title: Progesterone activates fatty acid amide hydrolase (FAAH) promoter in human T lymphocytes through the transcription factor Ikaros. Evidence for a synergistic effect of leptin.
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 approximately 270% 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.
authors.affiliation: Department of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, 64100 Teramo, Italy. Maccarrone@vet.unibe.it
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Monica
authors.initials: M
authors.lastname: Bari
authors.forename: Marianna
authors.initials: M
authors.lastname: Di Rienzo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Finazzi-Agrò
authors.forename: Antonello
authors.initials: A
authors.lastname: Rossi
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D000581:Amidohydrolases / Q000235:genetics* / Q000378:metabolism*; D001095:Arachidonic Acids / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D015153:Blotting, Western; D063385:Cannabinoid Receptor Modulators; D002467:Cell Nucleus / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005989:Glycerides / Q000494:pharmacology; D006801:Humans; D051740:Ikaros Transcription Factor; D008969:Molecular Sequence Data; D009154:Mutation; D010739:Phospholipase D / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D011374:Progesterone / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014176:Protein Biosynthesis; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism; D054411:Receptors, Leptin; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000276:Adjuvants, Immunologic; D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D015500:Chloramphenicol O-Acetyltransferase; D004268:DNA-Binding Proteins; D063388:Endocannabinoids; D005989:Glycerides; D051740:Ikaros Transcription Factor; D010739:Phospholipase D; D053284:Polyunsaturated Alkamides; D011374:Progesterone; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D054411:Receptors, Leptin; D014157:Transcription Factors; D000099252:Fatty Acid Amide Hydrolases; C497239:IKZF1 protein, human; C515448:LEPR protein, human; C094503:glyceryl 2-arachidonate; C078814:anandamide