Diminished macrophage apoptosis and reactive oxygen species generation after phorbol ester stimulation in Crohn's disease.
Diminished macrophage apoptosis and reactive oxygen species generation after phorbol ester stimulation in Crohn's disease.
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DOI：
10.1371/journal.pone.0007787
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发表时间：
2009-11-12
期刊：
影响因子：
3.7
通讯作者：
Smith AM
中科院分区：
文献类型：
--
作者：
Palmer CD;Rahman FZ;Sewell GW;Ahmed A;Ashcroft M;Bloom SL;Segal AW;Smith AM
克罗恩病（CD）是一种慢性复发性疾病，其特征是胃肠道肉芽肿性炎症。尽管其发病机制复杂，但我们最近发现CD患者巨噬细胞功能存在系统性缺陷，导致炎症部位细菌清除能力缺陷。在这里，我们发现了二酰基甘油（DAG）同源物佛波醇-12-肉豆蔻酸-13-乙酸酯（PMA）激活后CD中的许多额外的巨噬细胞缺陷。我们提供的证据表明，与健康受试者相比，PMA 暴露后 DNA 碎片减少、线粒体膜去极化减少、活性氧产生受损、细胞色素 c 释放减少和 IL-6 产生增加。 CD 中观察到的巨噬细胞缺陷是刺激特异性的，因为在 p53 激活和内质网应激后观察到正常反应。这些发现增加了越来越多的证据，强调 CD 中巨噬细胞功能紊乱，并且鉴于巨噬细胞在协调炎症反应中的关键作用，细胞凋亡缺陷可能会导致 CD 的发病机制。
Crohn's Disease (CD) is a chronic relapsing disorder characterized by granulomatous inflammation of the gastrointestinal tract. Although its pathogenesis is complex, we have recently shown that CD patients have a systemic defect in macrophage function, which results in the defective clearance of bacteria from inflammatory sites. Here we have identified a number of additional macrophage defects in CD following diacylglycerol (DAG) homolog phorbol-12-myristate-13-acetate (PMA) activation. We provide evidence for decreased DNA fragmentation, reduced mitochondrial membrane depolarization, impaired reactive oxygen species production, diminished cytochrome c release and increased IL-6 production compared to healthy subjects after PMA exposure. The observed macrophage defects in CD were stimulus-specific, as normal responses were observed following p53 activation and endoplasmic reticulum stress. These findings add to a growing body of evidence highlighting disordered macrophage function in CD and, given their pivotal role in orchestrating inflammatory responses, defective apoptosis could potentially contribute to the pathogenesis of CD.
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DOI：
10.1084/jem.20091683
发表时间：
2009-08-31
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Casanova JL;Abel L
通讯作者：
Abel L
影响因子：
15.9
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
24.5
作者：
Itoh, J;de la Motte, C;Fiocchi, C
通讯作者：
Fiocchi, C
影响因子：
3.9
作者：
Budas, G. R.;Mochly-Rosen, D.
通讯作者：
Mochly-Rosen, D.
影响因子：
24.5
作者：
Doering, J;Begue, B;Ruemmele, FM
通讯作者：
Ruemmele, FM