Faculty Collaboration Database

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. J Immunol 2013 Sep 15;191(6):3384-92

Date

08/13/2013

Pubmed ID

23935197

Pubmed Central ID

PMC3777655

DOI

10.4049/jimmunol.1203510

Scopus ID

2-s2.0-84884227097 (requires institutional sign-in at Scopus site)   47 Citations

Abstract

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.

Author List

Kearney SJ, Delgado C, Eshleman EM, Hill KK, O'Connor BP, Lenz LL

Author

Emily M. Eshleman PhD Assistant Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blotting, Western
Chromatin Immunoprecipitation
Down-Regulation
Early Growth Response Protein 3
Flow Cytometry
Gene Silencing
Humans
Interferon Type I
Macrophages
Mice
Mice, Inbred C57BL
Myeloid Cells
Real-Time Polymerase Chain Reaction
Receptors, Interferon
Repressor Proteins
Transcription, Genetic