The Feedback Phase of Type I Interferon Induction in Dendritic Cells Requires Interferon Regulatory Factor 8

Abstract

Dendritic cells (DCs) produce type I interferons (IFNs) in greater amounts than other cells, but the mechanisms remain elusive. Here we studied the role of a transcription factor, IRF8, in DC induction of type I IFNs. Upon newcastle disease virus (NDV) infection, bone marrow-derived plasmacytoid and conventional DCs induced IFN transcripts, exhibiting two-phase kinetics. The second, amplifying phase represented an IFN feedback response that accounted for much of IFN protein production. Induction of second phase transcription required IRF8. Mouse cytomegalovirus (MCMV) and Toll-like receptor-mediated IFN induction in DCs also required IRF8. Chromatin immunoprecipitation analysis showed that IRF7, IRF8, and RNA polymerase II were recruited to the IFN promoters upon stimulation. Moreover, sustained RNA polymerase II recruitment to the promoters critically depended on IRF8. Together, these data indicate that IRF8 magnifies the second phase of IFN transcription in DCs by prolonging binding of basic transcription machinery to the IFN promoters, thereby playing a role in innate immunity.

The TLR7 Ligand 9-Benzyl-2-Butoxy-8-Hydroxy Adenine Inhibits IL-17 Response by Eliciting IL-10 and IL-10–Inducing Cytokines

“…Indeed, 1 to 2 h after the treatment, we observed the peak of serum IL-10 and IFN-a, which rapidly declined, whereas a second peak of serum IFN-a and a concomitant high level of IL-27, with no detectable IL-10, were present at 10 h. The two IFN-a peaks agree with the described two-phase induction of IFN-a by DC (37). The early IFN-a production has been shown to be produced by plasmacytoid DC triggered by pathogen-associated molecules patterns, whereas the second amplifying phase represents a feedback response mostly sustained by conventional DC (37). In our system, the early serum IFN-a peak is due to IFN-aproducing resident peritoneal cells stimulated by SA-2, which can directly enroll and amplify spleen conventional DC to produce IFN-a.…”

A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

“…A striking feature of CD5 + CD81 + pDCs is that they produce little or no type I IFN upon stimulation with CpG oligonucleotides. IRF7 plays a central role in initiating type I IFN gene transcription in pDCs (35)(36)(37)(38)(39)(40), and IRF8, through a feedback mechanism, further magnifies type I IFN production (41,42). The CD5 + CD81 + pDCs express substantially less IRF7 mRNA than CD5 − CD81 − pDCs, which might explain their diminished type I IFN production.…”

Critical Role of the IFN-Stimulated Gene Factor 3 Complex in TLR-Mediated IL-27p28 Gene Expression Revealing a Two-Step Activation Process

“…For example, IRF8 plays an important role in the expression of IL-12p35 and p40 genes (41,42). This factor also contributes to the amplification of type I IFN production in DCs (43). Preliminary experiments indicated that the p28 promoter is not responsive to IRF8 overexpression.…”