Inhibition of basal and ultraviolet B-induced melanogenesis by cannabinoid CB1 receptors: a keratinocyte-dependent effect
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Ultraviolet radiation is the major environmental insult to the skin and stimulates the synthesis of melanin in melanocytes, which then distribute it to the neighboring keratinocytes where it confers photo-protection. Skin color results from the paracrine interaction between these two cell types. Recent studies suggest that endocannabinoids are potential mediators in the skin. Here, we investigated whether cannabinoid drugs play a role in melanogenesis and if ultraviolet radiation modifies the cutaneous endocannabinoid system. We used human melanotic melanoma cell line (SK-mel-1) in monoculture or co-culture with human keratinocytes (HaCat). Endocannabinoid levels, cannabinoid receptors expression, and melanin content were evaluated under basal conditions and after ultraviolet-B irradiation (311 nm). We provide evidence that human melanoma cells (SK-mel-1) express CB1 receptors, and when in co-culture with keratinocytes (HaCat), the selective CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA 1 and 10 μM) inhibited (by 33.4 and 37.3%, respectively) basal melanogenesis. In addition, ultraviolet-B-induced melanogenesis in co-cultures was abolished by ACEA 10 μM. Both ACEA inhibitory effects were reversed by AM251 (1 μM), a selective CB1 antagonist. Furthermore, ultraviolet-B radiation increased endocannabinoids levels only in keratinocytes, whereas CB1 cannabinoid receptor expression was up-regulated only in melanoma cells. Our results collectively suggest that ultraviolet radiation activates paracrine CB1-mediated endocannabinoid signaling to negatively regulate melanin synthesis. The endocannabinoid system in the skin may be a possible target for future therapies in pigmentary disorders.
KeywordsMelanin Melanoma Ultraviolet radiation Cannabinoids Co-culture
The authors wish to thank Fabiana Piscitelli for valuable technical help and Epitech Italia for partly supporting this study.
- 1.Berdyshev EV, Schmid PC, Dong Z, Schmid HH (2000) Stress-induced generation of N-acylethanolamines in mouse epidermal JB6 P+ cells. Biochem J 346(Pt 2):369–374Google Scholar
- 7.Karsak M, Gaffal E, Date R, Wang-Eckhardt L, Rehnelt J, Petrosino S, Starowicz K, Steuder R, Schlicker E, Cravatt B, Mechoulam R, Buettner R, Werner S, Di Marzo V, Tuting T, Zimmer A (2007) Attenuation of allergic contact dermatitis through the endocannabinoid system. Science 316:1494–1497PubMedCrossRefGoogle Scholar
- 9.Maccarrone M, Di Rienzo M, Battista N, Gasperi V, Guerrieri P, Rossi A, Finazzi-Agro A (2003) The endocannabinoid system in human keratinocytes. Evidence that anandamide inhibits epidermal differentiation through CB1 receptor-dependent inhibition of protein kinase C, activation protein-1, and transglutaminase. J Biol Chem 278:33896–33903PubMedCrossRefGoogle Scholar
- 14.Pertwee RG (2005) Pharmacological actions of cannabinoids. Handb Exp Pharmacol 168:1–51Google Scholar
- 15.Petrosino S, Cristino L, Karsak M, Gaffal E, Ueda N, Tuting T, Bisogno T, De Filippis D, D’Amico A, Saturnino C, Orlando P, Zimmer A, Iuvone T, Di Marzo V (2009) Protective role of palmitoylethanolamide in contact allergic dermatitis. Allergy 698–711Google Scholar
- 18.Schallreuter KU (2007) Advances in melanocyte basic science research. Dermatol Clin 25(vii):283–291Google Scholar