Molecular Determinants of Crosstalk between Nuclear Receptors and Toll-like Receptors
Copyright policy )Molecular Determinants of Crosstalk between Nuclear Receptors and Toll-like Receptors
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.
- University of California, Los Angeles United States
- University of California Los Angeles
- Howard Hughes Medical Institute United States
- Exelixis United States
- University of California, San Francisco United States
Lipopolysaccharides, Membrane Glycoproteins, Biochemistry, Genetics and Molecular Biology(all), Gene Expression Profiling, Interferon Regulatory Factor-7, Macrophages, NF-kappa B, Receptors, Cytoplasmic and Nuclear, Receptors, Cell Surface, Receptor Cross-Talk, Orphan Nuclear Receptors, Toll-Like Receptor 3, DNA-Binding Proteins, PPAR gamma, Toll-Like Receptor 4, Mice, Receptors, Glucocorticoid, Animals, Interferon Regulatory Factor-3, Liver X Receptors, Signal Transduction
Lipopolysaccharides, Membrane Glycoproteins, Biochemistry, Genetics and Molecular Biology(all), Gene Expression Profiling, Interferon Regulatory Factor-7, Macrophages, NF-kappa B, Receptors, Cytoplasmic and Nuclear, Receptors, Cell Surface, Receptor Cross-Talk, Orphan Nuclear Receptors, Toll-Like Receptor 3, DNA-Binding Proteins, PPAR gamma, Toll-Like Receptor 4, Mice, Receptors, Glucocorticoid, Animals, Interferon Regulatory Factor-3, Liver X Receptors, Signal Transduction
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).581 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 1% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 0.1%
Citations provided by BIP!Popularity provided by BIP!