Regulation of late cornified envelope genes relevant to psoriasis risk by plant-derived cyanidin

The PSORS4 genetic risk factor for psoriasis is a deletion of two late cornified envelope (LCE) genes (LCE3C-LCE3Bdel) in a cluster of five LCE3 genes with a proposed role in skin repair. We previously showed that 1,25-dihydroxyvitamin D₃ (1,25D) modestly upregulates transcripts from all five LCE3 genes as monitored by real time PCR in primary human keratinocytes. Herein we report that cyanidin, a plant-derived compound with anti-inflammatory/anti-oxidant properties, upregulates expression of all five LCE3 genes in cultures of differentiating primary human keratinocytes to a greater extent that does 1,25D. This action of cyanidin is dependent on the differentiation state of the keratinocytes, with a stronger effect after the cells have been incubated with 1.2 mM calcium for 24 h. Competition displacement assays using radiolabeled 1,25D revealed that cyanidin directly competes as a ligand for vitamin D receptor (VDR) binding with an estimated IC₅₀ of 500 μM. However, 20 μM cyanidin is sufficient to upregulate LCE3 genes. The 25-fold discrepancy between the cyanidin concentration required for upregulating LCE3 genes in intact keratinocytes vs. that required for direct binding to VDR in vitro suggests that cyanidin may be: (a) metabolized to a more active VDR ligand in keratinocytes and/or (b) functioning via a non-VDR mediated mechanism. The fact that cyanidin is the most potent upregulator of global LCE3 gene expression reported to date suggests that this or related compounds may have potential in psoriasis therapy.