Control of late cornified envelope genes relevant to psoriasis risk: upregulation by 1,25-dihydroxyvitamin D3 and plant-derived delphinidin
Control of late cornified envelope genes relevant to psoriasis risk: upregulation by 1,25-dihydroxyvitamin D3 and plant-derived delphinidin
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DOI：
10.1007/s00403-013-1390-1
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发表时间：
2013-12-01
影响因子：
3
通讯作者：
Whitfield, G. Kerr
中科院分区：
文献类型：
--
作者：
Hoss, Elika;Austin, Heather R.;Whitfield, G. Kerr
银屑病是一种以角质形成细胞异常增殖和分化为特征的慢性炎症性皮肤病。银屑病的一个遗传危险因素(PSORS4)是终末分化角质形成细胞中编码结构蛋白的LCE3B和LCE3C基因的缺失。由于1，25-二羟基维生素D-3(1，25D)的类似物用于银屑病的治疗，我们假设1，25D通过维生素D受体(VDR)上调LCE3A/3D/3E基因的表达，潜在地缓解LCE3B/LCE3C基因产物的缺失。结果在人角质形成细胞系HaCaT中，1，25D，低亲和力的VDR配体二十二碳六烯酸和姜黄素与一种新的候选配体Delphinidin共同诱导LCE转录本。在1.2 mM钙预先孵育的原代人角质形成细胞中的进一步实验表明，1，25D和10MU的Delphinin上调了所有五个LCE3基因(LCE3A-E)的表达。用放射性标记的1，25D进行的竞争结合分析表明，Delphinidin与VDR结合很弱(IC50a/10001 mm)。然而，在转染型角质形成细胞系(KERTr)中，20 mU的M delphinidin能够以VDRE依赖的方式上调荧光素酶报告基因。这些结果与Delphinidin被代谢成一种活性化合物，然后以VDR/VDRE依赖的方式刺激LCE3转录的情况一致。我们认为，LCE基因的上调可能是1，25D通过提供足够的LCE蛋白来改善银屑病疗效的一部分，特别是在缺乏LCE3B和3C基因的个体中。结果进一步表明，该化合物或其代谢物(S)可能是治疗银屑病的1，25D的替代药物。
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 D-3 (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 mu M delphinidin upregulate all five LCE3 genes (LCE3A-E). Competition binding assays employing radiolabeled 1,25D revealed that delphinidin binds VDR weakly (IC50 a parts per thousand 1 mM). However, 20 mu M 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.