We have shown recently that in human T lymphocytes, leptin stimulates activity and expression of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH), through STAT3 (signal transducer and activator of transcription 3) and its CRE (cAMP response element)-like transcriptional target in the FAAH promoter [Maccarrone, M., Di Rienzo, M., Finazzi-Agro, A., & Rossi, A. (2003) J. Biol. Chem. 278, 13318-13324]. We have also shown that progesterone, alone or additively with leptin, up-regulates the FAAH gene in human T-cells, through the Ikaros transcription factor [Maccarrone, M., Bari, M., Di Rienzo, M., Finazzi-Agro, A., & Rossi, A. (2003) J. Biol. Chem. 278, 32726-32732]. Here, we extend these observations to immortalized human lymphoma U937 cells, where stimulation of FAAH by leptin (up to approximately 300% of the controls) involves binding to a leptin receptor (Kd = 2.0 +/- 0.1 nm, Bmax = 382 +/- 5 fmol.mg protein(-1), apparent molecular mass of approximately 110 kDa), and stimulation by progesterone involves an intracellular receptor of approximately 120 kDa. Unlike FAAH, the other proteins of the endocannabinoid system are not modulated by the two hormones. Interestingly, human neuroblastoma CHP100 cells also have a leptin receptor (approximately 110 kDa, Kd = 2.2 +/- 0.2 nm, Bmax = 339 +/- 8 fmol.mg protein(-1)), a progesterone receptor (approximately 120 kDa), STAT3 and Ikaros, yet their FAAH is not activated by leptin or progesterone. These data, corroborated by transient expression and electrophoretic mobility-shift assays, demonstrate an unprecedented cell-specific regulation of the FAAH gene, which has important implications for the control of tone and activity of AEA along the neuroimmune axis.