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

Archives of Dermatological Research volume 305, pages 867–878 (2013)Cite this article

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 μM 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 μM 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.

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Abbreviations

1,25D:

1,25-Dihydroxyvitamin D3

VDR:

Vitamin D receptor

VDRE:

Vitamin D responsive element

LCE:

Late cornified envelope

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Acknowledgements

This work was supported by National Institutes of Health grants to MRH and a grant from the Dean of the College of Medicine—Phoenix to GKW. The authors thank Eric W. Moffet for his role in the bioinformatic identification of the LCE VDRE utilized in this study.

Conflict of interest

The authors state no conflict of interest.

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Authors and Affiliations

  1. Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, 425 N Fifth Street, Phoenix, AZ, 85004-2157, USA

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

  2. School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, 85306, USA

    Peter W. Jurutka

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  1. Elika Hoss
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  2. Heather R. Austin
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  3. Shane F. Batie
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  4. Peter W. Jurutka
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  5. Mark R. Haussler
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  6. G. Kerr Whitfield
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Correspondence to G. Kerr Whitfield.

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Hoss, E., Austin, H.R., Batie, S.F. et al. Control of late cornified envelope genes relevant to psoriasis risk: upregulation by 1,25-dihydroxyvitamin D3 and plant-derived delphinidin. Arch Dermatol Res 305, 867–878 (2013). https://doi.org/10.1007/s00403-013-1390-1

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Keywords

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