title: Interferon-γ regulates cellular metabolism and mRNA translation to potentiate macrophage activation.
abstract: 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.
authors.affiliation: Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021.|Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Su
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065.
authors.forename: Yingpu
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Computational Biology Department, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.|Biological Sciences Department, New York City College of Technology, City University of New York, Brooklyn, NY 11201.
authors.forename: Eugenia G
authors.initials: EG
authors.lastname: Giannopoulou
authors.affiliation: Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Hu
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.affiliation: Computational Biology Department, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Rätsch
authors.affiliation: Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021.|Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021.
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
mesh_terms: D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D035683:MicroRNAs / Q000235:genetics; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D039561:Eukaryotic Initiation Factor-4E; D018398:Homeodomain Proteins; D007371:Interferon-gamma; D047908:Intracellular Signaling Peptides and Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D035683:MicroRNAs; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; D051195:Toll-Like Receptor 2; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human; C491395:MKNK1 protein, human; C486342:MKNK2 protein, human