Immune cell-specific amplification of interferon signaling by the IRF-4/8-PU.1 complex

Both type I interferon (IFN-alpha/beta) and type II IFN (IFN-gamma) exert many functions that are restricted to immune cells. Thus, they play critical roles in innate and adaptive immunity. IFN regulatory factor-4 (IRF-4) and IRF-8 (formerly PU.1 interaction partner [Pip] and IFN consensus sequence binding domain [ICSBP], respectively) are immune cell-specific members of the IRF family that regulate the development of myeloid, lymphoid, and dendritic cells. They form a heterodimeric complex with another immune cell-specific transcription factor PU.1-Spi-1 and regulate transcription of genes in the immune system. This review describes the role of the IRF-8-PU.1 complex in modulating IFN signaling in an immune cell-specific manner. Our studies revealed that some but not all IFN-gamma-inducible genes carry an IFN-gamma activation site (GAS) element that contains a binding site for the IRF- 8-PU.1 complex. The IRF-8-PU.1 complex can take part in GAS-mediated transcription and amplify expression of IFN-gamma-responsive genes initiated by Stat1 in macrophages. Similarly, some but not all IFN-alpha/beta-responsive genes are shown to carry an IFN-stimulated response element (ISRE) that contains an IRF-8-PU.1 binding site. The participation of IRF-8-PU.1 in ISRE-mediated transcription results in the augmentation of IFN-stimulated gene factor 3 (ISGF3)-induced transcription in macrophages. Thus, GAS and ISRE elements, classically defined as universal IFN-alpha/beta and IFN-gamma response sequences, are not the same, and some harbor an embedded motif for IRF- 8-PU.1 binding that functions only in immune cells. Accordingly, the IRF-8-PU.1complex provides secondary IFN signaling pathways unique to the immune system. Collectively, the contribution of IRF-8 and PU.1 to IFN-regulated gene expression may in part account for immune cell-specific functions of IFNs.