NF-kappa B p50 regulates C/EBP alpha expression and inflammatory cytokine-induced neutrophil production.
NF-kappa B p50 regulates C/EBP alpha expression and inflammatory cytokine-induced neutrophil production.
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DOI：
10.4049/jimmunol.0803861
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发表时间：
2009-05-01
期刊：
影响因子：
--
通讯作者：
Friedman AD
中科院分区：
文献类型：
--
作者：
Wang D;Paz-Priel I;Friedman AD
NF-κB是成熟髓系细胞中炎症反应的关键转录诱导物，也刺激细胞存活，但其在未成熟髓系细胞发育中的作用尚未得到很好的表征。C/EBPα是从早期祖细胞向单核细胞和粒细胞髓样细胞发育所必需的，NF-κB和C/EBPβ协同诱导多种炎症介质。在发现C/EBPα优先结合NF-κB p50而非NF-κB p65后，我们现在研究了缺乏NF-κB p50的nfkb 1 −/−小鼠的骨髓生成。p50的缺失导致体外用G-CSF或GM-CSF获得的粒细胞祖细胞CFU-G的数量显著减少，并减少体内响应于G-CSF的嗜中性粒细胞产生，同时保持体外响应于细胞因子或LPS的单细胞生成。为了深入了解NF-κB p50缺失时粒细胞生成减少的机制，我们评估了几种髓系调节蛋白在谱系阴性的未成熟髓系细胞中的表达。尽管PU. 1、C/EBPβ和STAT 3水平无变化，但在不存在NF-κB p50的情况下，C/EBPα蛋白和RNA水平降低约3倍。此外，在染色质免疫沉淀试验中，NF-κB p50和C/EBPα结合内源性C/EBPα启动子，NF-κB p50单独或与C/EBPα协同反式激活C/EBPα启动子。尽管C/EBPα降低，但总骨髓和谱系阴性细胞中的GCSFR和MCSFR水平保持不变。总之，这些数据表明，急性炎症不仅激活成熟的骨髓细胞，而且通过NF-κB p50诱导C/EBPα转录刺激中性粒细胞产生。
NF-κB is a key transcriptional inducer of the inflammatory response in mature myeloid cells, and also stimulates cell survival, but its role in immature myeloid cell development has not been well characterized. C/EBPα is required for the development of monocytic and granulocytic myeloid cells from early progenitors, and NF-κB and C/EBPβ cooperatively induce several inflammatory mediators. Having found that C/EBPα binds NF-κB p50 preferentially compared with NF-κB p65, we have now investigated myelopoiesis in nfkb1−/− mice lacking NF-κB p50. Absence of p50 leads to a significant reduction in the number of granulocytic progenitors, CFU-G, obtained with G-CSF or GM-CSF in vitro and reduces neutrophil production in vivo in response to G-CSF, with preservation of monopoiesis in vitro in response to cytokines or LPS. To gain insight into the mechanism underlying reduced granulopoiesis in the absence of NF-κB p50, we assessed the expression of several myeloid regulatory proteins in lineage-negative, immature myeloid cells. Although PU.1, C/EBPβ, and STAT3 levels were unchanged, C/EBPα protein and RNA levels were reduced approximately 3-fold in the absence of NF-κB p50. In addition, NF-κB p50 and C/EBPα bound the endogenous C/EBPα promoter in a chromatin immunoprecipitation assay, and NF-κB p50 trans-activated the C/EBPα promoter, alone or in cooperation with C/EBPα. Despite reduction of C/EBPα, GCSFR and MCSFR levels were maintained or total marrow and in lineage-negative cells. Together, these data indicate that acute inflammation not only activates mature myeloid cells but also stimulates neutrophil production via NF-κB p50 induction of C/EBPα transcription.
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影响因子：
11.4
作者：
Wang, W;Wang, X;Friedman, AD
通讯作者：
Friedman, AD
影响因子：
5.2
作者：
Paz-Priel, I;Cai, DH;Friedman, AD
通讯作者：
Friedman, AD
影响因子：
20.3
作者：
Wang, QF;Friedman, AD
通讯作者：
Friedman, AD
影响因子：
64.8
作者：
SINGH, H;SEN, R;SHARP, PA
通讯作者：
SHARP, PA
DOI：
10.1016/s1357-2725(97)00083-6
发表时间：
1997-12-01
影响因子：
4
作者：
Xia, CL;Cheshire, JK;Woo, P
通讯作者：
Woo, P