Abstract
Glucocorticoids potently attenuate the production of inflammatory mediators by macrophages, a primary effector of innate immunity. Activation of different macrophage Toll-like receptors (TLRs) by their respective ligands presents a powerful system by which to evaluate stimulus-dependent glucocorticoid effects in the same cell type. Here, we test the hypothesis that glucocorticoids, acting through the glucocorticoid receptor, modulate macrophage activation preferentially depending upon the TLR-selective ligand and TLR adapters. We established that 2 adapters, Trif, MyD88, or both, determine the ability of glucocorticoids to suppress inhibitor of kappaB (IkappaB) degradation or Janus kinase (JNK) activation. Moreover, the sensitivity of transforming growth factor beta-activated kinase 1 (TAK1) activation to glucocorticoids determines these effects. These findings identify TAK1 as a novel target for glucocorticoids that integrates their anti-inflammatory action in innate immunity signaling pathways.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Dexamethasone / pharmacology
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Drug Delivery Systems
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Glucocorticoids / pharmacology*
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I-kappa B Proteins / metabolism*
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Immunity, Innate / drug effects
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Immunity, Innate / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism*
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MAP Kinase Kinase Kinases / antagonists & inhibitors*
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MAP Kinase Kinase Kinases / genetics
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Macrophage Activation / drug effects*
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Macrophage Activation / genetics
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Polydeoxyribonucleotides / pharmacology*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Toll-Like Receptor 3 / antagonists & inhibitors
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Toll-Like Receptor 3 / metabolism
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Toll-Like Receptor 9 / antagonists & inhibitors
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Toll-Like Receptor 9 / metabolism
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Toll-Like Receptors / agonists*
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Toll-Like Receptors / metabolism
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Toll-Like Receptors / physiology
Substances
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Glucocorticoids
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I-kappa B Proteins
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Polydeoxyribonucleotides
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TLR3 protein, mouse
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Tlr9 protein, mouse
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Toll-Like Receptor 3
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Toll-Like Receptor 9
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Toll-Like Receptors
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poly d(I-C)
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Dexamethasone
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7