Progesterone Activates Fatty Acid Amide Hydrolase (FAAH) Promoter in Human T Lymphocytes through the Transcription Factor Ikaros

Abstract

Physiological concentrations of progesterone stimulate the activity of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) in human T lymphocytes, up to a ϳ270% over the untreated controls. Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational level and was specific. Indeed, neither the activity of the anandamide-synthesizing N-acyltransferase and phospholipase D, nor the activity of the anandamide transporter, nor the binding to cannabinoid receptors were affected by progesterone under the same experimental conditions. The activation of FAAH by progesterone was paralleled by a decrease (down to 60%) of the cellular levels of anandamide and involved increased nuclear levels of the transcription factor Ikaros. Analysis of the FAAH promoter showed an Ikaros binding site, and mutation of this site prevented FAAH activation by progesterone in transient expression assays. Electrophoretic mobility shift and supershift assays further corroborated the promoter activity data. Furthermore, the effect of progesterone on FAAH promoter was additive to that of physiological amounts of leptin, which binds to a cAMP response element-like site in the promoter region. Taken together, these results suggest that progesterone and leptin, by up-regulating the FAAH promoter at different sites, enhance FAAH expression, thus tuning the immunomodulatory effects of anandamide. These findings might also have critical implications for human fertility.

A Critical Interaction between Dopamine D2 Receptors and Endocannabinoids Mediates the Effects of Cocaine on Striatal GABAergic Transmission

“…However, our values are in the same range as the endogenous levels of AEA in rat substantia nigra and globus pallidus (Di Marzo et al, 2000), in mouse cortex and hippocampus (Maccarrone et al, 2001), and in mouse uterus (Schmid et al, 1997). In addition, we have recently measured by our GC-MS procedure the levels of AEA in human T lymphocytes treated or not with progesterone, and found differences superimposable to those found in the same samples in Dr Kunos' laboratory at NIAAA-NIH by liquid chromatography-mass spectrometry (reported in Maccarrone et al, 2003b). Furthermore, the endogenous levels of AEA that we found in human keratinocytes (Maccarrone et al, 2003c) were comparable to those reported by others in mouse epidermal cells (Berdyshev et al, 2000).…”

Characterization of the endocannabinoid system in boar spermatozoa and implications for sperm capacitation and acrosome reaction

“…Moreover, AEA uptake by sperm cells was completely blocked by VDM11, a selective AMT inhibitor (De Petrocellis et al, 2001). In addition, sperm cells had an active FAAH, whose affinity and maximum velocity towards AEA resembled those of the same enzyme in human lymphocytes (Maccarrone et al, 2003a) and in rat Sertoli cells (Maccarrone et al, 2003b). As in lymphocytes and Sertoli cells, AEA hydrolysis was fully blocked by MAFP, a selective FAAH inhibitor (De Petrocellis et al, 2001).…”

“…For example, low FAAH in circulating maternal lymphocytes has been shown to be an early (<8 weeks of gestation) predictor of spontaneous abortion in humans (Maccarrone and Finazzi-Agrò, 2004), and consistently FAAH expression is under control of fertility signals like progesterone and leptin (Maccarrone et al, 2003a). By contrast, mouse uterus contains the highest amounts of AEA as yet measured in any tissue (Paria and Dey, 2000), and uterine AEA can activate CB1 receptors in this organ, thus allowing epithelial changes needed for reproduction (Maccarrone and Finazzi-Agrò, 2004).…”

Contributions of phosphorylation to regulation of OCTN2 uptake of carnitine are minimal in BeWo cells

“…However, the strong inhibition of carnitine uptake by progesterone without the accompanying impact on ALP activity suggests other effects of this hormone on OCTN2-mediated transport function. Progesterone is an essential steroid for maintenance of pregnancy, and it is involved in the regulation of the glucose transporter GLUT1, the peptide transporter PEPT1, and other enzymes [26][27][28]. Since the inhibition of carnitine uptake by progesterone was seen after only 20 minutes of preincubation, it is not likely that hormonal regulation of OCTN2 is responsible for these observations.…”