The EBV-Encoded dUTPase Activates NF-κB through the TLR2 and MyD88-Dependent Signaling Pathway
The EBV-Encoded dUTPase Activates NF-κB through the TLR2 and MyD88-Dependent Signaling Pathway
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DOI：
10.4049/jimmunol.182.2.851
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发表时间：
2009-01-15
影响因子：
4.4
通讯作者：
Williams, Marshall V.
中科院分区：
文献类型：
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作者：
Ariza, Maria-Eugenia;Glaser, Ronald;Williams, Marshall V.
先天性免疫应答作为宿主抵抗包括病毒在内的入侵病原体的主要防御起着关键作用。我们先前已经证明，用EBV编码的dUTR处理人单核细胞衍生的巨噬细胞通过激活NF-κ B诱导促炎细胞因子的表达。然而，负责EBV编码的dUTPase-mediated生物效应的受体尚不清楚。在这项研究中，我们证明了纯化的EBV编码的dUTR通过TLR 2以剂量依赖性方式激活NF-κ B B，并且需要募集衔接分子MyD 88而不是CD 14。此外，NF-κ B的活化被抗TLR 2、抗EBV编码的dUTR阻断Ab和MyD 88的显性阴性构建体在表达TLR 2的人胚肾293细胞中的过表达所消除。此外，用抗EBV编码的dUTR Ab 7136或抗TLR 2 Ab处理人单核细胞衍生的巨噬细胞可阻断EBV编码的dUTR产生IL-6。据我们所知，这是第一个报告表明，由EBV编码的非结构蛋白是一种病原体相关的分子模式，它具有免疫调节功能。虽然需要进一步的研究来确定由EBV编码的dUTR激活的信号通路，并确定其在调节EBV感染的免疫应答中的作用，但我们的研究结果表明，dUTR可能是开发针对EBV感染的新型治疗药物的潜在靶点。免疫学杂志，2009，182：851-859.
The innate immune response plays a key role as the primary host defense against invading pathogens including viruses. We have previously shown that treatment of human monocyte-derived macrophages with EBV-encoded dUTPase induces the expression of proinflammatory cytokines through the activation of NF-kappa B. However, the receptor responsible for EBV-encoded dUTPase-mediated biological effects is not known. In this study, we demonstrate that the purified EBV-encoded dUTPase activates NF-kappa B in a dose-dependent manner through TLR2 and requires the recruitment of the adaptor molecule MyD88 but not CD14. Furthermore, activation of NF-kappa B was abrogated by anti-TLR2, anti-EBV-encoded dUTPase blocking Abs and the overexpression of a dominant negative construct of MyD88 in human embryonic kidney 293 cells expressing TLR2. In addition, treatment of human monocyte-derived macrophages; with the anti-EBV-encoded dUTPase Ab 7136 or the anti-TLR2 Ab blocked the production of IL-6 by the EBV-encoded dUTPase. To our knowledge, this is the first report demonstrating that a nonstructural protein encoded by EBV is a pathogen-associated molecular pattern and that it has immunomodulatory functions. Although additional studies are necessary to define the signaling pathways activated by the EBV-encoded dUTPase and to determine its role in modulating immune responses to EBV infection, our results suggest that the dUTPase could be a potential target for the development of novel therapeutic agents against infections caused by EBV. The Journal of Immunology, 2009, 182: 851-859.