Review
Therapeutic Mechanisms of Glucocorticoids

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Owing to advances in numerous high-throughput and genome-wide technologies, many unexpected types of GR protein–protein interactions have been discovered, as well as novel DNA-sequences bound by GR, and hence novel mechanisms which add to the anti-inflammatory profile of GCs.

Genome-wide DNA binding studies allow crosstalk between GR and other transcription factors to be studied at the nucleotide level of resolution.

Modern genome-editing techniques (CRISPR/Cas) have allowed more GR mutant proteins and animals to be generated, leading to more refined insights.

Advances in pharmacological techniques have made targeting GCs in specific cell types much more reliable.

Treatment of acute and chronic inflammatory diseases requires different GC-based therapeutic strategies.

Glucocorticoids (GCs) have been used clinically for decades as potent anti-inflammatory and immunosuppressive agents. Nevertheless, their use is severely hampered by the risk of developing side effects and the occurrence of glucocorticoid resistance (GCR). Therefore, efforts to understand the complex mechanisms underlying GC function and GCR are ongoing. The goal is to generate new glucocorticoid receptor (GR) ligands that can dissociate anti-inflammatory from metabolic side effects and/or overcome GCR. In this review paper we discuss recent insights into GR-mediated actions in GCR and novel therapeutic strategies for acute and chronic inflammatory diseases.

Section snippets

The Clinical Importance of GCs

GCs (Box 1) were discovered in the 1940s, a tour de force which was awarded the Nobel Prize in Physiology and Medicine in 1950. GCs are essential stress hormones that bind to the GC receptor, GR, and play a role in different fundamental processes such as metabolic homeostasis, cognition, mental health, cell proliferation, development, reproduction, and inflammation [1]. Owing to their anti-inflammatory and immune-suppressive actions, GCs are among the most widely prescribed drugs. Various

The Genomic Effects of GCs

GCs are lipophilic and can freely diffuse through the cell membrane. Thereafter, they exert their functions by binding to the GR, a transcription factor (TF) encoded by the NR3C1 gene (Box 2). In the absence of GC, GR is predominantly localized in the cytoplasm in a complex containing heat shock proteins, immunophilins, and other factors that prevent its degradation and enhance its affinity for its ligand. Upon ligand binding, GR undergoes a conformational change resulting in partial

The Monomer–Dimer Concept

According to a decades-old hypothesis, the side effects of GC therapy were believed to be induced by dimer-mediated TA because genes induced by this mechanism play a role in glucose synthesis and fat metabolism, for example, the genes encoding glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PEPCK) in liver [19], and stearoyl-CoA desaturases 1–3 (SCD1–3) in adipocytes [20]. By contrast, the anti-inflammatory effects of GCs were mainly believed to be monomer-mediated via TR of

Consequences for Therapy: SEMOGRAMs and SEDIGRAMs

The ability to functionally dissociate TA from TR has prompted a search for dissociated GR ligands that selectively induce GR monomer formation for the treatment of chronic inflammatory diseases. Several selective GR agonists (SEGRAs), such as RU24782, RU24858, and RU40066, have reduced TA activity but still have anti-inflammatory activity as potent as that of prednisolone. Despite initial enthusiasm, these synthetic steroids evoke GC-induced side effects resembling those seen with typical GC

Improvement of Currently Available GCs To Avoid Side Effects

Use of GCs for chronic inflammatory diseases causes many side effects (Figure 2). Because the side effects of GCs are dose-dependent, dose reduction might reduce the side effects. Local delivery of GCs (creams, nasal sprays, inhalers) is used to reduce the systemic dose in the treatment of various inflammatory diseases. For example, inhaled GCs reach the lungs and suppress airway inflammation. Although pulmonary delivery is used extensively, a major limitation is that classic, strong GR

GR–PPAR Crosstalk To Circumvent GC-related Side Effects

Another approach to circumventing GC-related side effects is to stimulate TF crosstalk between GR and PPARs as one paradigm with potential benefit. Both GR and PPAR are members of the nuclear receptor superfamily. They have overlapping and complementary roles in many tissues, control key genes involved in the maintenance of blood glucose levels, cooperatively support fatty acid β-oxidation during fasting, and stimulate immunosuppression 57, 58. It was hypothesized that, by combining GR with

Glucocorticoid Resistance

Another limitation of the use of GCs is the development of GCR, which occurs in 4–10% of asthma patients, 30% of RA patients, and almost all COPD and sepsis patients [3]. GCR limits the therapeutic effect of GCs, while often preserving its detrimental effects 3, 75. The most attractive option for avoiding GCR in inflammatory diseases is to reverse its cause [76].

GCR may result from defects at different levels in GC signaling, such as reduced GR expression, reduced GC binding to GR, impaired

Concluding Remarks and Future Perspectives

The anti-inflammatory activities of classical GCs are useful for short-term treatment in most patients, but their chronic and systemic use usually causes side effects and can reduce GC sensitivity. Other diseases display inherent GCR. Finding solutions to these two problems drives GC research. Efforts have led to several novel fundamental insights into GC and GR biology, as well as to new therapeutic approaches, which have yet to find their way to clinical testing and application (see

Glossary

Allosteric regulation
conformational changes in one region of a molecule induced by binding of a modulator to a remote site on the target protein and consequent alteration of its function.
ChIP-exo
chromatin immunoprecipitation (ChIP) with lambda exonuclease (exo) digestion and sequencing, a technique that combines ChIP with subsequent exonuclease digestion to trim immunoprecipitated DNA down to fragments of ∼30 bp that are protected by a crosslinked protein. This allows the identification of

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