The NF-kappaB p50:p50:HDAC-1 repressor complex orchestrates transcriptional inhibition of multiple pro-inflammatory genes.
The NF-kappaB p50:p50:HDAC-1 repressor complex orchestrates transcriptional inhibition of multiple pro-inflammatory genes.
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DOI：
10.1016/j.jhep.2010.03.025
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发表时间：
2010-09
影响因子：
25.7
通讯作者：
Mann, Jelena
中科院分区：
文献类型：
--
作者：
Elsharkawy, Ahmed M.;Oakley, Fiona;Lin, Feng;Packham, Graham;Mann, Derek A.;Mann, Jelena
必须严格调节NF-κB的促炎功能，以防止由活化的炎症和伤口愈合细胞引起的不适当的组织损伤和重塑。NF-κB的p50亚基是免疫和炎症反应的重要抑制因子，但其机制尚不清楚。本研究的目的是描绘活化的肝星状细胞中的p50靶基因，并概述其抑制机制。从nfkb 1（p50）缺陷或Wt小鼠中分离肝星状细胞，并使用微阵列比较基因表达。通过qRT-PCR验证靶基因，并使用染色质免疫沉淀证明p50介导的HDAC-1募集至靶基因。我们确定p50作为多个促炎基因的转录抑制因子，包括Ccl 2，Cxcl 10，Gm-CSF和Mmp-13。这些基因在患有慢性肝炎的nfkb 1（p50）缺陷小鼠和从nfkb 1 −/−肝脏分离的纤维化/炎症肝星状细胞中过度表达。我们确定Mmp-13为p50的真正靶基因，并证明p50是Mmp-13启动子中转录抑制因子组蛋白脱乙酰酶（HDAC）-1到κB位点的募集所必需的。染色质免疫沉淀鉴定了HDAC-1与含有预测的κB结合基序的Ccl 2、Cxcl 10、Gm-csf基因的特异性调节区的结合。在nfkb 1 −/−细胞中没有观察到HDAC-1向这些基因的募集，这表明以与Mmp-13相似的方式需要p50。HDAC-1对炎症基因的募集提供了一种解释p50免疫抑制特性的广泛机制。
The pro-inflammatory functions of NF-κB must be tightly regulated to prevent inappropriate tissue damage and remodelling caused by activated inflammatory and wound-healing cells. The p50 subunit of NF-κB is emerging as an important repressor of immune and inflammatory responses, but by mechanisms that are poorly defined. This study aims to delineate p50 target genes in activated hepatic stellate cells and to outline mechanisms utilised in their repression. Hepatic stellate cells were isolated from nfkb1(p50)-deficient or Wt mice and gene expression compared using microarray. Target genes were verified by qRT-PCR and p50-mediated HDAC-1 recruitment to the target genes demonstrated using chromatin immunoprecipitation. We identify p50 as transcriptional repressor of multiple pro-inflammatory genes including Ccl2, Cxcl10, Gm-csf, and Mmp-13. These genes are over-expressed in nfkb1(p50)-deficient mice suffering from chronic hepatitis and in fibrogenic/inflammatory hepatic stellate cells isolated from nfkb1−/− liver. We identify Mmp-13 as a bona-fide target gene for p50 and demonstrate that p50 is required for recruitment of the transcriptional repressor histone deacetylase (HDAC)-1 to κB sites in the Mmp-13 promoter. Chromatin immunoprecipitations identified binding of HDAC-1 to specific regulatory regions of the Ccl2, Cxcl10, Gm-csf genes that contain predicted κB binding motifs. Recruitment of HDAC-1 to these genes was not observed in nfkb1−/− cells suggesting a requirement for p50 in a manner similar to that described for Mmp-13. Recruitment of HDAC-1 to inflammatory genes provides a widespread mechanism to explain the immunosuppressive properties of p50.
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影响因子：
3.7
作者：
Liacini, A;Sylvester, J;Zafarullah, M
通讯作者：
Zafarullah, M
DOI：
10.1016/j.biocel.2007.05.004
发表时间：
2008-01-01
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4
作者：
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通讯作者：
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Mengshol, JA;Vincenti, MP;Brinckerhoff, CE
通讯作者：
Brinckerhoff, CE
影响因子：
29.4
作者：
Mann J;Chu DC;Maxwell A;Oakley F;Zhu NL;Tsukamoto H;Mann DA
通讯作者：
Mann DA