Anandamide Suppresses Proinflammatory T Cell Responses In Vitro through Type-1 Cannabinoid Receptor-Mediated mTOR Inhibition in Human Keratinocytes.
The endocannabinoid system comprises cannabinoid receptors 1 and 2 (CB1and CB2), their endogenous ligands, anandamide (AEA) and 2-arachidonoylglycerol, and metabolic enzymes of these ligands. The endocannabinoid system has recently been implicated in the regulation of various pathophysiological processes of the skin that include immune competence and/or tolerance of keratinocytes, the disruption of which might promote the development of skin diseases. Recent evidence showed that CB1in keratinocytes limits the secretion of proinflammatory chemokines, suggesting that this receptor might also regulate T cell dependent inflammatory diseases of the skin. In this article, we sought to investigate the cytokine profile of IFN-γ-activated keratinocytes, and found that CB1activation by AEA suppressed production and release of signature TH1- and TH17-polarizing cytokines, IL-12 and IL-23, respectively. We also set up cocultures between a conditioned medium of treated keratinocytes and naive T cells to disclose the molecular details that regulate the activation of highly proinflammatory TH1 and TH17 cells. AEA-treated keratinocytes showed reduced an induction of IFN-γ-producing TH1 and IL-17-producing TH17 cells, and these effects were reverted by pharmacological inhibition of CB1Further analyses identified mammalian target of rapamycin as a proinflammatory signaling pathway regulated by CB1, able to promote either IL-12 and IL-23 release from keratinocytes or TH1 and TH17 polarization. Taken together, these findings demonstrate that AEA suppresses highly pathogenic T cell subsets through CB1-mediated mammalian target of rapamycin inhibition in human keratinocytes. Thus, it can be speculated that the latter pathway might be beneficial to the physiological function of the skin, and can be targeted toward inflammation-related skin diseases.
Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy.|Neurochemistry of Lipids, European Center for Brain Research, Santa Lucia Foundation, 00164 Rome, Italy.
Valerio
V
Chiurchiù
Faculty of Veterinary Medicine, University of Teramo, 64100 Teramo, Italy; and.
Cinzia
0000-0002-9759-2449
C
Rapino
Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy.|Neurochemistry of Lipids, European Center for Brain Research, Santa Lucia Foundation, 00164 Rome, Italy.
Emanuela
E
Talamonti
Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy.|Neurochemistry of Lipids, European Center for Brain Research, Santa Lucia Foundation, 00164 Rome, Italy.
Alessandro
A
Leuti
Neurochemistry of Lipids, European Center for Brain Research, Santa Lucia Foundation, 00164 Rome, Italy.
Mirko
0000-0003-0532-9270
M
Lanuti
L'Oréal Research and Innovation, 93601 Aulnay sous Bois, France.
Audrey
A
Gueniche
L'Oréal Research and Innovation, 93601 Aulnay sous Bois, France.
Roland
R
Jourdain
L'Oréal Research and Innovation, 93601 Aulnay sous Bois, France.
Lionel
L
Breton
Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy; m.maccarrone@unicampus.it.|Neurochemistry of Lipids, European Center for Brain Research, Santa Lucia Foundation, 00164 Rome, Italy.
Mauro
0000-0002-3990-2963
M
Maccarrone
D001095:Arachidonic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D063388:Endocannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000276:immunology; D015603:Keratinocytes / Q000502:physiology*; D008213:Lymphocyte Activation; D058990:Molecular Targeted Therapy; D053284:Polyunsaturated Alkamides / Q000494:pharmacology* / Q000627:therapeutic use; D043882:Receptors, Cannabinoid / Q000378:metabolism; D012871:Skin Diseases / Q000188:drug therapy* / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology
D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D016207:Cytokines; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D058570:TOR Serine-Threonine Kinases; C078814:anandamide