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Interferon-γ regulates cellular metabolism and mRNA translation to potentiate macrophage activation
Open accessAbstract
Interferon-γ (IFN-γ) primes macrophages for enhanced microbial killing and inflammatory activation by Toll-like receptors (TLRs), but little is known about the regulation of cell metabolism or mRNA translation during this priming. We found that IFN-γ regulated the metabolism and mRNA translation of human macrophages by targeting the kinases mTORC1 and MNK, both of which converge on the selective regulator of translation initiation eIF4E. Physiological downregulation of mTORC1 by IFN-γ was associated with autophagy and translational suppression of repressors of inflammation such as HES1. Genome-wide ribosome profiling in TLR2-stimulated macrophages showed that IFN-γ selectively modulated the macrophage translatome to promote inflammation, further reprogram metabolic pathways and modulate protein synthesis. These results show that IFN-γ-mediated metabolic reprogramming and translational regulation are key components of classical inflammatory macrophage activation.
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“Although the IFN-γ and the mTOR pathways seem to be tightly interwoven, no data exist on the in vivo outcomes of mTORi on IFN-γ signaling and function38–40.”
From Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation (2019) · cites this paper as [40]
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Metadata
- Authors
- Su, X., Yu, Y., Zhong, Y., Giannopoulou, E. G., Hu, X., Liu, H., Cross, J. R., Rätsch, G., Rice, C. M., & Ivashkiv, L. B.
- Affiliations
- Hospital for Special Surgery (US)
- Rockefeller University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Ivashkiv, Lionel B
- Venue
- Nature Immunology
- Published
- 2015-06-29
- Volume
- 16
- Issue
- 8
- Pages
- 838-849
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC4509841
- OpenAlex
- W1550446004
- Cited by
- 298
- References
- 50
- Citations by year
- 2026: 25 · 2025: 25 · 2024: 22 · 2023: 31 · 2022: 29 · 2021: 30 · 2020: 26 · 2019: 24 · 2018: 39 · 2017: 15 · 2016: 27 · 2015: 5
- FWCI
- 12.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CUNY Academic Works (City University of New York) (submittedVersion)
- Funders
- Hospital for Special Surgery
- National Institutes of Health (2r01ai046712-26)
- National Institute of Allergy and Infectious Diseases (R01-AI046712, R01AI044938)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR050401, R01AR046713)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- interferon-gamma, macrophage activation, metabolic reprogramming, mRNA translation, mTORC1, eIF4E, autophagy, Hes1, ribosome profiling, TLR2, inflammation, protein synthesis
- MeSH terms
- Transcription Factor HES-1, Mechanistic Target of Rapamycin Complex 1, Base Sequence, Cells, Cultured, Humans, Interferon-gamma, Macrophage Activation, Macrophages, Microscopy, Fluorescence, RNA, Messenger, Protein Biosynthesis, Blotting, Western, Signal Transduction, Protein Serine-Threonine Kinases, Homeodomain Proteins, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, RNA Interference, MicroRNAs, Eukaryotic Initiation Factor-4E, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Toll-Like Receptor 2, Basic Helix-Loop-Helix Proteins, TOR Serine-Threonine Kinases
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