title: Cutting Edge: Synchronization of IRF1, JunB, and C/EBPβ Activities during TLR3-TLR7 Cross-Talk Orchestrates Timely Cytokine Synergy in the Proinflammatory Response.
abstract: Multiple pathogen-associated molecular pattern-induced TLR pathway cross-talk provokes proinflammatory cytokine synergy in macrophages, which is important for pathogen resistance and immune homeostasis. However, the detailed mechanisms are unclear. In this article, we demonstrate viral RNA analog-induced transcription synergy of Il6 and Il12b via IFN regulatory factor (IRF)1 (TLR3-TIR domain-containing adaptor inducing IFN-β [TRIF] responsive), C/EBPβ (TLR7-MyD88 responsive), and JunB (all responsive). Coactivation of the TLR3 and TLR7 pathways synchronizes the interaction of IRF1, JunB, and C/EBPβ with the Il6 and Il12b promoters, facilitating maximal gene expression. MyD88 pathway activation suppresses TRIF-induced IRF1 in a delayed manner, controlling the magnitude and timing of cytokine expression. Our findings provide novel mechanisms of cooperation of different TLR pathways to achieve optimal immune responses, with the potential for immunomodulatory strategies.
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543; and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543; and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543; and.
authors.forename: Wai Khang
authors.initials: WK
authors.lastname: Yong
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637511.
authors.forename: Newman Siu Kwan
authors.initials: NS
authors.lastname: Sze
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637511.
authors.forename: Nguan Soon
authors.initials: NS
authors.lastname: Tan
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543; and dbsdjl@nus.edu.sg.
authors.forename: Jeak Ling
authors.initials: JL
authors.lastname: Ding
mesh_terms: D051702:Activating Transcription Factor 6 / Q000276:immunology; D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D007249:Inflammation / Q000276:immunology*; D050856:Interferon Regulatory Factor-1 / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D020239:Receptor Cross-Talk / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology
chemical_list: D051702:Activating Transcription Factor 6; D033942:Adaptor Proteins, Vesicular Transport; D050856:Interferon Regulatory Factor-1; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D014157:Transcription Factors; C574724:Atf6b protein, mouse; C494258:Irf1 protein, mouse; C584097:JunB protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C477038:Tlr7 protein, mouse