title: Glucocorticoids target suppressor of cytokine signaling 1 (SOCS1) and type 1 interferons to regulate Toll-like receptor-induced STAT1 activation.
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.
authors: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. sandip.bhattacharyya@vanderbilt.edu
authors: Sandip
authors: S
authors: Bhattacharyya
authors: Yuxing
authors: Y
authors: Zhao
authors: Thomas W H
authors: TW
authors: Kay
authors: Louis J
authors: LJ
authors: Muglia
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