Abstract
Endogenous and pharmacologic glucocorticoids (GCs) limit inflammatory cascades initiated by Toll-like receptor (TLR) activation. A long-standing clinical observation has been the delay between GC administration and the manifestation of GC's anti-inflammatory actions. We hypothesized that the GCs would have inhibitory effects that target late temporal pathways that propagate proinflammatory signals. Here we interrogated signal transducer and activator of transcription 1 (STAT1) regulation by GC and its consequences for cytokine production during activation of macrophages with TLR-specific ligands. We found that robust STAT1 activation does not occur until 2-3 h after TLR engagement, and that GC suppression of STAT1 phosphorylation first manifests at this time. GC attenuates TLR4-mediated STAT1 activation only through induction of suppressor of cytokine signaling 1 (SOCS1), which increases throughout the 6-h period after treatment. Inhibition of TLR3-mediated STAT1 activation occurs via two mechanisms, impairment of type I IFN secretion and induction of SOCS1. Our data show that SOCS1 and type I interferons are critical GC targets for regulating STAT1 activity and may account for overall GC effectiveness in inflammation suppression in the clinically relevant time frame.
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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Blotting, Western
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Cells, Cultured
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Dexamethasone / pharmacology
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Glucocorticoids / pharmacology*
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Interferon Regulatory Factor-3 / metabolism
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Interferon-alpha / metabolism*
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Interferon-beta / pharmacology
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Interleukin-12 Subunit p40 / metabolism
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Interleukin-6 / metabolism
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Janus Kinase 2 / metabolism
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Lipopolysaccharides / pharmacology
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Macrophages / cytology
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Macrophages / drug effects*
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Macrophages / metabolism
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Mice
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Knockout
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Phosphorylation / drug effects
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Poly I-C / pharmacology
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Receptors, Interferon / metabolism
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / metabolism*
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins / genetics
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Suppressor of Cytokine Signaling Proteins / metabolism*
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Toll-Like Receptors / metabolism*
Substances
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Glucocorticoids
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Interferon Regulatory Factor-3
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Interferon-alpha
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Interleukin-12 Subunit p40
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Interleukin-6
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Irf3 protein, mouse
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Lipopolysaccharides
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Receptors, Interferon
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STAT1 Transcription Factor
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Socs1 protein, mouse
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Stat1 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Toll-Like Receptors
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Interferon-beta
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Dexamethasone
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Jak2 protein, mouse
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Janus Kinase 2
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Poly I-C