Protective role of palmitoylethanolamide in keratinocytes and its involvement in contact allergic dermatitis

Stefania Petrosino1, Meliha Karsak2, Katarzyna Starowicz3, Luigia Cristino4, Evelyn Gaffal5, Thomas Tütting5, Carmela Saturnino6, Tiziana Bisogno3, Andreas Zimmer2, Vincenzo Di Marzo3. 1Department of Pharmaceutical Sciences, University of Salerno, Fisciano; Endocannabinoid Research Group; Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Napoli, Italy, 2Department of Molecular Psychiatry, University of Bonn, Bonn, Germany, 3Endocannabinoid Research Group; Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Napoli, Italy, 4Institute of Cybernetics, C.N.R., Pozzuoli, Napoli, Italy, 5Laboratory of Experimental Dermatology, University of Bonn, Bonn, Germany, 6Department of Pharmaceutical Sciences, University of Salerno, Fisciano, Salerno, Italy.

Palmitoylethanolamide (PEA) is an analgesic and anti-inflammatory compound produced by most mammalian cells together with the cannabinoid receptor (CB)- and vanilloid (TRPV1) receptor-active congener, arachidonoylethanolamide (anandamide), and other acyl-ethanolamides. The anti-inflammatory actions of PEA have been suggested to be effected at the level of the mast cell and to be due to several possible molecular mechanisms, including: “entourage effects” on CB1, CB2 and TRPV1-mediated effects of anandamide, direct activation of peroxisome proliferator-activated receptor-α (PPAR-α), and actions on GPR55 as well as other uncharacterised receptors. On the other hand, previous data have shown that CB1, CB2, TRPV1 and PPAR-α receptors play a protective role against contact allergic dermatitis in animal models (Sheu et al., 2002; Gaffal et al., 2006; Banvolgyi et al., 2005) and that PEA is effective against contact dermatitis in humans (Stander et al., 2006).

Therefore, we have examined here whether PEA is produced during 2,4-dinitrodifluorobenzene (DNFB)-induced contact allergic dermatitis in mice, and have investigated if it has any direct protective action on keratinocytes.

PEA levels were found to be elevated in the ear skin of DNFB-sensitized mice after challenge with DNFB, particularly in double CB1/CB2 null mice, which exhibit a much higher inflammatory phenotype than wild-type mice (Gaffal et al., 2006). DNFB treatment also induced a strong up-regulation of CB2 receptors in ear skin keratinocytes of wild-type mice. Also human HaCaT keratinocytes were found here to produce PEA, whilst expressing CB1, CB2, TRPV1 and PPAR-α receptors. These cells are also known to contain receptors for substance P, a pro-inflammatory agent released from sensory nerves and mast cells during neurogenic inflammation. Therefore, we decided next to study the effect of PEA on HaCaT cell death induced by this inflammatory agent. PEA (1-10 μM) concentration-dependently reversed the cytotoxic effect induced by substance P. Experiments are currently under way to assess the mechanism of action of these effects of PEA.

These findings suggest that PEA is an endogenous protective agent against inflammation induced by contact allergic dermatitis at the level of the keratinocyte.

Banvolgyi et al. (2005) J. Neuroimmunol; 169:86-96.

Gaffal et al. (2006) Proceedings of the International Cannabinoid Research Society

Sheu et al. (2002) J Invest Dermatol 118:94-101.

Stander et al. (2006) Hautarzt, 57:801-7.

Supported by Epitech Group S.r.l., Innovet Italia S.r.l. and the Deutsche Forschungsgemeinschaft (SFB645).