Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3 -: Involvement of NF-κB downregulation in transcriptional repression of the p40 gene
Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3 -: Involvement of NF-κB downregulation in transcriptional repression of the p40 gene
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DOI：
10.1172/jci1050
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发表时间：
1998-01-01
影响因子：
15.9
通讯作者：
Panina-Bordignon, P
中科院分区：
文献类型：
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作者：
D'Ambrosio, D;Cippitelli, M;Panina-Bordignon, P
白细胞介素12（IL-12）由骨髓单核细胞产生，在辅助性T细胞1（Th 1）的发育中起关键作用，辅助性T细胞1参与慢性炎性自身免疫性疾病的发病机制，1，25-二羟基维生素D-3 [1，25（OH）（2）D-3]抑制活化的巨噬细胞和树突状细胞产生IL-12，从而对其免疫抑制特性提供了新的解释。1，25（OH）（2）D-3在转录水平上显著抑制IL-12 p35和p40亚基的mRNA表达。通过将单核细胞RAW 264.7细胞与p40启动子/报告基因构建体和维生素D-3受体（VDR）和/或类维生素A X受体（RXR α）的表达载体连接，分析25（OH）（2）D-3对p40启动子激活的影响。我们观察到1，25（OH）（2）D-3对p40基因的转录抑制作用，这需要VDR与RXR共表达和完整的VDR DNA结合结构域。抑制作用定位于p40启动子中含有NF-κ B B结合位点的区域（p40-kappa B），p40-kappa B位点的缺失消除了对p40启动子的部分抑制作用，证实了该位点的功能相关性，在1，25（OH）（2）D-3存在下单核细胞THP-1细胞的活化导致与p40-κ B位点的结合减少。因此，1，25（OH）（2）D-3可能通过下调NF-κ B活化和与p40-κ B序列结合来负调节IL-12的产生。
Interleukin 12 (IL-12), produced by myelomonocytic cells, plays a pivotal role in the development of T helper 1 (Th1) cells, which are involved in the pathogenesis of chronic inflammatory autoimmune disorders, 1,25-Dihydroxyvitamin D-3 [1,25(OH)(2)D-3] inhibits IL-12 production by activated macrophages and dendritic cells, thus providing a novel interpretation to its immunosuppressive properties. 1,25(OH)(2)D-3 significantly inhibits mRNA expression for both IL-12 p35 and p40 subunits acting at the transcriptional level, The effect of 1,25(OH)(2)D-3 on p40 promoter activation was analyzed by cotransfecting monocytic RAW264.7 cells with p40 promoter/reporter constructs and expression vectors for vitamin D-3 receptor (VDR) and/or retinoid X receptor (RXR alpha). We observed transcriptional repression of the p40 gene by 1,25(OH)(2)D-3, which required coexpression of VDR with RXR and an intact VDR DNA-binding domain, The repressive effect maps to a region in the p40 promoter containing a binding site for NF-kappa B (p40-kappa B), Deletion of the p40-kappa B site abrogates part of the inhibitory effect on the p40 promoter, confirming the functional relevance of this site, Activation of monocytic THP-1 cells in the presence of 1,25(OH)(2)D-3 results in reduced binding to the p40-kappa B site. Thus, 1,25(OH)(2)D-3 may negatively regulate IL-12 production by downregulation of NF-kappa B activation and binding to the p40-kappa B sequence.