A new mechanism involving ERK contributes to rosiglitazone inhibition of tumor necrosis factor-α and interferon-γ inflammatory effects in human endothelial cells
A new mechanism involving ERK contributes to rosiglitazone inhibition of tumor necrosis factor-α and interferon-γ inflammatory effects in human endothelial cells
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DOI：
10.1161/atvbaha.107.160713
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发表时间：
2008-04-01
影响因子：
8.7
通讯作者：
Luconi, Michaela
中科院分区：
文献类型：
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作者：
Lombardi, Adriana;Cantini, Giulia;Luconi, Michaela
目的 - 微血管内皮是炎症反应的主要靶点之一。在特异性激活时，内皮细胞在炎症部位募集Th1淋巴细胞。我们研究了人微血管内皮细胞（HMEC - 1）中介导肿瘤坏死因子（TNF）-α和干扰素（IFN）-γ炎症反应的细胞内信号传导，以及过氧化物酶体增殖物激活受体（PPARγ）激动剂罗格列酮（RGZ）的干预作用。
方法与结果 - TNF - α和IFN - γ主要在联合作用时，通过酶联免疫吸附测定（ELISA）和TaqMan分析评估，可刺激10kDa的干扰素γ诱导蛋白（IP10）和 fractalkine的产生。这种作用不仅由核因子κB（NFκB）和信号转导子和转录激活子1（Stat1）经典通路的激活所介导，而且如通过蛋白质印迹法所测定的，还涉及细胞外信号调节激酶（ERK1/2）磷酸化和激活的快速增加。RGZ通过一种涉及阻断ERK激活的新型快速机制，干扰TNF - α和IFN - γ对IP10、fractalkine和黏附分子的刺激。
结论 - 我们的研究结果为微血管内皮炎症反应的潜在机制以及RGZ在涉及Th1反应的血管病变中的可能治疗用途提供了新的见解。
Objective - Microvascular endothelium is one of the main targets of the inflammatory response. On specific activation, endothelial cells recruit Th1-lymphocytes at the inflammatory site. We investigated the intracellular signaling mediating tumor necrosis factor ( TNF)- alpha and interferon (IFN)-gamma inflammatory response in human microvascular endothelial cells (HMEC-1) and the interfering effects of the peroxisome-proliferator-activated- receptor (PPAR gamma) agonist, rosiglitazone (RGZ).Methods and Results-TNF alpha and IFN gamma, mainly when combined, stimulate IFN gamma-inducible protein of 10 kDa (IP10) and fractalkine production evaluated by ELISA and TaqMan analyses. This effect is not only mediated by activation of the NFkB and Stat1 classic pathways, but also involves a rapid increase in phosphorylation and activation of extracellular signal-regulated kinases (ERK1/2) as measured by Western blot. RGZ interferes with TNF alpha and IFN gamma stimulation of IP10, fractalkine, and adhesion molecule through a novel rapid mechanism which involves the blocking of ERK activation.Conclusions - Our findings shed new light on the mechanisms underlying the inflammatory response of microvascular endothelium and on the possible therapeutic use of RGZ in vasculopathies involving Th1-responses.