Advertisement

Archives of Dermatological Research

, Volume 303, Issue 3, pp 201–210 | Cite as

Inhibition of basal and ultraviolet B-induced melanogenesis by cannabinoid CB1 receptors: a keratinocyte-dependent effect

  • Sofia MaginaEmail author
  • Carina Esteves-Pinto
  • Eduardo Moura
  • Maria Paula Serrão
  • Daniel Moura
  • Stefania Petrosino
  • Vincenzo Di Marzo
  • Maria Augusta Vieira-Coelho
Original Paper

Abstract

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.

Keywords

Melanin Melanoma Ultraviolet radiation Cannabinoids Co-culture 

Notes

Acknowledgments

The authors wish to thank Fabiana Piscitelli for valuable technical help and Epitech Italia for partly supporting this study.

References

  1. 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
  2. 2.
    Biro T, Toth BI, Hasko G, Paus R, Pacher P (2009) The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol Sci 30:411–420PubMedCrossRefGoogle Scholar
  3. 3.
    Blazquez C, Carracedo A, Barrado L, Real PJ, Fernandez-Luna JL, Velasco G, Malumbres M, Guzman M (2006) Cannabinoid receptors as novel targets for the treatment of melanoma. FASEB J 20:2633–2635PubMedCrossRefGoogle Scholar
  4. 4.
    Di Marzo V (2008) Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov 7:438–455PubMedCrossRefGoogle Scholar
  5. 5.
    Duval C, Regnier M, Schmidt R (2001) Distinct melanogenic response of human melanocytes in mono-culture, in co-culture with keratinocytes and in reconstructed epidermis, to UV exposure. Pigment Cell Res 14:348–355PubMedCrossRefGoogle Scholar
  6. 6.
    Gilsbach R, Brede M, Beetz N, Moura E, Muthig V, Gerstner C, Barreto F, Neubauer S, Vieira-Coelho MA, Hein L (2007) Heterozygous alpha 2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction. Cardiovasc Res 75:728–737PubMedCrossRefGoogle Scholar
  7. 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
  8. 8.
    Leonti M, Casu L, Raduner S, Cottiglia F, Floris C, Altmann KH, Gertsch J (2010) Falcarinol is a covalent cannabinoid CB1 receptor antagonist and induces pro-allergic effects in skin. Biochem Pharmacol 79:1815–1826PubMedCrossRefGoogle Scholar
  9. 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
  10. 10.
    Moura E, Afonso J, Serrao MP, Vieira-Coelho MA (2009) Effect of clonidine on tyrosine hydroxylase activity in the adrenal medulla and brain of spontaneously hypertensive rats. Basic Clin Pharmacol Toxicol 104:113–121PubMedCrossRefGoogle Scholar
  11. 11.
    Oka S, Wakui J, Gokoh M, Kishimoto S, Sugiura T (2006) Suppression by WIN55212–2, a cannabinoid receptor agonist, of inflammatory reactions in mouse ear: interference with the actions of an endogenous ligand, 2-arachidonoylglycerol. Eur J Pharmacol 538:154–162PubMedCrossRefGoogle Scholar
  12. 12.
    Paradisi A, Pasquariello N, Barcaroli D, Maccarrone M (2008) Anandamide regulates keratinocyte differentiation by inducing DNA methylation in a CB1 receptor-dependent manner. J Biol Chem 283:6005–6012PubMedCrossRefGoogle Scholar
  13. 13.
    Park HY, Kosmadaki M, Yaar M, Gilchrest BA (2009) Cellular mechanisms regulating human melanogenesis. Cell Mol Life Sci 66:1493–1506PubMedCrossRefGoogle Scholar
  14. 14.
    Pertwee RG (2005) Pharmacological actions of cannabinoids. Handb Exp Pharmacol 168:1–51Google Scholar
  15. 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
  16. 16.
    Potsch L, Emmerich P, Skopp G (2002) Preliminary approach to elucidate the role of pigment as a binding site for drugs and chemicals in anagen hairs: pigments as carriers for 3H-haloperidol in HaCaT/Sk-Mel-1 co-cultures. Int J Legal Med 116:12–16PubMedCrossRefGoogle Scholar
  17. 17.
    Rad HH, Yamashita T, Jin HY, Hirosaki K, Wakamatsu K, Ito S, Jimbow K (2004) Tyrosinase-related proteins suppress tyrosinase-mediated cell death of melanocytes and melanoma cells. Exp Cell Res 298:317–328PubMedCrossRefGoogle Scholar
  18. 18.
    Schallreuter KU (2007) Advances in melanocyte basic science research. Dermatol Clin 25(vii):283–291Google Scholar
  19. 19.
    Springer M, Engelhart K, Biesalski HK (2003) Effects of 3-isobutyl-1-methylxanthine and kojic acid on cocultures and skin equivalents composed of HaCaT cells and human melanocytes. Arch Dermatol Res 295:88–91PubMedCrossRefGoogle Scholar
  20. 20.
    Stander S, Schmelz M, Metze D, Luger T, Rukwied R (2005) Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J Dermatol Sci 38:177–188PubMedCrossRefGoogle Scholar
  21. 21.
    Sugimoto K, Nishimura T, Nomura K, Kuriki T (2004) Inhibitory effects of alpha-arbutin on melanin synthesis in cultured human melanoma cells and a three-dimensional human skin model. Biol Pharm Bull 27:510–514PubMedCrossRefGoogle Scholar
  22. 22.
    Zheng D, Bode AM, Zhao Q, Cho YY, Zhu F, Ma WY, Dong Z (2008) The cannabinoid receptors are required for ultraviolet-induced inflammation and skin cancer development. Cancer Res 68:3992–3998PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Sofia Magina
    • 1
    • 2
    • 3
    Email author
  • Carina Esteves-Pinto
    • 1
  • Eduardo Moura
    • 1
    • 2
  • Maria Paula Serrão
    • 1
  • Daniel Moura
    • 1
  • Stefania Petrosino
    • 4
  • Vincenzo Di Marzo
    • 4
  • Maria Augusta Vieira-Coelho
    • 1
    • 2
  1. 1.Institute of Pharmacology and Therapeutics, Faculty of MedicineUniversity of PortoPortoPortugal
  2. 2.Institute for Molecular and Cell BiologyUniversity of PortoPortoPortugal
  3. 3.Department of Dermatology and VenereologyH. S. JoãoPortoPortugal
  4. 4.Endocannabinoid Research Group, Institute of Biomolecular ChemistryConsiglio Nazionale delle RicerchePozzuoliItaly

Personalised recommendations