Vitamin D induces innate antibacterial responses in human trophoblasts via an intracrine pathway.
Vitamin D induces innate antibacterial responses in human trophoblasts via an intracrine pathway.
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DOI：
10.1095/biolreprod.108.073577
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发表时间：
2009-03
影响因子：
3.6
通讯作者：
Hewison M
中科院分区：
文献类型：
--
作者：
Liu N;Kaplan AT;Low J;Nguyen L;Liu GY;Equils O;Hewison M
维生素 D 的活性形式 1,25-二羟基维生素 D (1,25(OH)2D) 是抗菌蛋白导管素 CAMP (LL37) 的有效诱导剂。在巨噬细胞中，这种反应依赖于在 25-羟基维生素 D-1α-羟化酶 (CYP27B1) 的催化下，由前体 25-羟基维生素 D (25OHD) 分泌内合成 1,25(OH)2D。鉴于滋养层细胞也表达丰富的 CYP27B1，我们假设胎盘中诱导 CAMP 存在类似的内分泌途径。对胎盘外植体、人滋养层原代培养物以及用 1,25(OH)2D (1–100 nM) 处理的 3A 滋养层细胞系的分析表明，CAMP 的剂量依赖性诱导与人巨噬细胞原代培养物中观察到的情况类似。与巨噬细胞一致，滋养层 CAMP 的诱导通过 25OHD 分泌内转化为 1,25(OH)2D 得到增强。然而，与巨噬细胞相反，滋养层细胞中维生素 D 对 CAMP 的诱导并未通过 Toll 样受体配体（如脂多糖）的共刺激而增强。尽管如此，暴露于维生素 D 代谢物显着增强了滋养层细胞的抗菌反应：当用 25OHD (49.6% ± 10.9%) 或 1,25(OH)2D (45.4% ± 9.2%) 处理时，与媒介物处理的对照相比，感染大肠杆菌的 3A 细胞显示细菌集落形成单位数量减少，均 P < 0.001。用 25OHD (1–100 nM) 或 1,25(OH)2D (0.1–10 nM) 处理也可以保护 3A 细胞免于感染大肠杆菌后发生细胞死亡（分别为 13.6%–26.9% 和 22.3%–40.2% 保护）。这些观察结果表明，1,25(OH)2D 可以作为滋养细胞中 CAMP 的内分泌调节剂，因此可能为胎盘中先天免疫反应的激活提供一种新机制。
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), is a potent inducer of the antimicrobial protein cathelicidin, CAMP (LL37). In macrophages this response is dependent on intracrine synthesis of 1,25(OH)2D from precursor 25-hydroxyvitamin D (25OHD), catalyzed by the enzyme 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1). In view of the fact that trophoblastic cells also express abundant CYP27B1, we postulated a similar intracrine pathway for induction of CAMP in the placenta. Analysis of placenta explants, primary cultures of human trophoblast, and the 3A trophoblastic cell line treated with 1,25(OH)2D (1–100 nM) revealed dose-dependent induction of CAMP similar to that observed with primary cultures of human macrophages. Also consistent with macrophages, induction of trophoblastic CAMP was enhanced via intracrine conversion of 25OHD to 1,25(OH)2D. However, in contrast to macrophages, induction of CAMP by vitamin D in trophoblasts was not enhanced by costimulation with Toll-like receptor ligands, such as lipopolysaccharide. Despite this, exposure to vitamin D metabolites significantly enhanced antibacterial responses in trophoblastic cells: 3A cells infected with Escherichia coli showed decreased numbers of bacterial colony-forming units compared with vehicle-treated controls when treated with 25OHD (49.6% ± 10.9%) or 1,25(OH)2D (45.4% ± 9.2%), both P < 0.001. Treatment with 25OHD (1–100 nM) or 1,25(OH)2D (0.1–10 nM) also protected 3A cells against cell death following infection with E. coli (13.6%–26.9% and 22.3%–40.2% protection, respectively). These observations indicate that 1,25(OH)2D can function as an intracrine regulator of CAMP in trophoblasts, and may thus provide a novel mechanism for activation of innate immune responses in the placenta.