Glucocorticoids target suppressor of cytokine signaling 1 (SOCS1) and type 1 interferons to regulate Toll-like receptor-induced STAT1 activation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-06, Vol.108 (23), p.9554-9559
• Main Authors: Bhattacharyya, Sandip, Zhao, Yuxing, Kay, Thomas W.H, Muglia, Louis J
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Blotting, Western; Cell activation; Cells, Cultured; Cytokines; Data processing; Dexamethasone - pharmacology; Effects; Glucocorticoids; Glucocorticoids - pharmacology; Inflammation; Interferon; Interferon Regulatory Factor-3 - metabolism; Interferon-alpha - metabolism; Interferon-beta - pharmacology; Interferons; Interleukin-12 Subunit p40 - metabolism; Interleukin-6 - metabolism; Janus Kinase 2 - metabolism; Ligands; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Phosphorylation - drug effects; Physiological regulation; Poly I-C - pharmacology; Pretreatment; Receptors, Interferon - metabolism; Secretion; Signal transduction; SOCS-1 protein; Stat1 protein; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; T cell receptors; TLR3 protein; Toll-like receptors; Toll-Like Receptors - metabolism; transactivators; Transcription
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1017296108

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.