Type I interferons down regulate myeloid cell IFNGR by inducing recruitment of an Egr3/Nab1 complex that silences ifngr1 transcription1

• Published in: The Journal of immunology (1950) 2013-08, Vol.191 (6), p.3384-3392
• Main Authors: Kearney, Staci J., Delgado, Christine, Eshleman, Emily M., Hill, Krista K., O'Connor, Brian P., Lenz, Laurel L.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1203510

The ability of type I interferons (IFNs) to increase susceptibility to certain bacterial infections correlates with down regulation of myeloid cell surface IFNGR, the receptor for the type II IFN (IFNγ), and reduced myeloid cell responsiveness to IFNγ. Here, we show that the rapid reductions in mouse and human myeloid cell surface IFNGR1 expression that occur in response to type I IFN treatment reflect a rapid silencing of new ifngr1 transcription by repressive transcriptional regulators. Treatment of macrophages with IFNβ reduced cellular abundance of ifngr1 transcripts as rapidly and effectively as actinomycin D treatment. IFNβ treatment also significantly reduced the amounts of activated RNA polymerase II (pol II) and acetylated histones H3 and H4 at the ifngr1 promoter, and the activity of an ifngr1 -luc reporter construct in macrophages. The suppression of ifngr1 -luc activity required an intact early growth response factor (Egr)-binding site in the proximal ifngr1 promoter. Three Egr proteins and two Egr/NGFI-A binding (Nab) proteins were found to be expressed in bone macrophages, but only Egr3 and Nab1 were recruited to the ifngr1 promoter upon IFNβ stimulation. Knockdown of Nab1 in a macrophage cell line prevented down regulation of IFNGR1 and prevented the loss of acetylated histones from the ifngr1 promoter. These data suggest that type I IFN stimulation induces a rapid recruitment of a repressive Egr3/Nab1 complex that silences transcription from the ifngr1 promoter. This mechanism of gene silencing may contribute to the anti-inflammatory effects of type I IFNs.