Characterization of Endocannabinoid-Metabolizing Enzymes in Human Peripheral Blood Mononuclear Cells under Inflammatory Conditions

• Published in: Molecules (Basel, Switzerland) Switzerland), 2018-12, Vol.23 (12), p.3167
• Main Authors: Szafran, Brittany N, Lee, Jung Hwa, Borazjani, Abdolsamad, Morrison, Peter, Zimmerman, Grace, Andrzejewski, Kelly L, Ross, Matthew K, Kaplan, Barbara L F
• Format: Article
• Language: English
• Subjects: 2-Arachidonoylglycerol; Alzheimer's disease; Arachidonic Acids - metabolism; Biomarkers; Blood; Carboxylesterase; Carboxylic Ester Hydrolases - genetics; Carboxylic Ester Hydrolases - metabolism; CES; Correlation analysis; CpG islands; Cytokines - blood; Cytokines - metabolism; Deoxyribonucleic acid; DNA; Endocannabinoid system; endocannabinoids; Endocannabinoids - metabolism; Enzymes; Fatty-acid amide hydrolase; Feedback; Flow cytometry; Gene Expression Regulation, Enzymologic; Glycerides - metabolism; Humans; Huntington's disease; Hydrolase; Hydrolysis; Inflammation; Inflammation - enzymology; Inflammation - genetics; Inflammation - metabolism; Inflammation Mediators - blood; Inflammation Mediators - metabolism; Interleukin 6; Leukocytes (mononuclear); Leukocytes, Mononuclear - enzymology; Leukocytes, Mononuclear - metabolism; Lipopolysaccharides; Lymphocytes; Lymphocytes - immunology; Lymphocytes - metabolism; Lysates; MAGL; Monocytes; Negative feedback; Peripheral blood mononuclear cells; Plasma; Plasma levels; Proteins; Tumor necrosis factor-TNF
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules23123167

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's 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.