Progesterone up-regulates anandamide hydrolase in human lymphocytes: role of cytokines and implications for fertility.
Physiological concentrations of progesterone stimulate the activity of the endocannabinoid-degrading enzyme anandamide hydrolase (fatty acid amide hydrolase, FAAH) in human lymphocytes. At the same concentrations, the membrane-impermeant conjugate of progesterone with BSA was ineffective, suggesting that binding to an intracellular receptor was needed for progesterone activity. Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational level, and was partly mediated by the Th2 cytokines. In fact, lymphocyte treatment with IL-4 or with IL-10 had a stimulating effect on FAAH, whereas the Th1 cytokines IL-12 and IFN-gamma reduced the activity and the protein expression of FAAH. Human chorionic gonadotropin or cortisol had no effect on FAAH activity. At variance with FAAH, the lymphocyte anandamide transporter and cannabinoid receptors were not affected by treatment with progesterone or cytokines. Good FAAH substrates such as anandamide and 2-arachidonoylglycerol inhibited the release of leukemia-inhibitory factor from human lymphocytes, but N-palmitoylethanolamine, a poor substrate, did not. A clinical study performed on 100 healthy women showed that a low FAAH activity in lymphocytes correlates with spontaneous abortion, whereas anandamide transporter and cannabinoid receptors in these cells remain unchanged. These results add the endocannabinoids to the hormone-cytokine array involved in the control of human pregnancy.
Maccarrone
M
M
Department of Experimental Medicine and Biochemical Sciences and Division of Obstetrics and Gynecology, University of Rome Tor Vergata, Rome, Italy.
Valensise
H
H
Bari
M
M
Lazzarin
N
N
Romanini
C
C
Finazzi-Agrò
A
A
D000328:Adult; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D000595:Amino Acid Sequence; D001095:Arachidonic Acids / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects / Q000276:immunology; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism; D016207:Cytokines / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology; D063388:Endocannabinoids; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D005298:Fertility / Q000276:immunology*; D006131:Growth Inhibitors / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D008969:Molecular Sequence Data; D053284:Polyunsaturated Alkamides; D011374:Progesterone / Q000502:physiology*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism / Q000502:physiology; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D016207:Cytokines; D063388:Endocannabinoids; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D053284:Polyunsaturated Alkamides; D011374:Progesterone; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000099252:Fatty Acid Amide Hydrolases; C507837:LIF protein, human; C078814:anandamide