Gene Expression Control by Glucocorticoid Receptors during Innate Immune Responses

Abstract

Glucocorticoids (GCs) are potent anti-inflammatory compounds that have been extensively used in clinical practice for several decades. GC’s effects on inflammation are generally mediated through GC receptors (GRs). Signal transduction through these nuclear receptors leads to dramatic changes in gene expression programs in different cell types, typically due to GR binding to DNA or to transcription modulators. During the last decade, the view of GCs as exclusive anti-inflammatory molecules has been challenged. GR negative interference in pro-inflammatory gene expression was a landmark in terms of molecular mechanisms that suppress immune activity. In fact, GR can induce varied inhibitory molecules, including a negative regulator of Toll-like receptors pathway, or subject key transcription factors, such as NF-κB and AP-1, to a repressor mechanism. In contrast, the expression of some acute-phase proteins and other players of innate immunity generally requires GR signaling. Consequently, GRs must operate context-dependent inhibitory, permissive, or stimulatory effects on host defense signaling triggered by pathogens or tissue damage. This review aims to disclose how contradictory or comparable effects on inflammatory gene expression can depend on pharmacological approach (including selective GC receptor modulators; SEGRMs), cell culture, animal treatment, or transgenic strategies used as models. Although the current view of GR-signaling integrated many advances in the field, some answers to important questions remain elusive.

Modulation of glucocorticoid receptor in human epileptic endothelial cells impacts drug biotransformation in an in vitro blood–brain barrier model

“…29,30 For instance, whether GR activation or loss mediates the immune changes and inflammation occurring in seizure disorders remains to be further studied. [31][32][33]…”

Young alcohol binge drinkers have elevated blood endotoxin, peripheral inflammation and low cortisol levels: neuropsychological correlations in women

“…The decrease in cortisol levels could be reflecting the status of HPA axis activation; although to confirm this hypothesis, other elements of the axis must be measured. Anyhow, lower cortisol levels in ABDs would explain the higher peripheral inflammatory responses observed in this group because glucocorticoids have well‐known peripheral anti‐inflammatory properties and negatively regulate the TLR signaling and the NF‐κB pathway to control the immunity response (reviewed in Xavier et al ).…”

Mutant glucocorticoid receptor binding elements on Interleukin-6 promoter regulate dexamethasone effects

“…To predict which proteins bind to IL-6 promoter to mediate the gene expression, we searched the transcription factor binding sites on IL-6 promoter region using 14 bioinformatics tools and found several putative sites, such as AP-1, NF-κB, Sp1 and 5 GR sites. The sequences of these sites show high similarity among different species (Supplemental material, Fig S1).…”

“…GCs also negatively regulate IL-6 gene expression through downregulation of its promoter activity in various tissues [10,11]. The regulation of several cytokine gene expressions by activated GRs, which are interact with the GCs, may be through binding to genes or indirective interaction with other transcription factors, in particular NF-κB and activator protein-1 (AP-1) complexes [7,[12][13][14]. Transcription factors, such as NF-κB and AP-1, are known to mediate gene expression during inflammatory reaction extensively, especially in inflammatory cytokines, MMPs and cyclo-oxygenase-2 [12,15,16].…”