Lipopolysaccharide Activates Toll-like Receptor 4 (TLR4)-mediated NF-κB Signaling Pathway and Proinflammatory Response in Human Pericytes
Lipopolysaccharide Activates Toll-like Receptor 4 (TLR4)-mediated NF-κB Signaling Pathway and Proinflammatory Response in Human Pericytes
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DOI：
10.1074/jbc.m113.521161
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发表时间：
2014-01-24
影响因子：
4.8
通讯作者：
Sanz, Laura
中科院分区：
文献类型：
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作者：
Guijarro-Munoz, Irene;Compte, Marta;Sanz, Laura
周细胞和间充质干细胞（MSC）是个体发生相关的，事实上，没有显着的表型差异，可以通过流式细胞术观察到。人周细胞和MSC的转录组分析显示，与MSC相比，周细胞中有43个基因上调超过10倍。Toll样受体4（TLR 4）作为周细胞中相对于MSC最丰富的RNA种类之一的鉴定和TLR 4在细胞表面上表达的确认使我们获得了脂多糖（LPS）刺激的周细胞的表达程序的全面概述。LPS处理的细胞的转录谱显示，22个基因上调超过5倍。其中10个基因编码趋化因子和细胞因子（CXCL 10、CCL 20、IL 8、CXCL 1、IL 6、CCL 2、IL 1B、CXCL 2、IL 1A和CXCL 6），3个基因编码粘附分子（ICAM 1、VCAM 1和SELE）。LPS刺激的周细胞可诱导转录因子NF-B核转位。此外，SC-514对NF-B活化的抑制阻断了LPS诱导的趋化因子基因子集的上调，证实了NF-B在周细胞中LPS信号传导中的关键作用。在蛋白质水平，我们评估了促炎细胞因子和趋化因子IL-6，IL-8，CXCL 1，CXCL 2，CXCL 3和CCL 2的分泌，不仅在LPS处理后，而且在HMGB 1刺激的周细胞。粘附分子ICAM-1和VCAM-1的上调导致外周血白细胞与LPS处理的周细胞单层的粘附增加。周细胞在炎症环境中的作用几乎没有得到解决;根据这些结果，周细胞应被视为炎症级联反应中的积极参与者，具有潜在的生理病理学意义。
Pericytes and mesenchymal stem cells (MSCs) are ontogenically related, and in fact, no significant phenotypic differences could be observed by flow cytometry. Transcriptome analysis of human pericytes and MSCs revealed that 43 genes were up-regulated more than 10-fold in pericytes compared with MSCs. Identification of Toll-like receptor 4 (TLR4) as one of the most abundant RNA species in pericytes with respect to MSCs and confirmation of TLR4 expression on the cell surface led us to obtain a comprehensive overview of the expression program of lipopolysaccharide (LPS)-stimulated pericytes. Transcriptional profiling of LPS-treated cells revealed that 22 genes were up-regulated more than 5-fold. Of them, 10 genes encoded chemokines and cytokines (CXCL10, CCL20, IL8, CXCL1, IL6, CCL2, IL1B, CXCL2, IL1A, and CXCL6), and three genes encoded adhesion molecules (ICAM1, VCAM1, and SELE). LPS induced nuclear translocation of the transcription factor NF-B in stimulated pericytes. Moreover, inhibition of NF-B activation by SC-514 blocked LPS-induced up-regulation of a subset of chemokine genes, confirming the key role of NF-B in LPS signaling in pericytes. At the protein level, we assessed the secretion of the proinflammatory cytokines and chemokines IL-6, IL-8, CXCL1, CXCL2, CXCL3, and CCL2 not only after LPS treatment but also in HMGB1-stimulated pericytes. Up-regulation of the adhesion molecules ICAM-1 and VCAM-1 resulted in an increased adhesion of peripheral blood leukocytes to an LPS-treated pericyte monolayer. The role of pericytes in the inflammatory context has been scarcely addressed; according to these results, pericytes should be considered as active players in the inflammatory cascade with potential physiopathological implications.