A novel control of human keratin expression: cannabinoid receptor 1-mediated signaling down-regulates the expression of keratins K6 and K16 in human keratinocytesin vitroandin situ

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.

Activity-Guided Purification Identifies Lupeol, a Pentacyclic Triterpene, As a Therapeutic Agent Multiple Pathogenic Factors of Acne

“…the gland duct) may be exposed to a much higher concentration of lupeol than sebocytes within the gland. (Aldana et al, 1998;Ramot et al, 2013). Therefore, decreases of typical inducers and a marker of abnormal differentiation in vivo further support that lupeol not only has potential therapeutic effects against active acne as described, but also exerts a prophylactic activity in the prevention of comedone formation.…”

Thyrotropin-Releasing Hormone (TRH) Promotes Wound Re-Epithelialisation in Frog and Human Skin

“…We analysed the expression of cytokeratin 6 (CK6), which is found in human inter-follicular epidermis only upon injury and in states of hyperproliferation [50]–[53]. Strong CK6 immunoreactivity was evident one day post-wounding and was maintained at high levels thereafter.…”

Keratins and skin disease

“…For PC, a recent small molecule library screening identified cholesterol-lowering statins as active down-regulators of K6a and other keratins through the isoprenylation pathway, downstream of HMG-coA reductase in the cholesterol biosynthesis pathway (Zhao et al 2011). Stimulation of cannabinoid receptors reduces K6 and K16 expression, which might be relevant to the management of PC pain (Ramot et al 2013).…”