Journal
CELL
Volume 122, Issue 5, Pages 707-721Publisher
CELL PRESS
DOI: 10.1016/j.cell.2005.06.029
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Funding
- NCI NIH HHS [R01 CA052599, CA52599] Funding Source: Medline
- NIAID NIH HHS [R01 AI047182] Funding Source: Medline
- NIDDK NIH HHS [R01 DK091183, DK063491] Funding Source: Medline
- NIGMS NIH HHS [U54 GM069338, GM069338] Funding Source: Medline
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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. PPAR gamma 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.
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