Abstract
Lumisterol (L3) is a stereoisomer of 7-dehydrocholesterol and is produced through the photochemical transformation of 7-dehydrocholesteol induced by high doses of UVB. L3 is enzymatically hydroxylated by CYP11A1, producing 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3. Hydroxylumisterols function as reverse agonists of the retinoic acid-related orphan receptors α and γ (RORα/γ) and can interact with the non-genomic binding site of the vitamin D receptor (VDR). These intracellular receptors are mediators of photoprotection and anti-inflammatory activity. In this study, we show that L3-hydroxyderivatives significantly increase the expression of VDR at the mRNA and protein levels in keratinocytes, both non-irradiated and after UVB irradiation. L3-hydroxyderivatives also altered mRNA and protein levels for RORα/γ in non-irradiated cells, while the expression was significantly decreased in UVB-irradiated cells. In UVB-irradiated keratinocytes, L3-hydroxyderivatives inhibited nuclear translocation of NFκB p65 by enhancing levels of IκBα in the cytosol. This anti-inflammatory activity mediated by L3-hydroxyderivatives through suppression of NFκB signaling resulted in the inhibition of the expression of UVB-induced inflammatory cytokines, including IL-17, IFN-γ, and TNF-α. The L3-hydroxyderivatives promoted differentiation of UVB-irradiated keratinocytes as determined from upregulation of the expression at the mRNA of involucrin (IVL), filaggrine (FLG), and keratin 14 (KRT14), downregulation of transglutaminase 1 (TGM1), keratins including KRT1, and KRT10, and stimulation of ILV expression at the protein level. We conclude that CYP11A1-derived hydroxylumisterols are promising photoprotective agents capable of suppressing UVB-induced inflammatory responses and restoring epidermal function through targeting the VDR and RORs.
Highlights
Ultraviolet radiation (UVR) can mediate beneficial and harmful effects on the skin through a variety of biological responses [1,2]
Prolonged UVB exposure leads to the photochemical transformation of pre-vitamin D3 (pre-D3) to L3, which involves the resealing of the B-ring, but in a different configuration to 7-DHC, making L3 a stereoisomer of 7-DHC [3,11]
Exposure to high UVB radiation could result in the activation of transmembrane proteins such as toll-like receptor 4 (TLR4) and cluster of differentiation 14 (CD14), subsequently promoting the phosphorylation of IκB, promoting NFκB release from the NFκB/IκB
Summary
Ultraviolet radiation (UVR) can mediate beneficial and harmful effects on the skin through a variety of biological responses [1,2]. The hydroxyderivatives of L3 are structurally very similar to other sterols and as well as acting as reverse agonists on RORα and RORγ, they interact with the non-genomic binding site of the vitamin D receptor (VDR) [12]. These receptors are all expressed in human skin [4,19,20,21]. VDR/ROR pathways cause activation of IκB kinase β (IKKβ), which phosphorylates IκBα [34,35] This causes dissociation of NFκB from the NFκB/IκB complex which enables NFκB to translocate into the nucleus and activate the expression of genes encoding proinflammatory cytokines, producing a variety of inflammatory responses [36].
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