Leptin activates the anandamide hydrolase promoter in human T lymphocytes through STAT3.
Physiological concentrations of leptin stimulate the activity of the endocannabinoid-degrading enzyme anandamide hydrolase (fatty acid amide hydrolase, FAAH) in human T lymphocytes up to approximately 300% over the untreated controls. Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational levels and involved binding of leptin to its receptor with an apparent dissociation constant (K(d)) of 1.95 +/- 0.14 nm and maximum binding (B(max)) of 392 +/- 8 fmol x mg protein(-1). Leptin binding to the receptor triggered activation of STAT3 but not STAT1 or STAT5 or the mitogen-activated protein kinases p38, p42, and p44. Peripheral lymphocytes of leptin knock-out (ob/ob) mice showed decreased FAAH activity and expression (approximately 25% of the wild-type littermates), which were reversed to control levels by exogenous leptin. Analysis of the FAAH promoter showed a cAMP-response element-like site, which is a transcriptional target of STAT3. Consistently, mutation of this site prevented FAAH activation by leptin in transient expression assays. Electrophoretic mobility shift and supershift assays further corroborated the promoter activity data. Taken together, these results suggest that leptin, by up-regulating the FAAH promoter through STAT3, enhances FAAH expression, thus tuning the immunomodulatory effects of anandamide. These findings might also have critical implications for human fertility.
Maccarrone
Mauro
M
Department of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, 64100 Teramo, Italy. Maccarrone@vet.unite.it
Di Rienzo
Marianna
M
Finazzi-Agrò
Alessandro
A
Rossi
Antonello
A
D000209:Acute-Phase Proteins / Q000378:metabolism; D000581:Amidohydrolases / Q000235:genetics*; D001483:Base Sequence; D063385:Cannabinoid Receptor Modulators; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D020738:Leptin / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011956:Receptors, Cell Surface / Q000502:physiology; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D013601:T-Lymphocytes / Q000201:enzymology / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D000099252:Fatty Acid Amide Hydrolases
D000209:Acute-Phase Proteins; D000581:Amidohydrolases; D063385:Cannabinoid Receptor Modulators; D017931:DNA Primers; D004268:DNA-Binding Proteins; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000099252:Fatty Acid Amide Hydrolases; C515448:LEPR protein, human; C494086:STAT3 protein, human