Interferon-regulatory-factor 1 controls Toll-like receptor 9-mediated IFN- square production in myeloid dendritic cells

• Published in: European Journal of Immunology 2007-02, Vol.37 (2), p.315-327
• Main Authors: Schmitz, Frank, Heit, Antje, Guggemoos, Simone, Krug, Anne, Mages, Jorg, Schiemann, Matthias, Adler, Heiko, Drexler, Ingo, Haas, Tobias, Lang, Roland, Wagner, Hermann
• Format: Article
• Language: English
• ISSN: 0014-2980; 1365-2567
• DOI: 10.1002/eji.200636767

Activation of interferon regulatory factor (IRF)-3 and/or IRF-7 drives the expression of antiviral genes and the production of / 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- promoter activation. IRF-1 physically interacted with MyD88 and activation of mDC via TLR-9 induced IRF-1-dependent IFN- production paralleled by rapid transcriptional activation of IFN-stimulated genes. The NF-B-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. See accompanying commentary: http://dx.doi.org/10.1002/eji.200637009 .