Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
Infect Immun. 2012 Dec;80(12):4485-94. doi: 10.1128/IAI.06224-11. Epub 2012 Oct 8.
Vitamin D is an important regulator of the expression of antimicrobial peptides, and vitamin D deficiency is associated with respiratory infections. Regulating expression of antimicrobial peptides, such as the human cathelicidin antimicrobial peptide 18 (hCAP18)/LL-37, by vitamin D in bronchial epithelial cells requires local conversion of 25(OH)-vitamin D(3) (25D(3)) into its bioactive metabolite, 1,25(OH)(2)-vitamin D(3) (1,25D(3)), by CYP27B1. Low circulating vitamin D levels in childhood asthma are associated with more-severe exacerbations, which are often associated with infections. Atopic asthma is accompanied by Th2-driven inflammation mediated by cytokines such as interleukin 4 (IL-4) and IL-13, and the effect of these cytokines on vitamin D metabolism and hCAP18/LL-37 expression is unknown. Therefore, we investigated this with well-differentiated bronchial epithelial cells. To this end, cells were treated with IL-13 with and without 25D(3), and expression of hCAP18/LL-37, CYP27B1, the 1,25D(3)-inactivating enzyme CYP24A1, and vitamin D receptor was assessed by quantitative PCR. We show that IL-13 enhances the ability of 25D(3) to increase expression of hCAP18/LL-37 and CYP24A1. In addition, exposure to IL-13 resulted in increased CYP27B1 expression, whereas vitamin D receptor (VDR) expression was not significantly affected. The enhancing effect of IL-13 on 25D(3)-mediated expression of hCAP18/LL-37 was further confirmed using SDS-PAGE Western blotting and immunofluorescence staining. In conclusion, we demonstrate that IL-13 induces vitamin D-dependent hCAP18/LL-37 expression, most likely by increasing CYP27B1. These data suggest that Th2 cytokines regulate the vitamin D metabolic pathway in bronchial epithelial cells.
维生素 D 是抗菌肽表达的重要调节剂，而维生素 D 缺乏与呼吸道感染有关。维生素 D 通过细胞色素 P45027B1 （CYP27B1）在支气管上皮细胞中将 25（OH）-维生素 D（3）（25D（3））转化为其生物活性代谢物 1,25（OH）（2）-维生素 D（3）（1,25D（3）），从而调节抗菌肽的表达，如人抗菌肽 cathelicidin 18（hCAP18）/LL-37。儿童哮喘中循环维生素 D 水平较低与更严重的恶化有关，这些恶化通常与感染有关。特应性哮喘伴随着由细胞因子（如白细胞介素 4（IL-4）和白细胞介素 13（IL-13））介导的 Th2 驱动的炎症，这些细胞因子对维生素 D 代谢和 hCAP18/LL-37 表达的影响尚不清楚。因此，我们使用分化良好的支气管上皮细胞对此进行了研究。为此，用 IL-13 处理细胞，并用和不用 25D（3）处理，并通过定量 PCR 评估 hCAP18/LL-37、CYP27B1、1,25D（3）失活酶 CYP24A1 和维生素 D 受体的表达。我们表明，IL-13 增强了 25D（3）增加 hCAP18/LL-37 和 CYP24A1 表达的能力。此外，暴露于 IL-13 导致 CYP27B1 表达增加，而维生素 D 受体（VDR）表达没有显著影响。使用 SDS-PAGE Western 印迹和免疫荧光染色进一步证实了 IL-13 对 25D（3）介导的 hCAP18/LL-37 表达的增强作用。总之，我们证明 IL-13 诱导维生素 D 依赖性 hCAP18/LL-37 表达，这很可能是通过增加 CYP27B1 来实现的。这些数据表明，Th2 细胞因子调节支气管上皮细胞中的维生素 D 代谢途径。
