Further insights into the regulation of human FAAH by progesterone and leptin - Implications for endogenous levels of anandamide and apoptosis of immune and neuronal cells

We have recently reported that leptin (L) and progesterone (P) stimulate the activity, and the expression of the endocannabinoid-degrading enzyme anandamide hydrolase (fatty acid amide hydrolase, FAAH) in human lymphoma U937 cells, but not in human neuroblastoma CHP100 cells. We have also shown that leptin and progesterone do not affect the proteins of the endocannabinoid system that synthesize and transport AEA. Here, we have summarized these findings, and have extended them by investigating the effect of leptin and progesterone oil the endogenous levels of AEA. We show that leptin and progesterone significantly reduce AEA content in U937 cells (down to similar to 20% and similar to 50% of the controls, respectively), whereas they are ineffective oil AEA levels in CHP100 cells. 117 addition, we show that leptin and progesterone prevent the pro-apoptotic activity, of AEA in U937 cells, reducing DNA fragmentation by similar to 50% and similar to 35% compared to controls, respectively. Instead, neither hormone affects apoptosis induced by AEA in CHP100 cells. Since the anti-apoptotic activity of leptin and progesterone parallels their effect oil FAAH, it can be suggested that enhanced degradation of AEA is the means to protect U937 cells against the toxicity of this compound. Altogether these data suggest that a cell-specific regulation of FAAH gene might modulate the apoptotic potential of endocannabinoids along the neuroimmune axis. These findings might be relevant for the development of cell-selective drugs targeted towards FAAH. (c) 2005 Elsevier Inc. All rights reserved.