Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways
Serena Ghisletti,Wendy Huang,Kristen Jepsen,Christopher Benner,Gary Hardiman,Michael G. Rosenfeld,Christopher K. Glass +6 more
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TLDR
Findings reveal a combinatorial, corepressor-based strategy for integration of inflammatory and anti-inflammatory signals that play essential roles in immunity and homeostasis.Abstract:
Innate immune responses to bacterial or viral infection require rapid transition of large cohorts of inflammatory response genes from poised/repressed to actively transcribed states, but the underlying repression/derepression mechanisms remain poorly understood. Here, we report that, while the nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressors establish repression checkpoints on broad sets of inflammatory response genes in macrophages and are required for nearly all of the transrepression activities of liver X receptors (LXRs), they can be selectively recruited via c-Jun or the Ets repressor Tel, respectively, establishing NCoR-specific, SMRT-specific, and NCoR/SMRT-dependent promoters. Unexpectedly, the binding of NCoR and SMRT to NCoR/SMRT-dependent promoters is frequently mutually dependent, establishing a requirement for both proteins for LXR transrepression and enabling inflammatory signaling pathways that selectively target NCoR or SMRT to also derepress/activate NCoR/SMRT-dependent genes. These findings reveal a combinatorial, corepressor-based strategy for integration of inflammatory and anti-inflammatory signals that play essential roles in immunity and homeostasis.read more
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Macrophages, Inflammation, and Insulin Resistance
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Transcriptional control of the inflammatory response
Ruslan Medzhitov,Tiffany Horng +1 more
TL;DR: The mechanisms of and the emerging principles in the transcriptional regulation of inflammatory responses in diverse physiological settings are discussed.
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TNF biology, pathogenic mechanisms and emerging therapeutic strategies
TL;DR: Molecular mechanisms underlying the roles of T NF in homeostasis and inflammatory disease pathogenesis are presented, and novel strategies to advance therapeutic paradigms for the treatment of TNF-mediated diseases are discussed.
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Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells
Christopher K. Glass,Kaoru Saijo +1 more
TL;DR: Recent studies providing insights into the distinct mechanisms that enable nuclear receptors to antagonize pro-inflammatory programmes of gene expression in macrophages and T cells by altering the turnover or recruitment of co-repressors and co-activators in a gene-specific manner are reviewed.
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The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines
Julie E. Gibbs,John Blaikley,Stephen Beesley,Laura Matthews,Karen D. Simpson,Susan H. Boyce,Stuart N. Farrow,Kathryn J. Else,Dave Singh,David W. Ray,Andrew S. I. Loudon +10 more
TL;DR: It is demonstrated that the macrophage clockwork provides temporal gating of systemic responses to endotoxin, and REV-ERBα is identified as the key link between the clock and immune function, and may represent a unique therapeutic target in human inflammatory disease.
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