Bioactive Dietary VDR Ligands Regulate Genes Encoding Biomarkers of Skin Repair That Are Associated with Risk for Psoriasis

Abstract

Treatment with 1,25-dihydroxyvitamin D₃ (1,25D) improves psoriasis symptoms, possibly by inducing the expression of late cornified envelope (<i>LCE</i>)3 genes involved in skin repair. In psoriasis patients, the majority of whom harbor genomic deletion of <i>LCE3B</i> and <i>LCE3C</i> (<i>LCE3C_LCE3B-del</i>), we propose that certain dietary analogues of 1,25D activate the expression of residual <i>LCE3A/LCE3D/LCE3E</i> genes to compensate for the loss of <i>LCE3B</i>/<i>LCE3C</i> in the deletant genotype. Herein, human keratinocytes (HEKn) homozygous for <i>LCE3C_LCE3B-del</i> were treated with docosahexaenoic acid (DHA) and curcumin, two low-affinity, nutrient ligands for the vitamin D receptor (VDR). DHA and curcumin induce the expression of <i>LCE3A</i>/<i>LCE3D/LCE3E</i> mRNAs at concentrations corresponding to their affinity for VDR. Moreover, immunohistochemical quantitation revealed that the treatment of keratinocytes with DHA or curcumin stimulates <i>LCE3</i> protein expression, while simultaneously opposing the tumor necrosis factor-alpha (TNFα)-signaled phosphorylation of mitogen activated protein (MAP) kinases, p38 and Jun amino-terminal kinase (JNK), thereby overcoming inflammation biomarkers elicited by TNFα challenge. Finally, DHA and curcumin modulate two transcription factors relevant to psoriatic inflammation, the activator protein-1 factor Jun B and the nuclear receptor NR4A2/NURR1, that is implicated as a mediator of VDR ligand-triggered gene control. These findings provide insights into the mechanism(s) whereby dietary VDR ligands alter inflammatory and barrier functions relevant to skin repair, and may provide a molecular basis for improved treatments for mild/moderate psoriasis.