Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 24, Pages -Publisher
MDPI
DOI: 10.3390/ijms21249374
Keywords
photobiology; UV radiation; keratinocyte; inflammation; cell differentiation; lumisterol hydroxyderivatives
Funding
- National Institutes of Health, United States [1R01AR073004-01A1, R01AR071189-01A1]
- Veterans Affairs (VA) merit, United States [1I01BX004293-01A1, R21 AI149267-01A1, R21 MD015319]
- Thailand Research Fund, Thailand [RSA6280101]
- Mahidol University grant, Thailand
- Chalermphrakiat Grant, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand
- Chulabhorn Royal Academy, Thailand [RAA2563/007]
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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 alpha and gamma (ROR alpha/gamma) 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 ROR alpha/gamma in non-irradiated cells, while the expression was significantly decreased in UVB-irradiated cells. In UVB-irradiated keratinocytes, L3-hydroxyderivatives inhibited nuclear translocation of NF kappa B p65 by enhancing levels of I kappa B alpha in the cytosol. This anti-inflammatory activity mediated by L3-hydroxyderivatives through suppression of NF kappa B signaling resulted in the inhibition of the expression of UVB-induced inflammatory cytokines, including IL-17, IFN-gamma, and TNF-alpha. 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.
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