Vitamin D/VDR signaling inhibits LPS-induced IFN and IL-1 in Oral epithelia by regulating hypoxia-inducible factor-1 signaling pathway
Vitamin D/VDR signaling inhibits LPS-induced IFN and IL-1 in Oral epithelia by regulating hypoxia-inducible factor-1 signaling pathway
复制标题
维生素 D/VDR 信号通过调节缺氧诱导因子 1 信号通路抑制口腔上皮中 LPS 诱导的 IFN 和 IL-1
DOI：
10.1186/s12964-019-0331-9
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发表时间：
2019-02-27
影响因子：
8.4
通讯作者：
Du, Jie
中科院分区：
文献类型：
--
作者：
Ge, Xuejun;Wang, Lixiang;Du, Jie
口腔扁平苔藓（OLP）是一种慢性炎症性疾病。我们最近的研究表明，维生素D/维生素D受体（VDR）信号通过调节microRNA-802和p53上调的凋亡调节剂（PUMA）对口腔角化细胞凋亡起保护作用，但其在OLP口腔上皮炎症反应中的作用尚不清楚。在此，我们发现脂多糖（LPS）能够增强依赖于缺氧诱导因子-1 （HIF-1）的人口腔角质形成细胞（HOKs）中干扰素γ (IFN)和白细胞介素-1 β (IL-1)的产生。方法采用real-time PCR和western blotting检测LPS刺激后HOKs中hif -1和细胞因子水平。采用实时荧光定量PCR、western blotting、sirna干扰和质粒转染技术检测1,25(OH)(2)D-3对lps诱导的HIF-1和细胞因子的影响。采用western blotting、sirna干扰、质粒转染和染色质免疫沉淀（Chromatin Immunoprecipitation, ChIP）方法研究1,25(OH)(2)D-3在调节HIF-1水平中的作用。最后，采用实时荧光定量PCR、western blotting和免疫组织化学染色检测小鼠和个体口腔上皮中HIF-1、IFN和IL-1的表达。作为一种关键的调节因子，维生素D可抑制lps诱导的HIF-1，从而阻断IFN和IL-1的产生。机制上，维生素D使核因子- b （NF-B）通路失活，上调von Hippel-Lindau （VHL）水平，导致HIF-1降低。此外，在VDR-/- mie以及VDR缺陷的人类活检中，口腔上皮HIF-1水平升高，并伴有IFN和IL-1升高。综上所述，本研究揭示了维生素D/VDR信号在调节口腔角质形成细胞细胞因子中的作用，并揭示了其分子基础。
BackgroundOral lichen planus (OLP) is known as a chronic inflammatory disease. Our recent studies have suggested that vitamin D/vitamin D receptor (VDR) signaling exerts its protective effects on oral keratinocyte apoptosis by regulating microRNA-802 and p53-upregulated modulator of apoptosis (PUMA), but its roles in oral epithelial inflammatory responses in OLP are still unknown. Herein, we identify lipopolysaccharide (LPS) is able to enhance interferon gamma (IFN) and interleukin-1 beta (IL-1) productions in human oral keratinocytes (HOKs) dependent on hypoxia-inducible factor-1 (HIF-1).MethodsHIF-1 and cytokines levels in HOKs were investigated by real-time PCR and western blotting after LPS challenge. The effects of 1,25(OH)(2)D-3 on LPS-induced HIF-1 and cytokines were tested by real-time PCR, western blotting, siRNA-interference and plasmids transfection techniques. The roles of 1,25(OH)(2)D-3 in regulating HIF-1 levels were investigated using western blotting, siRNA-interference, plasmids transfection and Chromatin Immunoprecipitation (ChIP) assays. Finally, HIF-1, IFN and IL-1 expressions in oral epithelia derived from mice and individuals were measured by real-time PCR, western blotting and immunohistochemical staining.ResultsAs a critical regulator, vitamin D suppresses LPS-induced HIF-1 to block IFN and IL-1 productions. Mechanistically, vitamin D inactivates nuclear factor-B (NF-B) pathway and up-regulates von Hippel-Lindau (VHL) levels, leading to HIF-1 reduction. Moreover, HIF-1 status of oral epithelia is elevated in VDR-/- mie as well as in VDR-deficient human biopsies, accompanied with increased IFN and IL-1.ConclusionCollectively, this study uncovers an unrecognized roles of vitamin D/VDR signaling in regulating cytokines in oral keratinocytes and reveals the molecular basis of it.