Journal
NATURE IMMUNOLOGY
Volume 18, Issue 5, Pages 530-540Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3710
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Funding
- European Research Council
- Italian Ministry of University and Research [FIRB RBAP11H2R9]
- Telethon Foundation [TGT16F04]
- Cariplo Foundation [2015-0990]
- Italian Association for Research on Cancer
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Stimulation of macrophages with interferon-gamma (IFN-gamma) and interleukin 4 (IL-4) triggers distinct and opposing activation programs. During mixed infections or cancer, macrophages are often exposed to both cytokines, but how these two programs influence each other remains unclear. We found that IFN-gamma and IL-4 mutually inhibited the epigenomic and transcriptional changes induced by each cytokine alone. Computational and functional analyses revealed the genomic bases for gene-specific cross-repression. For instance, while binding motifs for the transcription factors STAT1 and IRF1 were associated with robust and IL-4-resistant responses to IFN-gamma, their coexistence with binding sites for auxiliary transcription factors such as AP-1 generated vulnerability to IL-4-mediated inhibition. These data provide a core mechanistic framework for the integration of signals that control macrophage activation in complex environmental conditions.
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