Viral and bacterial patterns induce TLR-mediated sustained inflammation and calcification in aortic valve interstitial cells
Viral and bacterial patterns induce TLR-mediated sustained inflammation and calcification in aortic valve interstitial cells
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DOI：
10.1016/j.ijcard.2010.12.089
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发表时间：
2012-06-28
影响因子：
3.5
通讯作者：
Garcia-Rodriguez, Carmen
中科院分区：
文献类型：
--
作者：
Lopez, Javier;Fernandez-Pisonero, Isabel;Garcia-Rodriguez, Carmen
背景资料：主动脉瓣狭窄股动脉粥样硬化和越来越多的证据Toll样受体（TLR）的动脉粥样硬化的一些ethiopathological功能链接到atherogenes.Methods：TLR介导的炎症和成骨作用进行了研究，从狭窄和非狭窄的主动脉瓣分离的人间质细胞。通过定量RT-PCR、流式细胞术、Western印迹分析、ELISA和细胞因子阵列评估TLR表达和信号传导。结果：对照瓣膜间质细胞表达最多的TLRs，其中TLR 4最丰富，而狭窄瓣膜间质细胞表达较高的TLR 4和TLR 2，较低的TLR 5和TLR 9转录水平。当分析促炎途径时，我们观察到TLR 4、TLR 2和TLR 3配体诱导来自对照和狭窄瓣膜的细胞中NF-κ B和p38 MAPK活化的早期活化。引人注目的是，当研究TLR感应病毒模式时，观察到持续的TLR 3介导的NF-κ B活化、催化活性环氧化酶（考克斯）-2和ICAM-1表达的κ B非依赖性诱导以及几种趋化因子表达的诱导。TLR 4，而不是TLR 2，接合产生类似的，但NF-κ B依赖性的影响。此外，TLR 3和TLR 4激动剂诱导碱性磷酸酶的表达和activity.Conclusions：暴露的主动脉瓣间质细胞的病毒和革兰氏阴性菌的分子模式诱导不同的和长期的TLR介导的促炎症和促成骨反应，可能是相关的退行性主动脉瓣狭窄的发病机制。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Background: Aortic stenosis shares some ethiopathological features with atherosclerosis and increasing evidence links Toll-like receptors (TLRs) to atherogenesis.Methods: TLR-mediated inflammation and osteogenesis were investigated in human interstitial cells isolated from stenotic and non-stenotic aortic valves. TLR expression and signalling were evaluated by quantitative RT-PCR, flow cytometry, Western blot analysis, ELISA, and cytokine arrays. Osteogenesis was evaluated by measuring alkaline phosphatase activity.Results: Interstitial cells from control valves express most TLRs, being TLR4 the most abundant, whereas cells from stenotic valves express higher TLR4 and TLR2 and lower TLR5 and TLR9 transcript levels. When pro-inflammatory pathways were analyzed, we observed that TLR4, TLR2 and TLR3 ligands induced an early activation of NF-kappa B and p38 MAPK activation in cells from control and stenotic valves. Strikingly, when TLRs sensing viral patterns were studied, a sustained TLR3-mediated activation of NF-kappa B, a kappa B-independent induction of catalytically active cyclooxigenase (COX)-2 and ICAM-1 expression, and induction of expression of several chemokines were observed. TLR4, but not TLR2, engagement produced a similar but NF-kappa B-dependent effect. Moreover, TLR3 and TLR4 agonists induced alkaline phosphatase expression and activity.Conclusions: Exposure of aortic valve interstitial cells to viral and Gram-negative bacteria molecular patterns induces distinct and long-term TLR-mediated pro-inflammatory and pro-osteogenic responses that might be relevant to the pathogenesis of degenerative aortic stenosis. (C) 2011 Elsevier Ireland Ltd. All rights reserved.