{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T10:49:01Z","timestamp":1778237341374,"version":"3.51.4"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2018,12,1]],"date-time":"2018-12-01T00:00:00Z","timestamp":1543622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R15ES015348"],"award-info":[{"award-number":["R15ES015348"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R15GM128206"],"award-info":[{"award-number":["R15GM128206"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MSU-CVM Office of Research and Graduate Studies","award":["Pilot Funds"],"award-info":[{"award-number":["Pilot Funds"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Endocannabinoid-metabolizing enzymes are downregulated in response to lipopolysaccharide (LPS)-induced inflammation in mice, which may serve as a negative feedback mechanism to increase endocannabinoid levels and reduce inflammation. Increased plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) and decreased fatty acid amide hydrolase (FAAH) activity in peripheral lymphocytes from individuals diagnosed with Huntington\u2019s disease (HD) suggests that a similar negative feedback system between inflammation and the endocannabinoid system operates in humans. We investigated whether CpG- (unmethylated bacterial DNA) and LPS-induced IL-6 levels in peripheral blood mononuclear cells (PBMCs) from non-HD and HD individuals modulated the activities of endocannabinoid hydrolases monoacylglycerol lipase (MAGL) and carboxylesterase (CES). Baseline plasma IL-6 levels and 2-arachidonoylglycerol (2-AG) hydrolytic activity in PBMC lysates were not different in HD and non-HD individuals. Inhibition of MAGL and CES1 activity in PBMCs using the inhibitors JZL184 and WWL113, respectively, demonstrated that MAGL was the dominant 2-AG hydrolytic enzyme in PBMCs, regardless of disease state. Correlative analyses of 2-AG hydrolytic activity versus enzyme abundance confirmed this conclusion. Flow cytometric analysis of PBMCs showed that MAGL and CES1 were primarily expressed in monocytes and to a lesser extent in lymphocytes. In conclusion, these data suggest that IL-6 did not influence 2-AG hydrolytic activity in human PBMCs; however, monocytic MAGL was shown to be the predominant 2-AG hydrolytic enzyme.<\/jats:p>","DOI":"10.3390\/molecules23123167","type":"journal-article","created":{"date-parts":[[2018,12,3]],"date-time":"2018-12-03T06:02:09Z","timestamp":1543816929000},"page":"3167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Characterization of Endocannabinoid-Metabolizing Enzymes in Human Peripheral Blood Mononuclear Cells under Inflammatory Conditions"],"prefix":"10.3390","volume":"23","author":[{"given":"Brittany N.","family":"Szafran","sequence":"first","affiliation":[{"name":"Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, MS 39759, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung Hwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, MS 39759, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdolsamad","family":"Borazjani","sequence":"additional","affiliation":[{"name":"Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, MS 39759, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Morrison","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Rochester, Rochester, NY 14627, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3233-2811","authenticated-orcid":false,"given":"Grace","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Rochester, Rochester, NY 14627, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly L.","family":"Andrzejewski","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Rochester, Rochester, NY 14627, USA"},{"name":"Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, NY 14211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9167-8452","authenticated-orcid":false,"given":"Matthew K.","family":"Ross","sequence":"additional","affiliation":[{"name":"Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, MS 39759, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1992-4145","authenticated-orcid":false,"given":"Barbara L.F.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, MS 39759, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,12,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1007\/s11481-013-9445-9","article-title":"Cannabinoid receptor 2: Potential role in immunomodulation and neuroinflammation","volume":"8","author":"Rom","year":"2013","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.pharmthera.2012.12.004","article-title":"The role of CB1 in immune modulation by cannabinoids","volume":"137","author":"Kaplan","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1111\/j.1476-5381.2012.02237.x","article-title":"The monoacylglycerol lipase inhibitor JZL184 attenuates LPS-induced increases in cytokine expression in the rat frontal cortex and plasma: Differential mechanisms of action","volume":"169","author":"Kerr","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1093\/toxsci\/kft126","article-title":"Induction of endocannabinoid levels in juvenile rat brain following developmental chlorpyrifos exposure","volume":"135","author":"Carr","year":"2013","journal-title":"Toxicol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7559","DOI":"10.1021\/bi401138s","article-title":"Identification of palmitoyl protein thioesterase 1 in human THP1 monocytes and macrophages and characterization of unique biochemical activities for this enzyme","volume":"52","author":"Wang","year":"2013","journal-title":"Biochemistry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1021\/tx1002194","article-title":"Inactivation of lipid glyceryl ester metabolism in human THP1 monocytes\/macrophages by activated organophosphorus insecticides: Role of carboxylesterases 1 and 2","volume":"23","author":"Xie","year":"2010","journal-title":"Chem. Res. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/j.1748-1716.2011.02280.x","article-title":"The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors","volume":"204","author":"Savinainen","year":"2012","journal-title":"Acta Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.biopsych.2015.07.028","article-title":"An introduction to the endogenous cannabinoid system","volume":"79","author":"Lu","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.prostaglandins.2015.09.005","article-title":"Lipopolysaccharide suppresses carboxylesterase 2g activity and 2-arachidonoylglycerol hydrolysis: A possible mechanism to regulate inflammation","volume":"121","author":"Szafran","year":"2015","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S0014-2999(00)00653-1","article-title":"2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factor-alpha production in murine macrophages, and in mice","volume":"406","author":"Gallily","year":"2000","journal-title":"Eur. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.brainres.2011.03.020","article-title":"Administration of 2-arachidonoylglycerol ameliorates both acute and chronic experimental autoimmune encephalomyelitis","volume":"1390","author":"Lourbopoulos","year":"2011","journal-title":"Brain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/glia.10177","article-title":"Cannabinoids ablate release of TNF? In rat microglial cells stimulated with lypopolysaccharide","volume":"41","author":"Facchinetti","year":"2002","journal-title":"Glia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1096\/fj.10-176602","article-title":"Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation","volume":"25","author":"Alhouayek","year":"2011","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"403","DOI":"10.3109\/08830185.2014.921165","article-title":"Role of endocannabinoid activation of peripheral CB1 receptors in the regulation of autoimmune disease","volume":"34","author":"Sido","year":"2015","journal-title":"Int. Rev. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.lfs.2012.06.020","article-title":"The monoacylglycerol lipase inhibitor JZL184 suppresses inflammatory pain in the mouse carrageenan model","volume":"92","author":"Ghosh","year":"2013","journal-title":"Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pihlaja, R., Takkinen, J., Eskola, O., Vasara, J., L\u00f3pez-Pic\u00f3n, F.R., Haaparanta-Solin, M., and Rinne, J.O. (2015). Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells. J. Neuroinflammation, 12.","DOI":"10.1186\/s12974-015-0305-9"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.drudis.2013.07.009","article-title":"Controlling 2-arachidonoylglycerol metabolism as an anti-inflammatory strategy","volume":"19","author":"Alhouayek","year":"2014","journal-title":"Drug Discov. Today"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejphar.2015.04.018","article-title":"The monoacylglycerol lipase inhibitor JZL184 decreases inflammatory response in skeletal muscle contusion in rats","volume":"761","author":"Jiang","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1124\/mol.107.036889","article-title":"Interleukin-6 alters the cellular responsiveness to clopidogrel, irinotecan, and oseltamivir by suppressing the expression of carboxylesterases HCE1 and HCE2","volume":"72","author":"Yang","year":"2007","journal-title":"Mol. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1097\/00005072-198511000-00003","article-title":"Neuropathological classification of Huntington\u2019s disease","volume":"44","author":"Vonsattel","year":"1985","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/ene.13413","article-title":"Huntington\u2019s disease: A clinical review","volume":"25","author":"McColgan","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1084\/jem.20080178","article-title":"A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington\u2019s disease","volume":"205","author":"Wild","year":"2008","journal-title":"J. Exp. Medicine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.it.2015.04.007","article-title":"The choreography of neuroinflammation in Huntington\u2019s disease","volume":"36","author":"Crotti","year":"2015","journal-title":"Trends Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"18259","DOI":"10.1523\/JNEUROSCI.4008-12.2012","article-title":"Cannabinoid receptor 2 signaling in peripheral immune cells modulates disease onset and severity in mouse models of Huntington\u2019s disease","volume":"32","author":"Bouchard","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.bbi.2014.09.011","article-title":"Plasma inflammatory biomarkers for Huntington\u2019s disease patients and mouse model","volume":"44","author":"Chang","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1021\/pr0700753","article-title":"Proteomic profiling of plasma in Huntington\u2019s disease reveals neuroinflammatory activation and biomarker candidates","volume":"6","author":"Dalrymple","year":"2007","journal-title":"J. Proteome Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.nbd.2007.04.012","article-title":"Severe deficiency of the fatty acid amide hydrolase (FAAH) activity segregates with the Huntington\u2019s disease mutation in peripheral lymphocytes","volume":"27","author":"Battista","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3376","DOI":"10.1111\/febs.12329","article-title":"In vitro and in vivo models of Huntington\u2019s disease show alterations in the endocannabinoid system","volume":"280","author":"Bari","year":"2013","journal-title":"FEBS J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.taap.2011.10.017","article-title":"Inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by chlorpyrifos oxon, paraoxon and methyl paraoxon","volume":"258","author":"Crow","year":"2012","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/nchembio.1429","article-title":"Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes","volume":"10","author":"Dominguez","year":"2013","journal-title":"Nat. Chem. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18832","DOI":"10.1016\/S0021-9258(18)55139-5","article-title":"A serine esterase released by human alveolar macrophages is closely related to liver microsomal carboxylesterases","volume":"266","author":"Munger","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.bbalip.2008.07.005","article-title":"Inhibition of carboxylesterase 1 is associated with cholesteryl ester retention in human THP-1 monocyte\/macrophages","volume":"1781","author":"Crow","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physiolgenomics.2000.2.1.1","article-title":"Cholesteryl ester hydrolase in human monocyte\/macrophage: Cloning, sequencing, and expression of full-length cDNA","volume":"2","author":"Ghosh","year":"2000","journal-title":"Physiol. Genomics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.intimp.2006.11.008","article-title":"Temporal variation in CB2R levels following T lymphocyte activation: Evidence that cannabinoids modulate CXCL12-induced chemotaxis","volume":"7","author":"Coopman","year":"2007","journal-title":"Int. Immunopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/j.1365-2826.2008.01685.x","article-title":"The role of the endocannabinoid system in atherosclerosis","volume":"20","author":"Mach","year":"2008","journal-title":"J. Neuroendocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s004030000148","article-title":"Evidence for degradation of cytokines in the serum of patients with atopic dermatitis by calcium-dependent protease","volume":"292","author":"Niwa","year":"2000","journal-title":"Arch. Dermatol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1097\/MCO.0b013e32833cf3bc","article-title":"Conceptual and methodological issues relevant to cytokine and inflammatory marker measurements in clinical research","volume":"13","author":"Zhou","year":"2010","journal-title":"Curr. Opion Clical Nutr. Metab. Care"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.cyto.2017.05.014","article-title":"Effect of the anticoagulant, storage time and temperature of blood samples on the concentrations of 27 multiplex assayed cytokines\u2014Consequences for defining reference values in healthy humans","volume":"97","author":"Henno","year":"2017","journal-title":"Cytokine"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7057","DOI":"10.3390\/ijms16047057","article-title":"Elevated levels of endocannabinoids in chronic hepatitis C may modulate cellular immune response and hepatic stellate cell activation","volume":"16","author":"Patsenker","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s00335-010-9284-4","article-title":"Recommended nomenclature for five mammalian carboxylesterase gene families: Human, mouse, and rat genes and proteins","volume":"21","author":"Holmes","year":"2010","journal-title":"Mamm. Genome"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.tem.2011.03.003","article-title":"Role of endoplasmic reticulum neutral lipid hydrolases","volume":"22","author":"Quiroga","year":"2011","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Corkum, C.P., Ings, D.P., Burgess, C., Karwowska, S., Kroll, W., and Michalak, T.I. (2015). Immune cell subsets and their gene expression profiles from human PBMC isolated by Vacutainer Cell Preparation Tube (CPT) and standard density gradient. BMC Immunol., 16.","DOI":"10.1186\/s12865-015-0113-0"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1002\/cyto.a.20859","article-title":"Evaluation of a 12-color flow cytometry panel to study lymphocyte, monocyte, and dendritic cell subsets in humans","volume":"77","author":"Autissier","year":"2010","journal-title":"Cytometry A."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1091\/mbc.e04-03-0224","article-title":"Triacylglycerol hydrolase is localized to the endoplasmic reticulum by an unusual retrieval sequence where it participates in VLDL assembly without utilizing VLDL lipids as substrates","volume":"16","author":"Gilham","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/j.chembiol.2007.11.006","article-title":"A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol","volume":"14","author":"Blankman","year":"2007","journal-title":"Chem. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s11010-017-3237-0","article-title":"Endocannabinoid hydrolases in avian HD11 macrophages identified by chemoproteomics: Inactivation by small-molecule inhibitors and pathogen-induced downregulation of their activity","volume":"444","author":"Lee","year":"2018","journal-title":"Mol. Cell. Biochem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/12\/3167\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:33:49Z","timestamp":1760196829000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/12\/3167"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,1]]},"references-count":46,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["molecules23123167"],"URL":"https:\/\/doi.org\/10.3390\/molecules23123167","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,1]]}}}