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J Immunol. 2015 Nov 1;195(9):4446-55. doi: 10.4049/jimmunol.1500204. Epub 2015 Sep 28.

ATF3 Is a Key Regulator of Macrophage IFN Responses.

Author information

1
Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany;
2
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
3
Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia;
4
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53127 Bonn, Germany;
5
Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; and German Center for Neurodegenerative Diseases, 53175 Bonn, Germany eicke.latz@uni-bonn.de denardo.d@wehi.edu.au.
6
Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany; Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia; eicke.latz@uni-bonn.de denardo.d@wehi.edu.au.

Abstract

Cytokines and IFNs downstream of innate immune pathways are critical for mounting an appropriate immune response to microbial infection. However, the expression of these inflammatory mediators is tightly regulated, as uncontrolled production can result in tissue damage and lead to chronic inflammatory conditions and autoimmune diseases. Activating transcription factor 3 (ATF3) is an important transcriptional modulator that limits the inflammatory response by controlling the expression of a number of cytokines and chemokines. However, its role in modulating IFN responses remains poorly defined. In this study, we demonstrate that ATF3 expression in macrophages is necessary for governing basal IFN-β expression, as well as the magnitude of IFN-β cytokine production following activation of innate immune receptors. We found that ATF3 acted as a transcriptional repressor and regulated IFN-β via direct binding to a previously unidentified specific regulatory site distal to the Ifnb1 promoter. Additionally, we observed that ATF3 itself is a type I IFN-inducible gene, and that ATF3 further modulates the expression of a subset of inflammatory genes downstream of IFN signaling, suggesting it constitutes a key component of an IFN negative feedback loop. Consistent with this, macrophages deficient in Atf3 showed enhanced viral clearance in lymphocytic choriomeningitis virus and vesicular stomatitis virus infection models. Our study therefore demonstrates an important role for ATF3 in modulating IFN responses in macrophages by controlling basal and inducible levels of IFNβ, as well as the expression of genes downstream of IFN signaling.

PMID:
26416280
DOI:
10.4049/jimmunol.1500204
[Indexed for MEDLINE]
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