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 (CB 1 and CB 2 ), 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 CB 1 in 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 CB 1 activation by AEA suppressed production and release of signature T H 1- and T H 17-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 T H 1 and T H 17 cells. AEA-treated keratinocytes showed reduced an induction of IFN-γ-producing T H 1 and IL-17-producing T H 17 cells, and these effects were reverted by pharmacological inhibition of CB 1 Further analyses identified mammalian target of rapamycin as a proinflammatory signaling pathway regulated by CB 1 , able to promote either IL-12 and IL-23 release from keratinocytes or T H 1 and T H 17 polarization. Taken together, these findings demonstrate that AEA suppresses highly pathogenic T cell subsets through CB 1 -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.