Abstract
Nuclear receptors (NRs) repress transcriptional responses to diverse signaling pathways as an essential aspect of their biological activities, but mechanisms determining the specificity and functional consequences of transrepression remain poorly understood. Here, we report signal- and gene-specific repression of transcriptional responses initiated by engagement of toll-like receptors (TLR) 3, 4, and 9 in macrophages. The glucocorticoid receptor (GR) represses a large set of functionally related inflammatory response genes by disrupting p65/interferon regulatory factor (IRF) complexes required for TLR4- or TLR9-dependent, but not TLR3-dependent, transcriptional activation. This mechanism requires signaling through MyD88 and enables the GR to differentially regulate pathogen-specific programs of gene expression. PPARgamma and LXRs repress overlapping transcriptional targets by p65/IRF3-independent mechanisms and cooperate with the GR to synergistically transrepress distinct subsets of TLR-responsive genes. These findings reveal combinatorial control of homeostasis and immune responses by nuclear receptors and suggest new approaches for treatment of inflammatory diseases.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology
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Gene Expression Profiling
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Interferon Regulatory Factor-3
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Interferon Regulatory Factor-7
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Lipopolysaccharides / administration & dosage
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Lipopolysaccharides / metabolism
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Liver X Receptors
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Macrophages / drug effects
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Macrophages / metabolism
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Mice
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NF-kappa B / metabolism
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Orphan Nuclear Receptors
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PPAR gamma / physiology
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Receptor Cross-Talk / physiology*
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / physiology*
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Receptors, Cytoplasmic and Nuclear / physiology*
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Receptors, Glucocorticoid / physiology
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Signal Transduction / physiology
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
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Transcription Factor RelA
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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DNA-Binding Proteins
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Interferon Regulatory Factor-3
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Interferon Regulatory Factor-7
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Irf3 protein, mouse
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Irf7 protein, mouse
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Lipopolysaccharides
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Liver X Receptors
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Membrane Glycoproteins
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NF-kappa B
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Orphan Nuclear Receptors
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PPAR gamma
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Receptors, Cell Surface
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Receptors, Cytoplasmic and Nuclear
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Receptors, Glucocorticoid
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
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Transcription Factor RelA
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Transcription Factors