Control of late cornified envelope genes relevant to psoriasis risk: Upregulation by 1,25-dihydroxyvitamin D3 and plant-derived delphinidin

Elika Hoss, Heather R. Austin, Shane F. Batie, Peter Jurutka, Mark R. Haussler, G. Kerr Whitfield

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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. 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 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 preincubated with 1.2 mM calcium indicated that 1,25D and 10 lM delphinidin upregulate all five LCE3 genes (LCE3A-E). Competition binding assays employing radiolabeled 1,25D revealed that delphinidin binds VDR weakly (IC50 ≈ 1 mM). However, 20 lM delphinidin was capable of upregulating a luciferase reporter gene in a VDRE-dependent manner in a transfected keratinocyte cell line (KERTr). 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.

Original languageEnglish (US)
Pages (from-to)867-878
Number of pages12
JournalArchives of Dermatological Research
Volume305
Issue number10
DOIs
StatePublished - 2013

Fingerprint

delphinidin
Calcitriol
Psoriasis
Up-Regulation
Keratinocytes
Calcitriol Receptors
Genes
Ligands
Curcumin
Docosahexaenoic Acids
Therapeutic Uses
Luciferases
Reporter Genes
Skin Diseases
Inhibitory Concentration 50

Keywords

  • Anthocyanidin
  • Late cornified envelope genes
  • Nuclear receptors
  • Skin barrier

ASJC Scopus subject areas

  • Dermatology

Cite this

Control of late cornified envelope genes relevant to psoriasis risk : Upregulation by 1,25-dihydroxyvitamin D3 and plant-derived delphinidin. / Hoss, Elika; Austin, Heather R.; Batie, Shane F.; Jurutka, Peter; Haussler, Mark R.; Whitfield, G. Kerr.

In: Archives of Dermatological Research, Vol. 305, No. 10, 2013, p. 867-878.

Research output: Contribution to journalArticle

Hoss, Elika ; Austin, Heather R. ; Batie, Shane F. ; Jurutka, Peter ; Haussler, Mark R. ; Whitfield, G. Kerr. / Control of late cornified envelope genes relevant to psoriasis risk : Upregulation by 1,25-dihydroxyvitamin D3 and plant-derived delphinidin. In: Archives of Dermatological Research. 2013 ; Vol. 305, No. 10. pp. 867-878.
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