Double-stranded RNA mediates interferon regulatory factor 3 activation and interleukin-6 production by engaging Toll-like receptor 3 in human brain astrocytes.
Toll-like receptor 3 (TLR3) participates in the innate immune response by recognizing viral pathogens. In this study, human brain astrocytes were found to constitutively express TLR3, and this expression was increased by interferon-gamma (IFN-gamma) or double-stranded RNA (dsRNA). Treatment employing dsRNA in astrocytes induced IFN regulatory factor 3 (IRF3) phosphorylation, dimer formation and nuclear translocation followed by STAT1 activation. This treatment also activated nuclear factor-kappaB, p38 and c-Jun N-terminal kinase significantly, while activating extracellular signal-regulated kinase to a lesser extent. Treatment with anti-TLR3 antibody inhibited dsRNA-mediated interleukin-6 (IL-6) production. In the presence of mitogen-activated protein kinase inhibitors, astrocytes failed to secrete IL-6 in response to dsRNA treatment. Therefore, dsRNA-induced IL-6 production is dependent on mitogen-activated protein kinases and type I IFN production is dependent on IRF3 in brain astrocytes. These results suggest that brain inflammation, which produces inflammatory cytokines and type I IFNs, may enhance TLR3 expression in astrocytes. Additionally, upregulated TLR3 might modulate inflammatory processes by producing proinflammatory cytokines.
Kim
Hyemi
H
Department of Microbiology and Institute for Immunology and Immunological Diseases, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
Yang
Eunjung
E
Lee
Jeonggi
J
Kim
Se-Hoon
SH
Shin
Jeon-Soo
JS
Park
Joo Young
JY
Choi
Sun Ju
SJ
Kim
Se Jong
SJ
Choi
In-Hong
IH
D001253:Astrocytes / Q000276:immunology*; D001921:Brain / Q000196:embryology / Q000276:immunology*; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005333:Fetus / Q000276:immunology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D011119:Polynucleotides / Q000276:immunology; D012330:RNA, Double-Stranded / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050794:STAT1 Transcription Factor / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
D020672:I-kappa B Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D015850:Interleukin-6; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011119:Polynucleotides; D012330:RNA, Double-Stranded; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D000072000:NF-KappaB Inhibitor alpha; C049667:poly(rI).poly(dC); D007371:Interferon-gamma; D020929:Mitogen-Activated Protein Kinase Kinases