Activated phenotype of circulating neutrophils in familial Mediterranean fever
Activated phenotype of circulating neutrophils in familial Mediterranean fever
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DOI：
10.1016/j.imbio.2012.10.007
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发表时间：
2013-06-01
期刊：
影响因子：
2.8
通讯作者：
Boyajyan, Anna
中科院分区：
文献类型：
--
作者：
Manukyan, Gayane;Petrek, Martin;Boyajyan, Anna
家族性地中海热（FMF）是一种自身炎症性疾病，其特征是MEFV基因突变和反复发作的发热和血清或滑膜炎症。中性粒细胞是FMF急性炎症发作的主要效应细胞;然而，这些细胞的致病作用和分子表型在很大程度上仍然未知。为了深入了解导致自我导向的自身炎症的过程，我们表征了FMF患者未受刺激和LPS激活的中性粒细胞中参与炎症调节的一系列基因的表达。采用定量RT-PCR方法检测了15例FMF患者和10例健康志愿者外周血中性粒细胞中编码炎症相关分子的12个候选免疫基因的表达。使用二阶导数法计算相对表达;将靶基因表达归一化为RPL 32基因的表达。FMF中性粒细胞的特征是c-FOS基因表达上调（9.5倍，p < 0.05），IL-8（12倍，p < 0.05），MMP 9（8倍，p < 0.01），TLR 2（7倍，p < 0.05）与来自对照受试者的中性粒细胞相比，caspase-1表达增加的趋势也是明显的。（3倍，p = 0.09）。判别分析将患者和对照受试者聚类为两个不同的组（Wilks λ = 0.165，p = 0.042）。此外，LPS诱导的表达谱改变在FMF和健康中性粒细胞之间共享，该谱即由上调的IL-1 β、TLR 4、IL-8和TNFAIP 6转录物组成。目前的研究表明，与健康对照组的中性粒细胞相比，FMF无发作期预活化中性粒细胞的表达模式不同。此外，我们的数据强调了宿主来源的配体在FMF中性粒细胞活化中的重要性。(C)2012 Elsevier GmbH. All rights reserved.
Familial Mediterranean fever (FMF) is autoinflammatory disorder, characterized by MEFV gene mutations and recurrent episodes of fever and serosal or synovial inflammation. Neutrophils are the predominant effector cells of acute inflammatory attacks in FMF; however pathogenic role and molecular phenotype of these cells remain largely unknown. To gain insight into the processes that contribute to the self-directed autoinflammation we characterized expression of a spectrum of genes involved in regulation of inflammation in unstimulated and LPS-activated neutrophils from FMF patients. Expression of 12 candidate immune genes encoding for inflammation-related molecules was assessed by quantitative RT-PCR in freshly isolated and LPS-stimulated peripheral polymorphonuclear neutrophils from fifteen FMF patients in attack-free period and ten healthy volunteers as controls. The relative expression was calculated using the second derivative method; the target gene expression was normalized to the expression of RPL32 gene. FMF neutrophils were characterized by up-regulated baseline gene expression of c-FOS (9.5-fold, p < 0.05), IL-8 (12-fold, p < 0.05), MMP9 (8-fold, p < 0.01), TLR2 (7-fold, p < 0.05) compared to the neutrophils from control subjects, a trend was also evident towards increased caspase-1 expression (3-fold, p = 0.09). Discriminant analysis clustered the patient and control subjects into two distinct groups (Wilks's lambda = 0.165, p = 0.042). Further, LPS-induced alterations of expression profiles were shared between FMF and healthy neutrophils, the profile consisting namely of up-regulated IL-1 beta, TLR4, IL-8, and TNFAIP6 transcripts. Present study demonstrates distinct expression patterns of pre-activated neutrophils during attack-free period of FMF when compared to neutrophils from healthy controls. Furthermore, our data emphasize the importance of host-derived ligands in activation of FMF neutrophils. (C) 2012 Elsevier GmbH. All rights reserved.