes. Moreover, the efficacy of leukocytes to hydrolyze 2‐AG and its metabolites was 2‐AG ≥ 15‐HETE‐G >> PGE2‐G for each leukocyte. Using the inhibitors methylarachidonoyl‐fluorophosphonate (MAFP), 4‐nitrophenyl‐4‐(dibenzo[d][1,3]dioxol‐5‐yl(hydroxy)methyl)piperidine‐1‐carboxylate (JZL184), Palmostatin B, 4′‐carbamoylbiphenyl‐4‐yl methyl(3‐(pyridin‐4‐yl)benzyl)carbamate, N‐methyl‐N‐[[3‐(4‐pyridinyl)phenyl]methyl]‐4′‐(aminocarbonyl)[1,1′‐biphenyl]‐4‐yl ester carbamic acid (WWL70), 4′‐[[[methyl[[3‐(4‐pyridinyl)phenyl]methyl]amino]carbonyl]oxy]‐[1,1′‐biphenyl]‐4‐carboxylic acid, ethyl ester (WWL113), tetrahydrolipstatin, and ML349, we could not pinpoint a specific hydrolase responsible for the hydrolysis of 2‐AG, PGE2‐G, and 15‐HETE‐G by these leukocytes. Furthermore, JZL184, a selective MAG lipase inhibitor, blocked the hydrolysis of 2‐AG, PGE2‐G, and 15‐HETE‐G by neutrophils and the hydrolysis of PGE2‐G and 15‐HETE‐G by lymphocytes, two cell types with limited/no MAG lipase. Using an activity‐based protein profiling (ABPP) probe to label hydrolases in leukocytes, we found that they express many MAFP‐sensitive hydrolases and an unknown JZL184‐sensitive hydrolase of ∼52 kDa. Altogether, our results indicate that human leukocytes are experts at hydrolyzing 2‐AG and its metabolites via multiple lipases and probably via a yet‐to‐be characterized 52 kDa hydrolase. Blocking 2‐AG hydrolysis in humans will likely abrogate the ability of human leukocytes to degrade 2‐AG and its metabolites and increase their anti‐inflammatory effects in vivo. | ||
| 700 | 1 | |a Dumais, Élizabeth |4 aut | |
| 700 | 1 | |a Archambault, Anne‐Sophie |4 aut | |
| 700 | 1 | |a Martin, Cyril |4 aut | |
| 700 | 1 | |a Blanchet, Marie‐Renée |4 aut | |
| 700 | 1 | |a Bissonnette, Élyse |4 aut | |
| 700 | 1 | |a Boulet, Louis‐Philippe |4 aut | |
| 700 | 1 | |a Laviolette, Michel |4 aut | |
| 700 | 1 | |a Di Marzo, Vincenzo |4 aut | |
| 700 | 1 | |a Flamand, Nicolas |4 aut | |
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