Interferon-regulatory-factor 1 controls Toll-like receptor 9-mediated IFN-beta production in myeloid dendritic cells.
Activation of interferon regulatory factor (IRF)-3 and/or IRF-7 drives the expression of antiviral genes and the production of alpha/beta IFN, a hallmark of antiviral responses triggered by Toll-like receptors (TLR). Here we describe a novel antiviral signaling pathway operating in myeloid (m) dendritic cells (DC) and macrophages that does not require IRF-3 and/or IRF-7 but is driven by IRF-1. IRF-1 together with myeloid differentiation factor 88 (MyD88) or IL-1 receptor-associated kinase (IRAK)-1 triggered IFN-beta promoter activation. IRF-1 physically interacted with MyD88 and activation of mDC via TLR-9 induced IRF-1-dependent IFN-beta production paralleled by rapid transcriptional activation of IFN-stimulated genes. The NF-kappaB-dependent production of pro-inflammatory cytokines, however, was not influenced by IRF-1. TLR-9 signaling through this pathway conferred cellular antiviral resistance while IRF-1-deficient mice displayed enhanced susceptibility to viral infection. These results demonstrate that TLR-9 activation of mDC and macrophages contributes to antiviral immunity via IRF-1.
Schmitz
Frank
F
Institute for Medical Microbiology, Immunology and Hygiene, Munich, Germany.
Heit
Antje
A
Guggemoos
Simone
S
Krug
Anne
A
Mages
Jörg
J
Schiemann
Matthias
M
Adler
Heiko
H
Drexler
Ingo
I
Haas
Tobias
T
Lang
Roland
R
Wagner
Hermann
H
D000818:Animals; D015153:Blotting, Western; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000276:immunology*; D016899:Interferon-beta / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology*; D014162:Transfection; D014615:Vaccinia / Q000276:immunology
D050856:Interferon Regulatory Factor-1; D053594:Myeloid Differentiation Factor 88; D051217:Toll-Like Receptor 9; D016899:Interferon-beta; D053592:Interleukin-1 Receptor-Associated Kinases