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.
Highlights
An inflammatory reaction relies on both fast triggering and tight control over intensity
Pioneering work showed that a hormone from adrenal cortex was necessary to keep adrenolectomized animals alive after bacterial challenge [1], while a specific steroidal corticoid reversed the effects associated with adrenolectomy [2]
The main anti-inflammatory mechanism associated with GCs was the synthesis of Lipocortin 1 (Annexin A1; ANXA1), a phospholipase-A2 inhibitory protein that prevents the production of downstream inflammatory mediators prostaglandins and leukotrienes [reviewed in Ref. [3]]
Summary
An inflammatory reaction relies on both fast triggering and tight control over intensity. The molecular cloning of steroid receptors increased the knowledge regarding GC receptor (GR) binding to the DNA and transcriptional control through GC response elements (GREs) These DNA sequences can mediate transactivation, as described above for ANXA1, or repression as well [reviewed in Ref. Different modalities of GR interference in inflammatory signaling were reported, but one particular mechanism was considered more relevant to the understanding of GR functions during inflammation This pathway drived the development of the concept of repression through tethering, which involves GR inhibitory physical interactions with nuclear activators of pro-inflammatory genes transcription [9,10,11]. We aim to contextualize the different models of transcriptional control associated with GCs, which do suppresses inflammatory signaling, and point key discrepant observed outcomes and their interpretations
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