title: TLR3-triggered reactive oxygen species contribute to inflammatory responses by activating signal transducer and activator of transcription-1.
abstract: Intracellular reactive oxygen species (ROS) are essential secondary messengers in many signaling cascades governing innate immunity and cellular functions. TLR3 signaling is crucially involved in antiviral innate and inflammatory responses; however, the roles of ROS in TLR3 signaling remain largely unknown. In this study, we show that TLR3-induced ROS generation is required for the activation of NF-κB, IFN-regulatory factor 3, and STAT1-mediated innate immune responses in macrophages. TLR3 induction led to a rapid increase in ROS generation and a physical association between components of the NADPH oxidase (NOX) enzyme complex (NOX2 and p47(phox)) and TLR3 via a Ca(2+)-c-Src tyrosine kinase-dependent pathway. TLR3-induced ROS generation, NOX2, and p47(phox) were required for the phosphorylation and nuclear translocation of STAT1 and STAT2. TLR3-induced activation of STAT1 contributed to the generation of inflammatory mediators, which was significantly attenuated in NOX2- and p47(phox)-deficient macrophages, suggesting a role for ROS-STAT1 in TLR3-mediated innate immune responses. Collectively, these results provide a novel insight into the crucial role that TLR3-ROS signaling plays in innate immune responses by activating STAT1.
authors.affiliation: Department of Microbiology, Chungnam National University, Daejeon 301-747, South Korea.
authors.forename: Chul-Su
authors.initials: CS
authors.lastname: Yang
authors.forename: Jwa-Jin
authors.initials: JJ
authors.lastname: Kim
authors.forename: Sung Joong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D007113:Immunity, Innate / Q000276:immunology*; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D017382:Reactive Oxygen Species / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology* / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3