Abstract
Innate sensing of pathogens initiates inflammatory cytokine responses that need to be tightly controlled. We found here that after engagement of Toll-like receptors (TLRs) in myeloid cells, deficient sumoylation caused increased secretion of transcription factor NF-κB-dependent inflammatory cytokines and a massive type I interferon signature. In mice, diminished sumoylation conferred susceptibility to endotoxin shock and resistance to viral infection. Overproduction of several NF-κB-dependent inflammatory cytokines required expression of the type I interferon receptor, which identified type I interferon as a central sumoylation-controlled hub for inflammation. Mechanistically, the small ubiquitin-like modifier SUMO operated from a distal enhancer of the gene encoding interferon-β (Ifnb1) to silence both basal and stimulus-induced activity of the Ifnb1 promoter. Therefore, sumoylation restrained inflammation by silencing Ifnb1 expression and by strictly suppressing an unanticipated priming by type I interferons of the TLR-induced production of inflammatory cytokines.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Chromatin / genetics
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Chromatin / metabolism
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Cytokines / metabolism
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Disease Models, Animal
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Disease Resistance*
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Disease Susceptibility
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Enhancer Elements, Genetic
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Gene Expression Profiling
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Gene Expression Regulation*
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Genetic Loci
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Immunity, Innate*
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Immunomodulation*
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Inflammation / genetics*
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Inflammation / immunology*
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Inflammation / metabolism*
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Inflammation / virology
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Inflammation Mediators / metabolism
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Interferon-beta / metabolism
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Lipopolysaccharides / immunology
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Mice
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Mice, Knockout
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Protein Binding
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Receptor, Interferon alpha-beta / metabolism
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Regulatory Elements, Transcriptional
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SUMO-1 Protein / metabolism
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Shock, Septic / genetics
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Shock, Septic / immunology
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Shock, Septic / metabolism
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Signal Transduction
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Sumoylation* / genetics
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Sumoylation* / immunology
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Toll-Like Receptors / metabolism
Substances
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Chromatin
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Cytokines
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Inflammation Mediators
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Lipopolysaccharides
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SUMO-1 Protein
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Toll-Like Receptors
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Receptor, Interferon alpha-beta
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Interferon-beta