Abstract
Cannabinoid receptors (CB) are expressed throughout human skin epithelium. CB1 activation inhibits human hair growth and decreases proliferation of epidermal keratinocytes. Since psoriasis is a chronic hyperproliferative, inflammatory skin disease, it is conceivable that the therapeutic modulation of CB signaling, which can inhibit both proliferation and inflammation, could win a place in future psoriasis management. Given that psoriasis is characterized by up-regulation of keratins K6 and K16, we have investigated whether CB1 stimulation modulates their expression in human epidermis. Treatment of organ-cultured human skin with the CB1-specific agonist, arachidonoyl-chloro-ethanolamide (ACEA), decreased K6 and K16 staining intensity in situ. At the gene and protein levels, ACEA also decreased K6 expression of cultured HaCaT keratinocytes, which show some similarities to psoriatic keratinocytes. These effects were partly antagonized by the CB1-specific antagonist, AM251. While CB1-mediated signaling also significantly inhibited human epidermal keratinocyte proliferation in situ, as shown by K6/Ki-67-double immunofluorescence, the inhibitory effect of ACEA on K6 expression in situ was independent of its anti-proliferative effect. Given recent appreciation of the role of K6 as a functionally important protein that regulates epithelial wound healing in mice, it is conceivable that the novel CB1-mediated regulation of keratin 6/16 revealed here also is relevant to wound healing. Taken together, our results suggest that cannabinoids and their receptors constitute a novel, clinically relevant control element of human K6 and K16 expression.
Highlights
Endocannabinoids as well as exocannabinoids control the function of various types of cells via cannabinoid receptor (CB)-dependent or independent manner (Kupczyk, Reich & Szepietowski, 2009)
The CB1-selective agonist, ACEA, down-regulates K6 protein expression in situ First, we asked whether the CB1-specific synthetic agonist ACEA (Pertwee et al, 2010; Sugawara et al, 2012) can modulate the expression of keratin K6 in human skin
K6 staining intensity within the epidermis of full-thickness human skin that had been organ-cultured for 24 h under serum-free conditions in the presence of ACEA (30 μM) or vehicle alone was assessed by quantitative immunohistomorphometry
Summary
Endocannabinoids as well as exocannabinoids (such as the active components of cannabis) control the function of various types of cells via cannabinoid receptor (CB)-dependent or independent manner (Kupczyk, Reich & Szepietowski, 2009). Many different types of cells are known to express functional CBs (Biro et al, 2009; Czifra et al, 2012; Pucci et al, 2012; Roelandt et al, 2012; Stander et al, 2005; Sugawara et al, 2012; Telek et al, 2007; Toth et al, 2011). CB1 signaling is important in mast cell activation and intracutaneous mast cell maturation from resident progenitors (Sugawara et al, 2012). It regulates fibrosis (Akhmetshina et al, 2009), sebocyte differentiation (Dobrosi et al, 2008) and eccrine epithelial biology (Czifra et al, 2012). The functions of CB-mediated signaling in human keratinocytes (KCs) in situ are as yet poorly understood
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