Research: HOSS and COLLEAGUES,

Listed in Issue 247

Abstract

HOSS and COLLEAGUES,  (1)Department of Basic Medical Sciences, University of Arizona College of Medicine,  Phoenix, 425 N Fifth Street, Phoenix, AZ, 85004-2157, USA studied metabolism and regulation of delphinidin as an alternative to 1,25D in psoriasis therapy.

Background

Psoriasis is a chronic inflammatory skin disease featuring abnormal keratinocyte proliferation and differentiation. A genetic risk factor for psoriasis (PSORS4) is a deletion of LCE3B and LCE3C genes encoding structural proteins in terminally differentiated keratinocytes.

Methodology

Because analogs of 1,25-dihydroxyvitamin D3 (1,25D) are used in psoriasis treatment, we hypothesized that 1,25D acts via the vitamin D receptor (VDR) to upregulate expression of LCE 3A/3D/3E genes, potentially mitigating the absence of LCE3B/LCE3C gene products.

Results

Results in a human keratinocyte line, HaCaT, suggested that 1,25D, low affinity VDR ligands docosahexaenoic acid and curcumin, along with a novel candidate ligand, delphinidin, induce LCE transcripts as monitored by qPCR. Further experiments in primary human keratinocytes pre-incubated with 1.2 mM calcium indicated that 1,25D and 10 μM delphinidin upregulate all five LCE3 genes (LCE3A-E). Competition binding assays employing radiolabelled 1,25D revealed that delphinidin binds VDR weakly (IC50 ≈ 1 mM). However, 20 μM delphinidin was capable of upregulating a luciferase reporter gene in a VDRE-dependent manner in a transfected keratinocyte cell line (KERTr).

Conclusion

These results are consistent with a scenario in which delphinidin is metabolized to an active compound that then stimulates LCE3 transcription in a VDR/VDRE-dependent manner. We propose that upregulation of LCE genes may be part of the therapeutic effect of 1,25D to ameliorate psoriasis by providing sufficient LCE proteins, especially in individuals missing the LCE3B and 3C genes. Results with delphinidin further suggest that this compound or its metabolite(s) might offer an alternative to 1,25D in psoriasis therapy.

References

Hoss E(1), Austin HR, Batie SF, Jurutka PW, Haussler MR, Whitfield GK. Control of late cornified envelope genes relevant to psoriasis risk: upregulation by 1,25-dihydroxyvitamin D3 and plant-derived delphinidin. Arch Dermatol Res. 305(10):867-78. Dec 2013 doi: 10.1007/s00403-013-1390-1. Epub Jul 10 2013.

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