Dobrosi Nóra, Tóth Balázs I, Nagy Georgina, Dózsa Anikó, Géczy Tamás, Nagy László, Zouboulis Christos C, Paus Ralf, Kovács László, Bíró Tamás
Department of Physiology, University of Debrecen, Medical and Health Science Center, 4032 Debrecen, Nagyerdei krt. 98. PO Box 22, Hungary.
FASEB J. 2008 Oct;22(10):3685-95. doi: 10.1096/fj.07-104877. Epub 2008 Jul 2.
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).
我们之前已经表明，内源性大麻素和外源性大麻素通过大麻素受体-1（CB1）都是人类毛发生长的强大抑制剂。为了进一步研究大麻素系统在毛囊皮脂腺单位生物学中的作用，我们在当前研究中使用人SZ95皮脂腺细胞作为细胞培养模型，探讨了内源性大麻素是否以及如何影响人皮脂腺生物学。在此，我们提供了首个证据，即SZ95皮脂腺细胞表达CB2而非CB1。此外，典型的内源性大麻素（花生四烯酸乙醇酰胺/阿南达米德、2-花生四烯酸甘油）存在于SZ95皮脂腺细胞中，并剂量依赖性地诱导脂质生成和（主要由凋亡驱动的）细胞死亡。内源性大麻素还上调参与脂质合成的关键基因的表达（例如，PPAR转录因子及其一些靶基因）。如特异性激动剂/拮抗剂和RNA干扰所揭示的，这些作用由涉及MAPK途径的CB2偶联信号选择性介导。由于CB2“沉默”的细胞表现出基础脂质生成显著受抑制，我们的结果共同表明，人皮脂腺利用旁分泌-自分泌、内源性激活、CB2介导的内源性大麻素信号系统来正向调节脂质生成和细胞死亡。因此，CB2拮抗剂或激动剂值得在以皮脂腺功能障碍为特征的皮肤疾病（如寻常痤疮、脂溢性皮炎、干性皮肤）的治疗中进行探索。
