Protective role of palmitoylethanolamide in contact allergic dermatitis

To cite this article: Petrosino S, Cristino L, Karsak M, Gaffal E, Ueda N, Tüting T, Bisogno T, De Filippis D, D’Amico A, Saturnino C, Orlando P, Zimmer A, Iuvone T, Di Marzo V. Protective role of palmitoylethanolamide in contact allergic dermatitis. Allergy 2010; 65 : 698–711. Abstract Background: Palmitoylethanolamide (PEA) is an anti‐inflammatory mediator that enhances the activation by anandamide (AEA) of cannabinoid receptors and transient receptor potential vanilloid type‐1 (TRPV1) channels, and directly activates peroxisome proliferator‐activated receptor‐α (PPAR‐α). In mice, 2,4‐dinitrofluorobenzene (DNFB)‐induced contact allergic dermatitis (CAD) in inflamed ears is partly mediated by the chemokine Monocyte Chemotactic Protein‐2 (MCP‐2) and accompanied by elevation of AEA levels. No datum is available on PEA regulation and role in CAD. Objective: We examined whether PEA is produced during DNFB‐induced CAD, and if it has any direct protective action in keratinocytes in vitro . Methods: Eight‐ to ten‐week‐old female C57BL/6J wild‐type and CB 1 /CB 2 double knock‐out mice were used to measure PEA levels and the expression of TRPV1, PPAR‐α receptors and enzymes responsible for PEA biosynthesis and degradation. Human keratinocytes (HaCaT) cells were stimulated with polyinosinic polycytidylic acid [poly‐(I:C)], and the expression and release of MCP‐2 were measured in the presence of PEA and antagonists of its proposed receptors. Results: 2,4‐Dinitrofluorobenzene increased ear skin PEA levels and up‐regulated TRPV1, PPAR‐α and a PEA‐biosynthesizing enzyme in ear keratinocytes. In HaCaT cells, stimulation with poly‐(I:C) elevated the levels of both PEA and AEA, and exogenous PEA (10 μM) inhibited poly‐(I:C)‐induced expression and release of MCP‐2 in a way reversed by antagonism at TRPV1, but not PPAR‐α. PEA (5–10 mg/kg, intraperitoneal) also inhibited DNFB‐induced ear inflammation in mice in vivo , in a way attenuated by TRPV1 antagonism. Conclusions: We suggest that PEA is an endogenous protective agent against DNFB‐induced keratinocyte inflammation and could be considered for therapeutic use against CAD.