Abstract
Viral double-stranded RNA (dsRNA) is recognised by pathogen recognition receptors such as Toll-Like Receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I), and results in cytokine and interferon production. Fas, a well characterised death receptor, has recently been shown to play a role in the inflammatory response. In this study we investigated the role of Fas in the anti-viral immune response. Stimulation of Fas on macrophages did not induce significant cytokine production. However, activation of Fas modified the response of macrophages to the viral dsRNA analogue poly I:C. In particular, poly I:C-induced IP-10 production was significantly enhanced. A similar augmentation of IP-10 by Fas was observed following stimulation with both poly A:U and Sendai virus. Fas activation suppressed poly I:C-induced phosphorylation of the MAP kinases p38 and JNK, while overexpression of the Fas adaptor protein, Fas-associated protein with death domain (FADD), activated AP-1 and inhibited poly I:C-induced IP-10 production. Consistent with an inhibitory role for AP-1 in IP-10 production, mutation of the AP-1 binding site on the IP-10 promoter resulted in augmented poly I:C-induced IP-10. These results demonstrate that engagement of the Fas receptor plays a role in modifying the innate immune response to viral RNA.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antiviral Agents / pharmacology*
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Apoptosis
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Blotting, Western
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Cell Proliferation
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Cells, Cultured
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Cytokines / genetics
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Cytokines / metabolism*
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Fas-Associated Death Domain Protein / genetics
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Fas-Associated Death Domain Protein / metabolism
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Humans
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Interleukin-10 / genetics
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Interleukin-10 / metabolism*
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism*
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Macrophages / virology
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Phosphorylation / drug effects
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Poly I-C / pharmacology*
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RNA, Messenger / genetics
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RNA, Viral / genetics
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Real-Time Polymerase Chain Reaction
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Respirovirus Infections / drug therapy
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Respirovirus Infections / metabolism
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Respirovirus Infections / virology
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Reverse Transcriptase Polymerase Chain Reaction
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Sendai virus / genetics
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Signal Transduction / drug effects*
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
Substances
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Antiviral Agents
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Cytokines
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FADD protein, human
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Fas-Associated Death Domain Protein
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IL10 protein, human
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NF-kappa B
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RNA, Messenger
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RNA, Viral
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Transcription Factor AP-1
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Interleukin-10
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Poly I-C
Grants and funding
The authors would like to acknowledge Science Foundation Ireland for financial support (grant numbers 10/RFP/CAN2894 and 10/RFP/BIC2737. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.