期刊
JOURNAL OF IMMUNOLOGY
卷 182, 期 2, 页码 851-859出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.182.2.851
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资金
- University of South Carolina Centenary Plan
- National Institutes of Health [AG16321, DE13749]
- Gilbert and Kathryn Mitchell Endowment
- Ohio State University Comprehensive Cancer Center Core [CA16058]
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.
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