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Sci Rep. 2019 Mar 27;9(1):5288. doi: 10.1038/s41598-019-40503-y.

Sequential conditioning-stimulation reveals distinct gene- and stimulus-specific effects of Type I and II IFN on human macrophage functions.

Author information

1
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, 90095, United States.
2
Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, United States.
3
Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA, 90095, United States.
4
Division of Dermatology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, United States.
5
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, 90095, United States. ahoffmann@ucla.edu.
6
Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA, 90095, United States. ahoffmann@ucla.edu.

Abstract

Macrophages orchestrate immune responses by sensing and responding to pathogen-associated molecules. These responses are modulated by prior conditioning with cytokines such as interferons (IFNs). Type I and II IFN have opposing functions in many biological scenarios, yet macrophages directly stimulated with Type I or II IFN activate highly overlapping gene expression programs. We hypothesized that a sequential conditioning-stimulation approach would reveal with greater specificity the differential effects of Type I and II IFN on human macrophages. By first conditioning with IFN then stimulating with toll-like receptor ligands and cytokines, followed by genome-wide RNA-seq analysis, we identified 713 genes whose expression was unaffected by IFN alone but showed potentiated or diminished responses to a stimulus after conditioning. For example, responses to the cytokine TNF were restricted by Type II IFN conditioning but potentiated by Type I IFN conditioning. We observed that the effects of IFN were not uniformly pro- or anti-inflammatory, but highly gene-specific and stimulus-specific. By assessing expression levels of key signal transducers and characterizing chromatin accessibility by ATAC-seq, we identify the likely molecular mechanisms underlying Type I and Type II-specific effects, distinguishing between modulation of cytoplasmic signaling networks and the nuclear epigenome that synergistically regulate macrophage immune responses.

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