Control of Late Cornified Envelope Genes Relevant to Psoriasis Risk: Upregulation by 1,25-Dihydroxyvitamin D3 and Plant-derived Delphinidin

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 238-262-Vitamin D Action, Deficiency & Disorders
Bench to Bedside
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-259
Elika Hoss*1, Heather R Austin1, Mark R Haussler1, G Kerr Whitfield1 and Peter W Jurutka2
1University of Arizona College of Medicine Phoenix, Phoenix, AZ, 2Arizona State University, Phoenix, AZ
Psoriasis (Psx) is a chronic inflammatory skin disease featuring abnormal keratinocyte proliferation and differentiation that affects approximately 1% of the U.S. population. One reported genetic risk factor for Psx (denoted 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 Psx treatment, we hypothesized that 1,25D acts via the vitamin D receptor (VDR) to upregulate expression of LCE3A/3D/3E genes, potentially mitigating the absence of LCE3B/LCE3C gene products by providing sufficient LCE proteins for effective skin barrier formation. Results in a human keratinocyte line, HaCaT, incubated with 1,25D or with the low affinity VDR ligands docosahexaenoic acid, curcumin and a novel candidate VDR ligand, delphinidin, indicated a trend for induction of LCE transcripts as monitored by quantitative real time PCR. Further experiments in primary human keratinocytes either maintained in basal calcium medium (60 µM), or preincubated with 1.2 mM calcium to induce differentiation, indicated that 1,25D and delphinidin can upregulate the full set of five LCE3 genes (LCE3A-E), as well as the nearby LCE2B gene, in a dose-dependent manner, but only after incubation with 1.2 mM calcium. Competition binding assays employing radiolabeled 1,25D revealed that delphinidin is capable of direct VDR binding, albeit at high concentrations (>100 µM), well above the 1-10 µM concentrations sufficient to upregulate LCE genes. These results suggest that either a metabolite of delphinidin is the true VDR ligand, or that delphinidin is acting via a different mechanism to upregulate LCE genes. Also, preliminary tests of delphinidin with a reporter gene construct linked to a vitamin D responsive element (VDRE) indicated that, whereas 1,25D activated strongly in this context, delphinidin only weakly affected transactivation of the reporter gene, again suggesting a VDR- and/or VDRE-independent mechanism. In summary, we propose that upregulation of LCE genes may be part of the therapeutic effect of 1,25D to ameliorate psoriasis by providing adequate LCE proteins for an effective skin barrier, especially in those individuals missing the LCE3B and 3C genes. Further, the fact that alternative VDR ligands such as delphinidin also upregulate LCE genes suggests that this or related compounds might have potential as alternative Psx therapies.

Nothing to Disclose: EH, HRA, MRH, GKW, PWJ

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH grants to MRHInstitutional funds from Dean of COM-Phx to GKW