Lipopolysaccharide downregulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes.
Lipopolysaccharide (LPS) increases the levels of the endogenous cannabinoid anandamide (N-arachidonoylethanolamine, AEA) in rat macrophages, but the mechanism responsible for this effect has not been elucidated. Here we demonstrate that LPS enhances the levels of AEA (fourfold over controls) also in human lymphocytes. We show that in these cells LPS inhibits the activity of the AEA-degrading enzyme fatty acid amide hydrolase (FAAH), by downregulating the gene expression at transcriptional level. Lymphocytes have also a specific AEA transporter and a functional CB1 cannabinoid receptor, which were not modulated by LPS. The effect of this endotoxin on FAAH was not mediated by AEA-induced activation of cannabinoid receptors. Conversely, the stimulatory action of LPS on AEA levels might be due to inhibition of FAAH, as suggested by the observation that an increase of AEA amounts was also induced by an irreversible FAAH inhibitor. These results suggest that lymphocytes take part in regulating the peripheral endocannabinoid system and endocannabinoid homeostasis.
Maccarrone
M
M
Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata,", Via di Tor Vergata 135, Rome, I-00133, Italy. Maccarrone@med.uniroma2.it
De Petrocellis
L
L
Bari
M
M
Fezza
F
F
Salvati
S
S
Di Marzo
V
V
Finazzi-Agrò
A
A
D000581:Amidohydrolases / Q000378:metabolism*; D001095:Arachidonic Acids / Q000378:metabolism*; D001665:Binding Sites; D001692:Biological Transport; D063385:Cannabinoid Receptor Modulators; D003511:Cyclohexanols / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D063388:Endocannabinoids; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D014316:Tritium; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D003511:Cyclohexanols; D063388:Endocannabinoids; D008070:Lipopolysaccharides; D053284:Polyunsaturated Alkamides; D014316:Tritium; D000099252:Fatty Acid Amide Hydrolases; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C078814:anandamide