Journal
JOURNAL OF IMMUNOLOGY
Volume 190, Issue 12, Pages 6368-6377Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1202574
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Funding
- National Research Foundation of Korea
- Korean Ministry of Science and Technology through Infection Signaling Network Research Center at Chungnam National University [2007-0054932]
- Korea Research Institute of Bioscience and Biotechnology Research Initiative Program
- National Research Foundation of Korea [2007-0054932] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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-kappa B, 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 Ca2+ -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 NOX2and 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.
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