Robust and rapid induction of interferon-␤ (IFN-␤) in monocytes after pathogenic stimulation is a hallmark of innate immune responses. Here, we reveal the molecular mechanism underlying this key property that is exclusive to human blood monocytes. We found that IFN-␤ was produced rapidly in primary human monocytes as a result of cooperation between the myeloid-specific transcription factor IRF8 and the ubiquitous transcription factor IRF3. Knockdown of IRF8 in monocytes abrogated IFN-␤ transcription, whereas reintroduction of IRF8 into the IRF8 ؊/؊ 32Dcl3 murine myeloid cell line reinstated IFN-␤ transcription. Moreover, we provide evidence that IRF8 constitutively binds to the ETS/IRF composite element of the IFN-␤ promoter region together with PU.1 in vivo. Furthermore we uncovered a requirement for IRF3, a master regulator of IFN-␤ production, as a previously un-indentified interaction partner of IRF8. We mapped the protein- IntroductionProduction of interferon-␤ (IFN-␤) by the host is an essential first line of defense against both viral and nonviral pathogens. [1][2][3] As well as its involvement in innate immunity, IFN-␤ is an important initiator and modulator of the adaptive immune response. [4][5][6] For example, IFN-␤ influences the differentiation, maturation, and migration of dendritic cells. 7 In addition, it regulates antibody production and antigen-mediated apoptosis of B cells, 8 alongside promoting the generation of CD4 ϩ Th1 responses, 9 and the expansion of antigen-specific CD8 ϩ T cells. 10 Interestingly, Stockinger et al have recently demonstrated that IFN-␤ production contributes to Listeria monocytogenes-induced lethality in mice. 11 As such, IFN-␤ seems able to induce immunopathology as well as influence the resolution of infections, thus making it important to understand the mechanisms linking pathogen stimulation of immune cells with the production of IFN-␤.IFN-␤ transcription is initiated after cellular recognition of pathogen-associated molecular patterns by pattern recognition receptors. 12 Many cell types express IFN-␤ after microbial exposure, [13][14][15] although the underlying mechanisms vary. In murine embryonic fibroblasts, IFN-␤ induction is mediated by the activation of both IRF3 and IRF7. 16,17 In contrast, induction of IFN-␤ in murine plasmacytoid dendritic cells occurs after CpG recognition by Toll-like receptor 9 and is entirely dependent on IRF7, 18 whereas in murine macrophages transcription of IFN-␤ is dependent on IRF3 alone. 19 IRF3 is a ubiquitous cytosolic transcription factor that translocates to the nucleus on activation, 20 where it is able to induce IFN-␤ expression. However, this process takes more than 6 hours to produce detectable levels of IFN-␤ mRNA in HeLa cells, with levels peaking even later at 9 to 19 hours. 21 Monocytes are myeloid cells of the immune system that play a key role in the rapid innate response to pathogens, including the production of IFN-␤. 11,22 However, the molecular mechanisms underlying the rapid induction of IFN-␤ in monocytes hav...

Interferons (IFNs) were discovered more than half a century ago, and extensive research has since identified multifarious roles for type I IFN in human immune responses. Here, we review the functions of IFN-β in innate and adaptive immunity. We also discuss the activation and influence of IFN-β on myeloid cell types, including monocytes and dendritic cells, as well as address the effects of IFN-β on T cells and B cells. Findings from our own laboratory, which explores the molecular mechanisms of IFN-β activation by LPS and viruses, as well as from other groups investigating the regulation of IFN-β by viral proteins and endogenous factors are described. The effects of post-translational modifications of the interferon regulatory factor (IRF)-3 on IFN-β induction are also highlighted. Many unanswered questions remain concerning the regulation of the type I IFN response in inflammation, especially the role of transcription factors in the modulation of inflammatory gene expression, and these questions will form the basis for exciting avenues of future research.

IRF-7 mediates robust production of type I IFN via MyD88 of the TLR9 pathway in plasmacytoid dendritic cells (pDCs). Previous in vitro studies using bone marrow-derived dendritic cells lacking either Irf7 or Irf3 have demonstrated that only IRF-3 is required for IFN-β production in the TLR4 pathway. Here, we show that IRF-7 is essential for both type I IFN induction and IL-1β responses via TLR4 in mice. Mice lacking Irf7 were defective in production of both IFN-β and IL-1β, an IFN-β-induced pro-inflammatory cytokine, after LPS challenge. IFN-β production in response to LPS was impaired in IRF-7-deficient macrophages, but not dendritic cells. Unlike pDCs, IRF-7 is activated by the TRIF-, but not MyD88-, dependent pathway via TBK-1 in macrophages after LPS stimulation. Like pDCs, resting macrophages constitutively expressed IRF-7 protein. This basal IRF-7 protein was completely abolished in either Ifnar1 −/− or Stat1 −/− macrophages, which corresponded with the loss of LPS-stimulated IFN-β induction in these macrophages. These findings demonstrate that macrophage IRF-7 is critical for LPS-induced type I IFN responses, which in turn facilitate IL-1β production in mice.