COX-2 expression induced by diesel particles involves chromatin modification and degradation of HDAC1
COX-2 expression induced by diesel particles involves chromatin modification and degradation of HDAC1
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DOI：
10.1165/rcmb.2006-0449oc
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发表时间：
2007-08-01
影响因子：
6.4
通讯作者：
Samet, James M.
中科院分区：
文献类型：
--
作者：
Cao, Dongsun;Bromberg, Philip A.;Samet, James M.
环氧合酶-2（考克斯-2）在生理和应激刺激诱导的炎症反应中起重要作用。暴露于柴油机排气颗粒物（DEP）已被证明会诱发肺部炎症，并加剧哮喘和慢性阻塞性肺病。DEP是人气道上皮细胞炎症反应的有效诱导剂。DEP吸入诱导炎症介质表达的机制尚不清楚。在本报告中，我们证明DEP可以诱导考克斯-2基因在人支气管上皮细胞系（BEAS-2B）在转录和蛋白质水平的表达。考克斯-2基因表达的诱导涉及染色质修饰，特别是组蛋白的乙酰化和脱乙酰化。我们发现暴露于DEP增加了与考克斯-2启动子相关的组蛋白H4的乙酰化，并导致组蛋白去乙酰化酶1（HDAC 1）的降解。此外，我们确定HDAC 1在介导暴露于DEP的BEAS-2B细胞中的考克斯-2基因的转录激活中起关键作用，证据支持使用siRNA下调HDAC 1导致考克斯-2基因表达的激活，而HDAC 1的过表达导致其抑制。最后，DEP暴露诱导招募组蛋白乙酰转移酶（HAT）p300的启动子的考克斯-2基因，表明乙酰化也是重要的，在调节其表达响应DEP暴露。这些结果首次显示了通过HDAC 1的选择性降解的乙酰化，并且HAT的募集在DEP诱导的考克斯-2基因的表达中起重要作用。
Cyclooxygenase-2 (COX-2) plays an important role in the inflammatory response induced by physiologic and stress stimuli. Exposure to diesel exhaust particulate matter (DEP) has been shown to induce pulmonary inflammation and exacerbate asthma and chronic obstructive pulmonary disease. DEP is a potent inducer of inflammatory reponses in human airway epithelial cells. The mechanism through which DEP inhalation induces inflammatory mediator expression is not understood. In this report, we demonstrate that DEP can induce the expression of COX-2 gene in a human bronchial epithelial cell line (BEAS-2B) at both transcriptional and protein levels. The induction of COX-2 gene expression involves chromatin modification, in particular acetylation and deacetylation of histones. We show that exposure to DEP increases the acetylation of histone H4 associated with the COX-2 promoter and causes degradation of histone deacetylase 1 (HDAC1). Further, we establish that HDAC1 plays a pivotal role in mediating the transcriptional activation of the COX-2 gene in BEAS-2B cells exposed to DEP, supported by evidence that the down-regulation of HDAC1 using siRNA leads to activation of COX-2 gene expression, whereas overexpression of HDAC1 results in its repression. Finally, DEP exposure induced recruitment of histone acetyltransferase (HAT) p300 to the promoter of the COX-2 gene, suggesting that acetylation is also important in regulating its expression in response to DEP exposure. These results show for the first time acetylation via selective degradation of HDAC1, and that recruitment of HAT plays an important role in DEP-induced expression of the COX-2 gene.