Abstract
In RNA virus-infected cells, retinoic acid-inducible gene-I-like receptors (RLRs) sense foreign RNAs and activate signaling cascades to produce IFN-α/β. However, not every infected cell produces IFN-α/β that exhibits cellular heterogeneity in antiviral immune responses. Using the IFN-β-GFP reporter system, we observed bimodal IFN-β production in the uniformly stimulated cell population with intracellular dsRNA. Mathematical simulation proposed the strength of autocrine loop via RLR as one of the contributing factor for biphasic IFN-β expression. Bimodal IFN-β production with intracellular dsRNA was disturbed by blockage of IFN-α/β secretion or by silencing of the IFN-α/β receptor. Amplification of RLRs was critical in the generation of bimodality of IFN-β production, because IFN-β(high) population expressed more RLRs than IFN-β(low) population. In addition, bimodality in IFN-β production results in biphasic cellular response against infection, because IFN-β(high) population was more prone to apoptosis than IFN-β(low) population. These results suggest that RLR-mediated biphasic cellular response may act to restrict the number of cells expressing IFN-β and undergoing apoptosis in the infected population.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / immunology*
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Autocrine Communication / immunology*
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Brefeldin A / pharmacology
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DEAD Box Protein 58
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DEAD-box RNA Helicases / antagonists & inhibitors
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DEAD-box RNA Helicases / biosynthesis
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / physiology*
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Gene Expression Regulation / immunology*
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Genes, Reporter
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Hep G2 Cells / drug effects
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Hep G2 Cells / metabolism
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Humans
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Interferon Inducers / pharmacology
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Interferon-Induced Helicase, IFIH1
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Interferon-beta / biosynthesis*
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Interferon-beta / genetics
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Interferon-beta / immunology
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Interferon-beta / metabolism
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Models, Immunological*
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Poly I-C / pharmacology
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Protein Transport / drug effects
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RNA Interference
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RNA, Double-Stranded / pharmacology
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RNA, Small Interfering / pharmacology
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / immunology
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Reverse Transcriptase Polymerase Chain Reaction
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Stochastic Processes
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Transcription, Genetic
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Transfection
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Virus Diseases / immunology*
Substances
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Interferon Inducers
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RNA, Double-Stranded
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Brefeldin A
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Interferon-beta
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Ddx58 protein, mouse
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Ifih1 protein, mouse
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DEAD Box Protein 58
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DEAD-box RNA Helicases
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Interferon-Induced Helicase, IFIH1
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Poly I-C