Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands,
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
J Innate Immun. 2020;12(1):74-89. doi: 10.1159/000497415. Epub 2019 Apr 10.
Airway epithelium is an important site for local vitamin D (VD) metabolism; this can be negatively affected by inflammatory mediators. VD is an important regulator of respiratory host defense, for example, by increasing the expression of hCAP18/LL-37. TGF-β1 is increased in chronic obstructive pulmonary disease (COPD), and known to decrease the expression of constitutive host defense mediators such as secretory leukocyte protease inhibitor (SLPI) and polymeric immunoglobulin receptor (pIgR). VD has been shown to affect TGF-β1-signaling by inhibiting TGF-β1-induced epithelial-to-mesenchymal transition. However, interactions between VD and TGF-β1, relevant for the understanding host defense in COPD, are incompletely understood. Therefore, the aim of the present study was to investigate the combined effects of VD and TGF-β1 on airway epithelial cell host defense mechanisms. Exposure to TGF-β1 reduced both baseline and VD-induced expression of hCAP18/LL-37, partly by increasing the expression of the VD-degrading enzyme CYP24A1. TGF-β1 alone decreased the number of secretory club and goblet cells and reduced the expression of constitutive host defense mediators SLPI, s/lPLUNC and pIgR, effects that were not modulated by VD. These results suggest that TGF-β1 may decrease the respiratory host defense both directly by reducing the expression of host defense mediators, and indirectly by affecting VD-mediated effects such as expression of hCAP18/LL-37.
气道上皮是局部维生素 D（VD）代谢的重要部位；这可能会受到炎症介质的负面影响。VD 是呼吸道宿主防御的重要调节剂，例如，通过增加 hCAP18/LL-37 的表达。转化生长因子-β1（TGF-β1）在慢性阻塞性肺疾病（COPD）中增加，并且已知会降低固有宿主防御介质的表达，例如分泌白细胞蛋白酶抑制剂（SLPI）和多聚免疫球蛋白受体（pIgR）。VD 已被证明通过抑制 TGF-β1 诱导的上皮-间充质转化来影响 TGF-β1 信号。然而，对于理解 COPD 中的宿主防御，VD 和 TGF-β1 之间的相互作用尚不完全清楚。因此，本研究旨在研究 VD 和 TGF-β1 对气道上皮细胞宿主防御机制的联合作用。TGF-β1 的暴露降低了 hCAP18/LL-37 的基础表达和 VD 诱导的表达，部分是通过增加 VD 降解酶 CYP24A1 的表达来实现的。TGF-β1 单独降低了分泌性 club 和 goblet 细胞的数量，并降低了固有宿主防御介质 SLPI、s/lPLUNC 和 pIgR 的表达，VD 对这些作用没有调节作用。这些结果表明，TGF-β1 可能通过降低宿主防御介质的表达，直接降低呼吸道宿主防御，并且通过影响 VD 介导的效应，例如 hCAP18/LL-37 的表达，间接降低呼吸道宿主防御。
