The endocannabinoid system (ECS) regulates multiple physiological processes, including cutaneous cell growth and differentiation. Here, we explored the effects of the major nonpsychotropic phytocannabinoid of Cannabis sativa, (-)-cannabidiol (CBD), on human sebaceous gland function and determined that CBD behaves as a highly effective sebostatic agent. Administration of CBD to cultured human sebocytes and human skin organ culture inhibited the lipogenic actions of various compounds, including arachidonic acid and a combination of linoleic acid and testosterone, and suppressed sebocyte proliferation via the activation of transient receptor potential vanilloid-4 (TRPV4) ion channels. Activation of TRPV4 interfered with the prolipogenic ERK1/2 MAPK pathway and resulted in the downregulation of nuclear receptor interacting protein-1 (NRIP1), which influences glucose and lipid metabolism, thereby inhibiting sebocyte lipogenesis. CBD also exerted complex antiinflammatory actions that were coupled to A2a adenosine receptor-dependent upregulation of tribbles homolog 3 (TRIB3) and inhibition of the NF-κB signaling. Collectively, our findings suggest that, due to the combined lipostatic, antiproliferative, and antiinflammatory effects, CBD has potential as a promising therapeutic agent for the treatment of acne vulgaris.
Introduction
Acne vulgaris is the most common human skin disease, affecting the quality of life of millions worldwide. In spite of heroic basic and applied research efforts, we still lack indisputably curative anti-acne agents, which target multiple pathogenetic steps of acne (sebum overproduction, unwanted sebocyte proliferation, inflammation) and, moreover, which possess favorable side effect profiles. Investigations over the last two decades have confirmed unambiguously that the human body expresses such receptors, which are able to specifically bind and recognize characteristic terpene-phenol compounds of the infamous plant Cannabis sativa, collectively referred to as phytocannabinoids. These receptors, their endogenous ligands (the endocannabinoids [eCBs]), and the enzymes involved in the synthesis and degradation of the eCBs collectively constitute the eCB system (ECS), a complex intercellular signaling network markedly involved in the regulation of various physiological processes.
Investigation of the cutaneous cannabinoid system seems to be a promising choice when searching for novel therapeutic possibilities. Indeed, we have shown previously that the skin ECS regulates cutaneous cell growth and differentiation, and it reportedly exerts anti-inflammatory effects. Of further importance, we have also demonstrated that ECS plays a key role in the regulation of sebum production. According to our recent findings, prototypic eCBs, such as N-arachidonoyl ethanolamide (anandamide [AEA]) and 2-arachidonoylglycerol, are constitutively produced in human sebaceous glands. Moreover, using human immortalized SZ95 sebocytes, we have also demonstrated that these locally produced eCBs (acting through a CB2 cannabinoid receptor→ERK1/2 MAPK→PPAR pathway) induce terminal differentiation of these cells, which is characterized by increased neutral lipid (sebum) production of the sebocytes. These findings confirmed unambiguously that human sebocytes have a functionally active ECS; yet, we did not possess data on the potential effect(s) of plant-derived cannabinoids.
(-)-Cannabidiol (CBD) is the most studied nonpsychotropic phytocannabinoid. It has already been applied in clinical practice without any significant side effects (Sativex) , and numerous ongoing phase II and III trials intend to explore its further therapeutic potential. Hence, within the confines of the current study, we intended to reveal the biological actions of CBD on the human sebaceous gland. Since we lack adequate animal models, we used human immortalized SZ95 sebocytes, the best available cellular system, and the full-thickness human skin organ culture (hSOC) technique.
Results
CBD normalizes “pro-acne agent”–induced excessive lipid synthesis of human sebocytes.
We first assessed the biological effects of CBD (1–10 μM) on the lipogenesis of SZ95 sebocytes. Although eCBs are known to show intense lipogenic actions via the metabotropic CB2 receptors, neither semiquantitative Oil Red O nor quantitative Nile Red staining indicated changes in the basal neutral (sebaceous) lipid synthesis of SZ95 sebocytes following 24-hour CBD treatment (Figure (Figure1,1, A–C) (or 48-hour CBD treatment; data not shown). Intriguingly, however, CBD markedly inhibited the lipogenic action of the prototypic eCB, AEA, in a dose-dependent manner (1–10 μM; Figure Figure1,1, C–E).
