Mechanism of 1α,25-dihydroxyvitamin D3-dependent repression of interleukin-12B
Mechanism of 1α,25-dihydroxyvitamin D3-dependent repression of interleukin-12B
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DOI：
10.1016/j.bbamcr.2011.01.037
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发表时间：
2011-05-01
影响因子：
5.1
通讯作者：
Vaisanen, Sami
中科院分区：
文献类型：
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作者：
Gynther, Petra;Toropainen, Sari;Vaisanen, Sami
白介素 12 (IL-12) 是一种异二聚体促炎细胞因子，在 CD4(+) T 细胞活化和分化为分泌干扰素 γ 的 1 型辅助性 T 细胞的过程中发挥着核心作用。 IL-12B 是编码活性 IL-12 较大亚基的基因，据报道可被核激素 1 α,25-二羟基维生素 D-3 (1 α,25(OH)(2)D-3) 下调，但调节机制尚不清楚。在本研究中，我们研究了脂多糖（LPS）处理的人单核细胞（THP-1）中1α,25(OH)(2)D-3对IL-12B基因转录调节的分子机制。定量 RT-PCR 显示，IL-12B mRNA 显示出周期性表达谱，在暴露于 1 α,25(OH)(2)D-3 后的前 8 小时内下调 2.8 倍，甚至在 24 小时内下调 12.1 倍。凝胶位移和定量染色质免疫沉淀 (ChIP) 测定表明维生素 D 受体 (VDR) 与 IL-12B 转录起始位点 (TSS) 上游基因组区域 480 和 6300 bp 结合。定量 ChIP 测定还显示，与 VDR 及其伙伴 RXR 一起，上述区域招募了共阻遏物 NCOR2/SMRT 和组蛋白脱乙酰酶 3，导致 IL-12B 启动子及其 TSS 处的组蛋白 4 乙酰化减少和组蛋白 3 三甲基化增加。我们认为这些抑制性表观遗传变化最终会导致 IL-12 表达下调。 (C) 2011 Elsevier B.V. 保留所有权利。
Interleukin 12 (IL-12) is a heterodimeric, pro-inflammatory cytokine that plays a central role in activation and differentiation of CD4(+) T cells into interferon-gamma secreting T-helper type 1 cells. IL-12B, a gene encoding the larger subunit of active IL-12, has been reported to be down-regulated by the nuclear hormone 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3), but the mechanism of the regulation is unknown. In this study, we have examined the molecular mechanism of transcriptional regulation of the IL-12B gene by 1 alpha,25(OH)(2)D-3 in lipopolysaccharide (LPS)-treated human monocytes (THP-1). Quantitative RT-PCR showed that IL-12B mRNA displays a cyclical expression profile and is down-regulated 2.8-fold during the first 8 h and even 12.1-fold 24 h after exposure to 1 alpha,25(OH)(2)D-3. Gel shift and quantitative chromatin immunoprecipitation (ChIP) assays demonstrated vitamin D receptor (VDR) binding to genomic regions 480 and 6300 bp upstream of the IL-12B transcription start site (TSS). Quantitative ChIP assays also revealed that together with VDR and its partner RXR the above regions recruited the co-repressor NCOR2/SMRT and histone deacetylase 3 leading to a decreased histone 4 acetylation and increased histone 3 trimethylation at the IL-12B promoter and its TSS. We suggest that these repressive epigenetic changes eventually cause downregulation of IL-12 expression. (C) 2011 Elsevier B.V. All rights reserved.