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BackgroundNumerous studies introduced epidermal keratinocytes as 'nonclassical' immune-competent cells, hence potent primary regulators and active participants of cutaneous immune functions (1), (s1-6). Therefore, targeting them might provide a novel, highly specific anti-inflammatory therapeutic possibility. The endocannabinoid system (ECS) is an emerging signalling network which regulates multiple cutaneous functions (2,3). The loss of homoeostatic endocannabinoid (eCB) signalling of epidermal keratinocytes was shown to dramatically enhance inflammatory processes, arguing for that the cutaneous eCB tone plays a 'gatekeeper' role in the initiation phase of skin inflammation (4); for further details see Supplementary Background section). Moreover, elevation of the eCB tone, for example by the inhibition of fatty acid amide hydrolase (FAAH), the most important enzyme engaged with the degradation of the eCB anandamide (AEA); (5), exerts ECS-mediated anti-inflammatory actions in multiple organs (5). Questions addressedBased on these data, we hypothesized that upregulation of expression/activity of FAAH [thereby decreasing the eCB tone, and increasing the level of the pro-inflammatory 'eCB degradation product' arachidonic acid (AA)] might contribute to the development of the inflammatory processes. Therefore, we aimed at investigating (i) mRNA and protein expressions and activity of FAAH in human keratinocytes in Toll-like receptor (TLR)-induced inflammation models and (ii) the suggested anti-inflammatory effects of two newly developed, potent and selective N-alkylcarbamate FAAH inhibitors WOBE440 (IC 50 = 25 AE 8 nM) and WOBE479 (IC 50 = 78 AE 13 nM) (Fig. S1) which show high specificity over other known targets within the ECS [IC 50 > 10 lM for cannabinoid receptor (CNR)-1, CNR2, monoacylglycerol lipase and the putative endocannabinoid membrane transporter] (6) on primary (NHEK) and immortalized (HPV-KER) (7,8) human epidermal keratinocytes as well as in NC/Tnd mice, a widely used animal model of atopic dermatitis (AD) (9).