Type I IFNs downregulate myeloid cell IFN-γ receptor by inducing recruitment of an early growth response 3/NGFI-A binding protein 1 complex that silences ifngr1 transcription.
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-γ), and reduced myeloid cell responsiveness to IFN-γ. 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-β reduced cellular abundance of ifngr1 transcripts as rapidly and effectively as actinomycin D treatment. IFN-β 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-β 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.
Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA.
Staci J
SJ
Kearney
Christine
C
Delgado
Emily M
EM
Eshleman
Krista K
KK
Hill
Brian P
BP
O'Connor
Laurel L
LL
Lenz
D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D051776:Early Growth Response Protein 3 / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017471:Receptors, Interferon / Q000276:immunology / Q000378:metabolism*; D012097:Repressor Proteins / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic; D000096743:Interferon gamma Receptor
D051776:Early Growth Response Protein 3; D007370:Interferon Type I; D017471:Receptors, Interferon; D012097:Repressor Proteins; D000096743:Interferon gamma Receptor; C094815:NAB1 protein, human; C490624:Nab1 protein, mouse