Progesterone up-regulates anandamide hydrolase in human lymphocytes: Role of cytokines and implications for fertility

Physiological concentrations of progesterone stimulate the activity of the endocannabinoid-degrading enzyme anandamide bydrolase (fatty acid amide hyd rolase, FAAH) in human lymphocytes. At the same concentrations, the membran e-impermeant conjugate of progesterone with BSA was ineffective, suggesting that binding to an intracellular receptor was needed for progesterone acti vity. Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational level, and was partly mediated by the Th2 cytokines. In fact, lymphocyte treatment with IL-4 or with IL-10 had a stimulating effect on FAAH, whereas the Th1 cytokines IL-12 and IFN-T redu ced the activity and the protein expression of FAAH. Human chorionic gonado tropin or cortisol had no effect on FAAH activity. At variance with FAAH, t he lymphocyte anandamide transporter and cannabinoid receptors were not aff ected by treatment with progesterone or cytokines. Good FAAH substrates suc h as anandamide and 2-arachidonoylglycerol inhibited the release of leukemi a-inhibitory factor from human lymphocytes, but N-palmitoylethanolamine, a poor substrate, did not. A clinical study performed on 100 healthy women sh owed that a low FAAH activity in lymphocytes correlates with spontaneous ab ortion, whereas anandamide transporter and cannabinoid receptors in these c ells remain unchanged. These results add the endocannabinoids to the hormon e-cytokine array involved in the control of human pregnancy.