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Endocannabinoids enhance lipid synthesis and apoptosis of human sebocytes via cannabinoid receptor-2-mediated signaling

Nóra Dobrosi^*, Balázs I. Tóth^*, Georgina Nagy, Anikó Dózsa, Tamás Géczy^*, László Nagy, Christos C. Zouboulis^,||, Ralf Paus^¶,#, László Kovács^* and Tamás Bíró^*,1

^* Department of Physiology,

Department of Dermatology, and

Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Research Center for Molecular Medicine, Debrecen, Hungary;

Departments of Dermatology, Venereology, Allergology, and Immunology, Dessau Medical Center, Dessau, Germany;

^|| Laboratory of Biogerontology, Dermato-Pharmacology, and Dermato-Endocrinology, Institute of Clinical Pharmacology and Toxicology, Charité, Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany;

^¶ Department of Dermatology, University Hospital Schleswig-Holstein, University of Lübeck, Lübeck, Germany; and

^# School of Translational Medicine, University of Manchester, Manchester, UK

¹Correspondence: Department of Physiology, University of Debrecen, Medical and Health Science Center, Research Center for Molecular Medicine, 4032 Debrecen, Nagyerdei krt. 98. PO Box 22, Hungary. E-mail: biro{at}phys.dote.hu

We had previously shown that both locally produced endocannabinoids and exocannabinoids, via cannabinoid receptor-1 (CB1), are powerful inhibitors of human hair growth. To further investigate the role of the cannabinoid system in pilosebaceous unit biology, we have explored in the current study whether and how endocannabinoids have an impact on human sebaceous gland biology, using human SZ95 sebocytes as cell culture model. Here, we provide the first evidence that SZ95 sebocytes express CB2 but not CB1. Also, prototypic endocannabinoids (arachidonoyl ethanolamide/anandamide, 2-arachidonoyl glycerol) are present in SZ95 sebocytes and dose-dependently induce lipid production and (chiefly apoptosis-driven) cell death. Endocannabinoids also up-regulate the expression of key genes involved in lipid synthesis (e.g., PPAR transcription factors and some of their target genes). These actions are selectively mediated by CB2-coupled signaling involving the MAPK pathway, as revealed by specific agonists/antagonists and by RNA interference. Because cells with "silenced" CB2 exhibited significantly suppressed basal lipid production, our results collectively suggest that human sebocytes utilize a paracrine-autocrine, endogenously active, CB2-mediated endocannabinoid signaling system for positively regulating lipid production and cell death. CB2 antagonists or agonists therefore deserve to be explored in the management of skin disorders characterized by sebaceous gland dysfunctions (e.g., acne vulgaris, seborrhea, dry skin).—Dobrosi, N., Tóth, B. I., Nagy, G., Dózsa, A., Géczy, T., Nagy, L., Zouboulis, C. C., Paus, R., Kovács, L., Bíró, T. Endocannabinoids enhance lipid synthesis and apoptosis of human sebocytes via cannabinoid receptor-2-mediated signaling.

Key Words: cannabinoid receptor subtypes • human sebaceous gland-derived SZ95 sebocytes • acne vulgaris • signal transduction • peroxisome proliferator-activated receptor • gene expression