Journal
JOURNAL OF IMMUNOLOGY
Volume 191, Issue 6, Pages 3384-3392Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1203510
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Funding
- National Institutes of Health [R56AI65638, RO1AI065638, R21AI102264, R21AI103782, P01AI22296, P30CA046934]
- Walter Scott Foundation
- Cancer Research Institute
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The ability of type I IFNs to increase susceptibility to certain bacterial infections correlates with downregulation of myeloid cell surface IFNGR, the receptor for the type II IFN (IFN-gamma), and reduced myeloid cell responsiveness to IFN-gamma. In this study, 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 IFN-beta reduced cellular abundance of ifngr1 transcripts as rapidly and effectively as actinomycin D treatment. IFN-beta 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 IFN-b stimulation. Knockdown of Nab1 in a macrophage cell line prevented downregulation 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.
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