TLR-4 and -6 agonists reverse apoptosis and promote maturation of simian virus 5-infected human dendritic cells through NFκB-dependent
TLR-4 and -6 agonists reverse apoptosis and promote maturation of simian virus 5-infected human dendritic cells through NFκB-dependent
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DOI：
10.1016/j.virol.2007.02.035
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发表时间：
2007-08-15
期刊：
影响因子：
3.7
通讯作者：
Parks, Griffith D.
中科院分区：
文献类型：
--
作者：
Arimilli, Subhashini;Johnson, John B.;Parks, Griffith D.
用副粘病毒猿猴病毒5（SV 5）感染人未成熟单核细胞衍生的树突状细胞（moDC）的原代培养物导致广泛的细胞病变效应（CPE）和诱导凋亡，但DC成熟途径未被激活。在这项研究中，我们研究了SV 5诱导的细胞凋亡和缺乏DC成熟之间的关系。通过加入pancaspase抑制剂减少SV 5感染的未成熟DC中的CPE和凋亡导致成熟标志物CD 40、CD 80和CD 86的仅低水平表达，表明SV 5感染主动阻断成熟途径或未能提供足够的信号来激活成熟。为了区分这些假设，用刺激Toll样受体（TLR）的激动剂攻击SV 5感染的未成熟DC。用TLR-4激动剂LPS或TLR-6激动剂FSL I处理增强了SV 5感染的细胞上的CD 40、CD 80和CD 86的细胞表面表达至接近模拟感染的TLR处理的moDC的水平，但用TLR-2、TLR-3、TLR-5或TLR-8的激动剂处理几乎没有效果。加入TLR-4或TLR-6激动剂也显著降低了CPE和细胞凋亡，但病毒蛋白水平和病毒产量不受影响。类似地，SV 5感染的未成熟moDC通过用IL-1 β处理而成熟，并且这些成熟感染的细胞也显示出减少的CPE和凋亡。在存在NF κ B抑制剂的情况下，TLR-4和TLR-6激动剂不促进SV 5感染的DC的成熟或减少其凋亡，表明成熟和细胞存活都依赖于通过NF κ B依赖性途径的信号传导。我们的研究结果表明，一个模型，即SV 5复制诱导未成熟的DC细胞凋亡，但未能提供强大的成熟信号，而激活NF κ B依赖性途径的外源性配体可以导致moDC成熟和推翻SV 5诱导的细胞死亡。(c)2007爱思唯尔公司All rights reserved.
Infection of primary cultures of human immature monocyte-derived dendritic cells (moDC) with the paramyxovirus Simian Virus 5 (SV5) results in extensive cytopathic effect (CPE) and induction of apoptosis, but DC maturation pathways are not activated. In this study, we investigated the relationship between SV5-induced apoptosis and the lack of DC maturation. Reducing CPE and apoptosis in SV5-infected immature DC by the addition of a pancaspase inhibitor resulted in only low level expression of maturation markers CD40, CD80 and CD86, suggesting that SV5 infection either actively blocked maturation pathways or failed to provide sufficient signals to activate maturation. To distinguish between these hypotheses, SV5-infected immature DC were challenged with agonists that stimulate toll-like receptors (TLRs). Treatment with the TLR-4 agonist LPS or TLR-6 agonist FSL I enhanced cell surface expression of CD40, CD80 and CD86 on SV5-infected cells to levels approaching that of mock-infected TLR-treated moDC, but treatment with agonists for TLR-2, -3, -5 or -8 had little effect. Addition of TLR-4 or -6 agonists to SV5-infected DC also dramatically reduced CPE and apoptosis, but the levels of viral protein and virus yield were not affected. Similarly, SV5-infected immature moDC were matured by treatment with IL-1 beta, and these mature infected cells also showed reduced CPE and apoptosis. In the presence of NFk beta inhibitors, TLR-4 and -6 agonists did not promote maturation or reduce apoptosis of SV5-infected DC, indicating that maturation and cell survival were both dependent on signaling through NFkB-dependent pathways. Our results suggest a model whereby SV5 replication induces apoptosis in immature DC but fails to provide strong maturation signals, while activation of NFkB-dependent pathways by exogenous ligands can lead to moDC maturation and override SV5-induced cell death. (c) 2007 Elsevier Inc. All rights reserved.