Trends in Endocrinology & Metabolism
ReviewTherapeutic Mechanisms of Glucocorticoids
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
References (95)
- et al.
Glucocorticoid resistance in inflammatory diseases
Lancet
(2009) - et al.
Glucocorticoid resistance as a major drive in sepsis pathology
Cytokine Growth Factor Rev.
(2017) - et al.
Corticosteroids. Mechanisms of action in health and disease
Rheum. Dis. Clin. North Am.
(2016) How glucocorticoid receptors modulate the activity of other transcription factors: A scope beyond tethering
Mol. Cell. Endocrinol.
(2013)DNA binding of the glucocorticoid receptor is not essential for survival
Cell
(1998)Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor
Cell Metab.
(2010)Activation of the glucocorticoid receptor in acute inflammation: the SEDIGRAM concept
Trends Pharmacol. Sci.
(2016)Polyethylene glycol–drug ester conjugates for prolonged retention of small inhaled drugs in the lung
J. Control. Release
(2013)Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition
Bioorganic Med. Chem. Lett.
(2016)Targeting the hemoglobin scavenger receptor CD163 in macrophages highly increases the anti-inflammatory potency of dexamethasone
Mol. Ther.
(2012)
Macrophages and liposomes in inflammatory disease: Friends or foes?
Int. J. Pharm.
Novel p65 binding glucocorticoid-induced leucine zipper peptide suppresses experimental autoimmune encephalomyelitis
J. Biol. Chem.
Molecular mechanism of PPAR a action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease
J. Hepatol.
Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression
J. Lipid Res.
PPAR-α modulate the anti-inflammatory effect of glucocorticoids in the secondary damage in experimental spinal cord trauma
Pharmacol. Res.
Transcriptional inactivation of STAT3 by PPARγ suppresses IL-6-responsive multiple myeloma cells
Immunity
PPARγ activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties
Cell Metab.
Endogenous PPARγ mediates anti-inflammatory activity in murine ischemia–reperfusion injury
Gastroenterology
An open-label trial of the PPAR-gamma ligand rosiglitazone for active ulcerative colitis
Am. J. Gastroenterol.
Involvement of glucocorticoid receptor and peroxisome proliferator activated receptor-γ in pioglitazone mediated chronic gastric ulcer healing in rats
Eur. J. Pharmacol.
Statins synergize dexamethasone-induced adipocyte fatty acid binding protein expression in macrophages
Atherosclerosis
Dominance of the strongest: inflammatory cytokines versus glucocorticoids
Cytokine Growth Factor Rev.
Tumor necrosis factor inhibits glucocorticoid receptor function in mice: a strong signal toward lethal shock
J. Biol. Chem.
p38 mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: Role in steroid-insensitive asthma
J. Allergy Clin. Immunol.
Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients
J. Allergy Clin. Immunol.
Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase
Lancet
Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD
Chest
Cellular processing of the glucocorticoid receptor gene and protein: New mechanisms for generating tissue-specific actions of glucocorticoids
J. Biol. Chem.
Glucocorticoid receptor (GR) β has intrinsic, GRα-independent transcriptional activity
Biochem. Biophys. Res. Commun.
Antiinflammatory action of glucocorticoids – new mechanisms for old drugs
N. Engl. J. Med.
Glucocorticoid signaling: an update from a genomic perspective
Annu. Rev. Physiol.
Comprehensive overview of the structure and regulation of the glucocorticoid receptor
Endocr. Rev.
Glucocorticoid-targeted therapies for the treatment of rheumatoid arthritis
Expert Opin. Investig. Drugs
Will we ever have better glucocorticoids?
Clin. Immunol.
ChIP-exo signal associated with DNA-binding motifs provides insight into the genomic binding of the glucocorticoid receptor and cooperating transcription factors
Genome Res.
DNA binding site sequence directs glucocorticoid receptor structure and activity
Science
The glucocorticoid receptor dimer interface allosterically transmits sequence-specific DNA signals
Nat. Struct. Mol. Biol.
The structural basis of direct glucocorticoid-mediated transrepression
Nat. Struct. Mol. Biol.
Chromatin accessibility pre-determines glucocorticoid receptor binding patterns
Nat. Genet.
Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo
Genome Res.
Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes
Genome Biol.
Anti-inflammatory chromatinscape suggests alternative mechanisms of glucocorticoid receptor action
Immunity
Glucocorticoid receptor control of transcription: precision and plasticity via allostery
Nat. Rev. Mol. Cell Biol.
Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options?
Eur. J. Clin. Invest.
Genome-wide analysis of glucocorticoid receptor binding regions in adipocytes reveal gene network involved in triglyceride homeostasis
PLoS One
A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1
EMBO J.
Live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor
PLoS Biol.
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