title: Biphasic RLR-IFN-β response controls the balance between antiviral immunity and cell damage.
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.
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Hwang
authors.forename: Kye-Yeon
authors.initials: KY
authors.lastname: Hur
authors.forename: Jeong-Rae
authors.initials: JR
authors.lastname: Kim
authors.forename: Kwang-Hyun
authors.initials: KH
authors.lastname: Cho
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Kim
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Yoo
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D019898:Autocrine Communication / Q000276:immunology*; D020126:Brefeldin A / Q000494:pharmacology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology*; D017930:Genes, Reporter; D056945:Hep G2 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018448:Models, Immunological; D011070:Poly I-C / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013269:Stochastic Processes; D014158:Transcription, Genetic; D014162:Transfection; D014777:Virus Diseases / Q000276:immunology*
chemical_list: D007369:Interferon Inducers; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D020126:Brefeldin A; D016899:Interferon-beta; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C