Interferon regulatory factors (IRFs) are critical components of virus-induced immune activation and type I interferon regulation. IRF3 and IRF7 are activated in response to a variety of viruses or after engagement of Toll-like receptor (TLR) 3 and TLR4 by double-stranded RNA and lipopolysaccharide, respectively. The activation of IRF5, is much more restricted. Here we show that in contrast to IRF3 and IRF7, IRF5 is not a target of the TLR3 signaling pathway but is activated by TLR7 or TLR8 signaling. We also demonstrate that MyD88, interleukin 1 receptor-associated kinase 1, and tumor necrosis factor receptor-associated factor 6 are required for the activation of IRF5 and IRF7 in the TLR7 signaling pathway. Moreover, ectopic expression of IRF5 enabled type I interferon production in response to TLR7 signaling, whereas knockdown of IRF5 by small interfering RNA reduced type I interferon induction in response to the TLR7 ligand, R-848. IRF5 and IRF7, therefore, emerge from these studies as critical mediators of TLR7 signaling.Members of the Toll-like receptor family are essential recognition and signaling components of mammalian anti-viral host defense (1). TLR3, 1 TLR7, TLR8, and TLR9 recognize viral nucleic acids and induce type I IFNs. TLR7 and TLR8 are similar in sequence and together with TLR9 form an evolutionarily related subgroup within the TLR superfamily (2, 3).Whereas unmethylated CpG DNA (4), herpes simplex virus (HSV) type 1 (5), and HSV type 2 genomic DNA (6) specifically stimulate TLR9 (7, 8), TLR7 is activated by infections with single-stranded RNA viruses, including influenza virus and vesicular stomatitis virus (VSV) (7, 9). Consequently, plasmacytoid dendritic cells (pDCs) from TLR7-deficient mice fail to produce type I IFNs upon infection with influenza virus or VSV (7, 10). In addition to single-stranded RNA, the synthetic imidazoquinoline, imiquimod, a low molecular weight immune response modifier, activates TLR7 in both humans and mice, whereas its derivative resiquimod (R-848) activates TLR7 and TLR8 in humans but only TLR7 in mice (10, 11). Both imiquimod and R-848 elicit robust anti-viral and anti-tumor immune responses in vivo, which correlate with a strong induction of type I IFNs (12-14). As a consequence of this activity, imiquimod is used for the treatment of external genital warts caused by human Papillomavirus (15).Interferon regulatory factors (IRFs) coordinate the expression of type I IFNs (16 -19) as well as chemokines such as IP-10 and RANTES (regulated on activation normal T cell expressed and secreted) (20 -22). Viral infections, dsRNA, or LPS signaling can activate . In contrast, the activation of IRF5, another member of the IRF family, is much more restricted. Only certain viruses, including Newcastle disease virus (NDV), VSV, and herpes simplex virus type 1, have been shown to activate IRF5 (22), whereas Sendai virus (SeV) and dsRNA poly(I) poly(C) (pI:C), which activate IRF3 and IRF7, do not activate IRF5 (22). These observations suggest that IRF5 is activated by distinct...

The rapid response to infection is essential for host defense. A regulatory network in which a set of transcription factors stimulates expression of the diverse genes encoding for early inflammatory proteins mediates this response. The functional diversity of these factors is dependent on their cell-specific expression, post-translational modifications, and interacting cross-talk.

Human IFN regulatory factor-5 (IRF-5) is a candidate tumor suppressor gene that mediates cell arrest, apoptosis, and immune activation. Here we show that ectopic IRF-5 sensitizes p53-proficient and p53-deficient colon cancer cells to DNA damage-induced apoptosis. The combination IFN-B and irinotecan (CPT-11) cooperatively inhibits cell growth and IRF-5 synergizes with it to further promote apoptosis. The synergism is due to IRF-5 signaling since a striking defect in apoptosis and cell death was observed in IRF-5-deficient cells, which correlated well with a reduction in DNA damageinduced cellular events. Components of this IRF-5 signaling pathway are investigated including a mechanism for DNA damage-induced IRF-5 activation. Thus, IRF-5-regulated pathways may serve as a target for cancer therapeutics. (Cancer Res 2005; 65(16): 7403-12)