title: Control of late cornified envelope genes relevant to psoriasis risk: upregulation by 1,25-dihydroxyvitamin D3 and plant-derived delphinidin.
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.
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, 425 N Fifth Street, Phoenix, AZ, 85004-2157, USA.
authors.forename: Elika
authors.initials: E
authors.lastname: Hoss
authors.forename: Heather R
authors.initials: HR
authors.lastname: Austin
authors.forename: Shane F
authors.initials: SF
authors.lastname: Batie
authors.forename: Peter W
authors.initials: PW
authors.lastname: Jurutka
authors.forename: Mark R
authors.initials: MR
authors.lastname: Haussler
authors.forename: G Kerr
authors.initials: GK
authors.lastname: Whitfield
mesh_terms: D000872:Anthocyanins / Q000378:metabolism / Q000494:pharmacology*; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D002460:Cell Line; D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics*; D003474:Curcumin / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics; D018167:Receptors, Calcitriol / Q000378:metabolism; D012306:Risk; D015854:Up-Regulation
chemical_list: D000872:Anthocyanins; D055233:Cornified Envelope Proline-Rich Proteins; C524766:LCE2B protein, human; C549748:LCE3B protein, human; C524768:LCE3C protein, human; C524769:LCE3D protein, human; D018167:Receptors, Calcitriol; D004281:Docosahexaenoic Acids; C017185:delphinidin; D002117:Calcitriol; D003474:Curcumin; D002118:Calcium