IRF8 and IRF3 cooperatively regulate rapid interferon-β induction in human blood monocytes

Robust and rapid induction of interferon-beta (IFN-beta) 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-beta 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-beta transcription, whereas reintroduction of IRF8 into the IRF8(-/-) 32Dcl3 murine myeloid cell line reinstated IFN-beta transcription. Moreover, we provide evidence that IRF8 constitutively binds to the ETS/IRF composite element of the IFN-beta promoter region together with PU.1 in vivo. Furthermore we uncovered a requirement for IRF3, a master regulator of IFN-beta production, as a previously un-indentified interaction partner of IRF8. We mapped the protein-protein interacting regions of IRF3 and IRF8, and found that their interaction was independent of the DNA-binding domain and the IRF association domain of IRF8 and IRF3, respectively. Therefore, we propose a model for the rapid induction of IFN-beta in monocytes, whereby IRF8 and PU.1 form a scaffold complex on the IFN-beta promoter to facilitate the recruitment of IRF3, thus enabling rapid IFN-beta transcription. (Blood. 2011; 117(10): 2847-2854)