Lipopolysaccharide downregulates fatty acid amide hydrolase expression andincreases anandamide levels in human peripheral lymphocytes

Lipopolysaccharide (LPS) increases the levels of the endogenous cannabinoid anandamide (N-arachidonoylethanolamine, AFA) in rat macrophages, but the m echanism responsible for this effect has not been elucidated. Here we demon strate that LPS enhances the levels of AEA (fourfold over controls) also in human lymphocytes. We show that in these cells LPS inhibits the activity o f the AEA-degrading enzyme fatty acid amide hydrolase (FAAH), by downregula ting the gene expression at transcriptional level. Lymphocytes have also a specific ARA transporter and a functional CB1 cannabinoid receptor, which w ere not modulated by LPS. The effect of this endotoxin on FAAH was not medi ated by AEA-induced activation of cannabinoid receptors. Conversely, the st imulatory action of LPS on AEA levels might be due to inhibition of FAAH, a s suggested by the observation that an increase of AFA amounts was also ind uced by an irreversible FAAH inhibitor. These results suggest that lymphocy tes take part in regulating the peripheral endocannabinoid system and endoc annabinoid homeostasis. (C) 2001 Academic Press.