Molecular mechanism underlying the impact of vitamin D on disease activity of MS.
Molecular mechanism underlying the impact of vitamin D on disease activity of MS.
复制标题
维生素 D 对 MS 疾病活动性影响的分子机制。
DOI：
10.1002/acn3.91
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发表时间：
2014
影响因子：
5.3
通讯作者：
Pohl,Christo
中科院分区：
文献类型：
--
作者：
Munger,KassandraL;Köchert,Karl;Simon,KellyC;Kappos,Ludwig;Polman,ChrisH;Freedman,MarkS;Hartung,HansP;Miller,DavidH;Montalbán,Xavier;Edan,Gilles;Barkhof,Frederik;Pleimes,Dirk;Sandbrink,Rupert;Ascherio,Alberto;Pohl,Christo
一些先前的研究表明，25-羟基维生素D（25（OH）D）对多发性硬化症（MS）活动有中度至强烈的影响。本研究的目的是探讨可能解释25（OH）D潜在临床效应的机制原理。MethodsThis study measured serum 25（OH）D levels and global gene expression profile over a course of up to 2 years in patients starting treatment with interferon beta-1b（IFNB-1b）after a clinical isolated syndrome. MS疾病的活动性进行了评估，钆增强病变的数量存在于重复的磁共振成像（MRI）。ResultsThe钆增强病变的数量与25（OH）D水平高度显着相关。在分子水平上进行各种系统水平的分析，多条证据表明，25（OH）D调节大型基因-基因相互作用系统的表达动力学，该系统主要调节调节MS活性的免疫调节过程。维生素D反应元件在该系统中显著富集，表明通过维生素D受体直接调节该基因相互作用网络。随着25（OH）D水平的增加，该系统的调节与MS活性的降低有关。在受25（OH）D调控的复杂基因网络中，发现了IFNB-1b和鞘氨醇-1-磷酸生物利用度调节剂的良好描述靶点。IFNB-1b可叠加增强25（OH）D对MS活性的影响。解释在此，我们提供了不平衡的25（OH）D基因表达系统可能影响MS活性的机制证据。我们的研究结果支持监测和管理维生素D水平的潜在益处（例如，通过补充）在接受IFN-β-1b治疗的早期MS患者中。
ObjectiveSome previous studies suggest modest to strong effects of 25‐hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.MethodsThis study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta‐1b (IFNB‐1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium‐enhancing lesions present on repeated magnetic resonance imaging (MRIs).ResultsThe number of gadolinium‐enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems‐level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene–gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well‐described targets of IFNB‐1b and a regulator of sphingosine‐1‐phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB‐1b.InterpretationHere, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN‐beta‐1b.