Tristetraprolin Down-Regulation Contributes to Persistent TNF-Alpha Expression Induced by Cigarette Smoke Extract through a Post-Transcriptional Mechanism.
Tristetraprolin Down-Regulation Contributes to Persistent TNF-Alpha Expression Induced by Cigarette Smoke Extract through a Post-Transcriptional Mechanism.
复制标题
DOI：
10.1371/journal.pone.0167451
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Ding Q
中科院分区：
文献类型：
--
作者：
Zhao XK;Che P;Cheng ML;Zhang Q;Mu M;Li H;Luo Y;Liang YD;Luo XH;Gao CQ;Jackson PL;Wells JM;Zhou Y;Hu M;Cai G;Thannickal VJ;Steele C;Blalock JE;Han X;Chen CY;Ding Q
肿瘤坏死因子-α是一种强有力的促炎介质，其在慢性阻塞性肺疾病中的表达上调。雷公藤红素参与调节肿瘤坏死因子-α的表达，但是否参与香烟烟雾诱导的肿瘤坏死因子-α的表达尚不清楚。用免疫印迹法检测香烟烟雾提取物(CSE)对小鼠肺泡巨噬细胞和肺泡上皮细胞TTP表达的影响。实时荧光定量RT-α检测肿瘤坏死因子-αm RNA的稳定性和衰减率。同时检测这些细胞的肿瘤坏死因子-α蛋白水平。为了确定相关的分子机制，构建了一个含有肿瘤坏死因子-α3‘-非翻译区的人β-珠蛋白报告基因的表达载体，用于鉴定肿瘤坏死因子-α基因中的TTP靶点。CSE诱导肺泡巨噬细胞和肺泡上皮细胞TTP表达下调。TTP表达降低可显著提高肿瘤坏死因子-α基因的稳定性。重要的是，由于α功能受损而增加的肿瘤坏死因子-TTP m RNA的稳定性导致这些细胞中肿瘤坏死因子-α的水平显著增加。TTP的强制表达抑制了CSE诱导的肿瘤坏死因子-α基因稳定性和表达的增加。利用含有肿瘤坏死因子-αmRNA3‘非翻译区的珠蛋白报告结构，结果表明TTP直接靶向肿瘤坏死因子-αmRNA腺嘌呤和尿苷富集区，并在转录后水平负向调节肿瘤坏死因子-α的表达。结果表明，香烟烟雾暴露使肺泡巨噬细胞和肺上皮细胞TTP表达减少，功能受损，导致肺泡巨噬细胞和肺上皮细胞α-α表达增强。这些数据表明，TTP是一种新的转录后调节因子，可以抑制香烟烟雾诱导的肿瘤坏死因子-α的过度表达和炎症反应。
Tumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory mediator and its expression is up-regulated in chronic obstructive pulmonary disease (COPD). Tristetraprolin (TTP) is implicated in regulation of TNF-α expression; however, whether TTP is involved in cigarette smoke-induced TNF-α expression has not been determined. TTP expression was examined by western blot analysis in murine alveolar macrophages and alveolar epithelial cells challenged without or with cigarette smoke extract (CSE). TNF-α mRNA stability, and the decay of TNF-α mRNA, were determined by real-time quantitative RT-PCR. TNF-α protein levels were examined at the same time in these cells. To identify the molecular mechanism involved, a construct expressing the human beta-globin reporter mRNA containing the TNF-α 3’-untranslated region was generated to characterize the TTP targeted site within TNF-α mRNA. CSE induced TTP down-regulation in alveolar macrophages and alveolar epithelial cells. Reduced TTP expression resulted in significantly increased TNF-α mRNA stability. Importantly, increased TNF-α mRNA stability due to impaired TTP function resulted in significantly increased TNF-α levels in these cells. Forced TTP expression abrogated the increased TNF-α mRNA stability and expression induced by CSE. By using the globin reporter construct containing TNF-α mRNA 3’-untranslated region, the data indicate that TTP directly targets the adenine- and uridine-rich region (ARE) of TNF-α mRNA and negatively regulates TNF-α expression at the post-transcriptional level. The data demonstrate that cigarette smoke exposure reduces TTP expression and impairs TTP function, resulting in significantly increased TNF-α mRNA stability and excessive TNF-α expression in alveolar macrophages and epithelial cells. The data suggest that TTP is a novel post-transcriptional regulator and limits excessive TNF-α expression and inflammatory response induced by cigarette smoke.
登录
查看更多内容
DOI：
10.1164/rccm.200207-756ws
发表时间：
2003-04-15
影响因子：
24.7
作者：
Croxton, TL;Weinmann, GG;Buist, AS
通讯作者：
Buist, AS
DOI：
10.1164/ajrccm.164.8.2008109
发表时间：
2001-10-15
影响因子：
24.7
作者：
Eid, AA;Ionescu, AA;Shale, DJ
通讯作者：
Shale, DJ
影响因子：
9.6
作者：
Canonica, G. Walter
通讯作者：
Canonica, G. Walter
DOI：
10.3109/10409230903277340
发表时间：
2009-11
影响因子：
6.5
作者：
Dominguez R
通讯作者：
Dominguez R
影响因子：
4.6
作者：
Che P;Yang Y;Han X;Hu M;Sellers JC;Londono-Joshi AI;Cai GQ;Buchsbaum DJ;Christein JD;Tang Q;Chen D;Li Q;Grizzle WE;Lu YY;Ding Q
通讯作者：
Ding Q