Glucocorticoid-independent modulation of GR activity: Implications for immunotherapy

Abstract

Pharmacological doses of glucocorticoids (GCs), acting via the glucocorticoid receptor (GR) to repress inflammation and immune function, remain the most effective therapy in the treatment of inflammatory and immune diseases. Since many patients on GC therapy exhibit GC-resistance and severe side-effects, much research is focussed on developing more selective GCs and combination therapies, with greater anti-inflammatory potency. GCs mediate their classical genomic transcriptional effects by binding to the cytoplasmic GR, followed by nuclear translocation and modulation of transcription of target genes by direct DNA-binding of the GR or its tethering to other transcription factors. Recent evidence suggests, however, that the responses mediated by the GR are much more complex and involve multiple parallel mechanisms integrating simultaneous signals from other receptors, both in the absence and presence of GCs, to shift the sensitivity of a target cell to GCs. The level of cellular stress, immune activation status, or the cell cycle phase may be crucial for determining GC sensitivity and GC responsiveness as well as subcellular localization of the GR and GR levels. Central to the development of new drugs that target GR signalling alone or as add-on therapies, is an in-depth understanding of the molecular mechanisms of GC-independent GR desensitization, priming and activation of the unliganded GR, as well as synergy and cross-talk with other signalling pathways. This review will discuss the information currently available on these topics and their relevance to immunotherapy, as well as identify unanswered questions and future areas of research.

ACTH Induces Oxidative Stress and Decreases DNA Methylation of Fkbp5 in Suhuai Sow

“…Glucocorticoid production is induced by stress and it regulates gene expression by binding to its intracellular receptor (Hapgood et al, 2016). It has been demonstrated that glucocorticoids increase the transcription of DUSP1 gene by binding to GRE region in A549 human lung adenocarcinoma cells (Shipp et al, 2010).…”

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

“…In the second phase, when regulated systemic inflammation prevails, GC-GRα exerts classic anti-inflammatory action by (i) inhibiting NF-κB, AP-1 and other signaling pathways involved in inflammation, and (ii) increasing transcription of anti-inflammatory genes and the NF-κB inhibitory protein IκB (68,103). GC-GRα anti-inflammatory action has been extensively investigated, and we direct the reader to excellent reviews on the (11,68,101,(104)(105)(106). In upcoming sections, we will review selected mechanisms involved in GC-GRα failure to downregulate systemic inflammation and achieve disease resolution.…”

Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)

“…Several transcriptional and translational isoforms of the GR exist, which appear to vary in their tissue distribution and gene-specific effects. Our current understanding of the GR's mechanism of action is mainly obtained from research on the almost ubiquitous and most abundant full-length GRα isoform [20].…”

“…Also, differences in chromatin structure and DNA methylation status of GR-target genes determine cell specific cortisol effects [27]. Besides classical genomic and rapid GC-induced non-genomic ligand-dependent steroid receptor actions and crosstalk, there is increasing evidence that the unliganded GR can modulate cell signaling in the absence of glucocorticoids, adding another level of complexity [20].…”