Glucocorticoid receptors: finding the middle ground

Abstract

Glucocorticoids (GCs; referred to clinically as corticosteroids) are steroid hormones with potent anti-inflammatory and immune modulatory profiles. Depending on the context, these hormones can also mediate pro-inflammatory activities, thereby serving as primers of the immune system. Their target receptor, the GC receptor (GR), is a multi-tasking transcription factor, changing its role and function depending on cellular and organismal needs. To get a clearer idea of how to improve the safety profile of GCs, recent studies have investigated the complex mechanisms underlying GR functions. One of the key findings includes both pro- and anti-inflammatory roles of GR, and a future challenge will be to understand how such paradoxical findings can be reconciled and how GR ultimately shifts the balance to a net anti-inflammatory profile. As such, there is consensus that GR deserves a second life as a drug target, with either refined classic GCs or a novel generation of nonsteroidal GR-targeting molecules, to meet the increasing clinical needs of today to treat inflammation and cancer.

Glucocorticoids counteract hypertrophic effects of myostatin inhibition in dystrophic muscle

“…While previous reports have suggested that Mstn-null mice do not exhibit glucocorticoid-induced skeletal muscle atrophy (42), the conflicting findings of the current work could be due to differences in glucocorticoids used, duration of glucocorticoid administration, and/or background of mouse strain used for the study. The mechanism of action for glucocorticoid-based therapeutics is traditionally considered to be the suppression of inflammatory gene expression (61). Paradoxically, we find that chronic Pred treatment in D2.mdx mice, in fact, increases gene signatures associated with heightened inflammation, including Spp1, a gene that encodes a negative modifier of DMD disease progression, osteopontin (62)(63)(64).…”

The glucocorticoid receptor in monocyte‐derived macrophages is critical for cardiac infarct repair and remodeling

“…Glucocorticoids exert profound regulatory effects on components of immunity via different and complex mechanisms and by interfering with several signaling pathways (8). Cell- and tissue-specific and stress-dependent transcriptional responses to glucocorticoids are mediated by the glucocorticoid receptor (GR) (9–11). …”

“…Glucocorticoids exert profound ABBREVIATIONS: 11b-HSD1, 11b-hydroxysteroid dehydrogenase type 1; FACS, fluorescence-activated cell sorting; GR, glucocorticoid receptor; Ly6C, lymphocyte antigen 6 complex, locus C; Ly6G, lymphocyte antigen 6 complex, locus G; LV, left ventricle; MI, myocardial infarction; MMP, matrix metalloproteinase; SMA, smooth muscle actin regulatory effects on components of immunity via different and complex mechanisms and by interfering with several signaling pathways (8). Cell-and tissuespecific and stress-dependent transcriptional responses to glucocorticoids are mediated by the glucocorticoid receptor (GR) (9)(10)(11).…”

Development of a Molecular Signature to Monitor Pharmacodynamic Responses Mediated by In Vivo Administration of Glucocorticoids

“…B, NHVs were administered 5 mg, 10 mg, or 30 mg prednisolone or placebo (i.e., 0 mg). Blood was drawn before administration and at different time points postdose (2,4,8,48,144, and 216 hours). Whole blood expression profiles were analyzed for the GC gene signature.…”