Enhanced expression and activation of pro-inflammatory transcription factors distinguish aneurysmal from atherosclerotic aorta: IL-6- and IL-8-dominated inflammatory responses prevail in the human aneurysm
Enhanced expression and activation of pro-inflammatory transcription factors distinguish aneurysmal from atherosclerotic aorta: IL-6- and IL-8-dominated inflammatory responses prevail in the human aneurysm
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DOI：
10.1042/cs20070352
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发表时间：
2008-06-01
期刊：
影响因子：
6
通讯作者：
Kleemann, Robert
中科院分区：
文献类型：
--
作者：
Lindeman, Jan H. N.;Abdul-Hussien, Hazem;Kleemann, Robert
炎症在腹主动脉瘤的发病机制中起着关键作用；然而，参与腹主动脉瘤生长的炎症因子和细胞反应的性质(S)存在争议。在目前的研究中，我们开始确定与下游炎症转录因子和细胞反应相关的主动脉炎症细胞因子水平。将AAA管壁样本与取自同一主动脉区域的动脉粥样硬化壁样本进行比较，可以确定AAA特有的炎症参数，将AAA与ASD(主动脉粥样硬化性疾病)区分开来。采用实时定量聚合酶链式反应(RT-PCR)、酶联免疫吸附试验(ELISA)、Western blotting和免疫组织化学相结合的方法，检测细胞因子和转录因子在mRNA和蛋白水平的表达及其活化状态。与ASD相比，AAA患者Th1型[T-bet、IL(IL)-2、干扰素-γ(干扰素-γ)、肿瘤坏死因子-α(TNF-α)、IL-1α和细胞毒性T细胞]和Th2型[GATA3、IL-4、IL-10、IL-13和B细胞]相关炎症参数均升高。对主要下游炎性转录因子的评估显示，AAA样本中C/EBP(CCAAT/增强子结合蛋白)α、β和Delta的基线水平较高。基础p65核因子-kappaB和c-jun[AP-1(激活蛋白-1)]水平相近，但其激活形式在AAA样本中显著增加。P65核因子-kappaB、c-jun、IL-6、IL-8等下游靶基因高表达。与IL-6和IL-8高激活相关的分子和细胞过程增强，如信号转导和转录激活因子-3和穿孔素的表达增加，浆细胞、中性粒细胞和血管含量增加。总之，我们的研究结果表明，AAA是一种全身性炎症状态，其特征是促炎症转录因子的表达和激活增强，并伴有IL-6和IL-8的高表达和下游细胞反应的夸大，这些共同明确地区分了AAA和ASD。
Inflammation plays a key role in the pathogenesis of an AAA (abdominal aortic aneurysm); however, the nature of the inflammatory factors and cellular response(s) involved in AAA growth is controversial. In the present study, we set out to determine the aortic levels of inflammatory cytokines in relation to downstream inflammatory transcription factors and cellular responses. A comparison of AAA wall samples with atherosclerotic wall samples taken from the same aortic region allowed AAA-specific inflammatory parameters to be identified that distinguish AAAs from ASD (aortic atherosclerotic disease). RT-PCR (real-time PCR), ELISA, Western blotting and immunohistochemistry were combined to assess cytokines and transcription factors at the mRNA and protein level, and their activation status. Compared with ASD, inflammatory parameters associated with Th1-type [T-bet, IL (interleukin)-2, IFN-gamma (interferon-gamma), TNF-alpha (tumour necrosis factor-a), IL-1 alpha and cytotoxic T-cells] and Th2-type [GATA3, IL-4, IL-10, IL-13 and B-cells] responses were all increased in AAA samples. Evaluation of major downstream inflammatory transcription factors revealed higher baseline levels of C/EBP (CCAAT/enhancer-binding protein) alpha, beta and delta in the AAA samples. Baseline p65 NF-kappa B (nuclear factor kappa B) and c-Jun [AP-1 (activator protein-1)] levels were comparable, but their activated forms were strongly increased in the AAA samples. Downstream target genes of p65 NF-kappa B, c-Jun, IL-6 and IL-8 were hyperexpressed. Molecular and cellular processes associated with IL-6 and IL-8 hyperactivation were enhanced in the AAA samples, i.e. the expression of phospho-STAT-3 (signal transducer and activator of transcription-3) and perforin were elevated, and the content of plasma cells, neutrophils and vasa vasorum was increased. In conclusion, our findings demonstrate that an AAA is a general inflammatory condition which is characterized by enhanced expression and activation of pro-inflammatory transcription factors, accompanied by IL-6 and IL-8 hyperexpression and exaggerated downstream cellular responses, which together clearly distinguish an AAA from ASD.