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Glucocorticoid sensitivity in health and disease

Abstract

Glucocorticoids regulate many physiological processes and have an essential role in the systemic response to stress. For example, gene transcription is modulated by the glucocorticoid–glucocorticoid receptor complex via several mechanisms. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Differences in sensitivity to glucocorticoids in healthy individuals are partly genetically determined by functional polymorphisms of the gene that encodes the glucocorticoid receptor. Hereditary syndromes have also been identified that are associated with increased and decreased sensitivity to glucocorticoids. As a result of their anti-inflammatory properties, glucocorticoids are widely used in the treatment of allergic, inflammatory and haematological disorders. The variety in clinical responses to treatment with glucocorticoids reflects the considerable variation in glucocorticoid sensitivity between individuals. In immune-mediated disorders, proinflammatory cytokines can induce localized resistance to glucocorticoids via several mechanisms. Individual differences in how tissues respond to glucocorticoids might also be involved in the predisposition for and pathogenesis of the metabolic syndrome and mood disorders. In this Review, we summarize the mechanisms that influence glucocorticoid sensitivity in health and disease and discuss possible strategies to modulate glucocorticoid responsiveness.

Key Points

  • The biologic effects of glucocorticoids are determined by not only the concentrations of glucocorticoids but also individual and tissue sensitivity to glucocorticoids

  • Differences between individuals in sensitivity to glucocorticoids can be demonstrated in both health and disease

  • Glucocorticoid sensitivity is modulated by genetic and acquired disease-related factors

  • Genetic factors that affect glucocorticoid sensitivity are involved in the predisposition for certain diseases, the phenotype of inflammatory and mood disorders and the clinical response to glucocorticoid therapy

  • In immune disorders, proinflammatory cytokines induce tissue resistance to glucocorticoids by interfering with local glucocorticoid availability, the glucocorticoid receptor and its signalling pathway and the interaction of glucocorticoid receptor with target genes

  • Pharmacological modulation of glucocorticoid sensitivity might be an innovative strategy to improve the treatment outcome of inflammatory diseases and the metabolic syndrome

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Figure 1: The gene that encodes the glucocorticoid receptor, NR3C1, is located on chromosome 5q31–32 and has splice variants.
Figure 2: Distribution of plasma concentrations of cortisol before (blue bars) and after (pink bars) administration of 0.25 mg dexamethasone in 164 healthy older (>55 years) individuals.
Figure 3: Glucocorticoid receptor bioassays in healthy individuals that show variation in dose-dependent effects of 4 h incubation with dexamethasone on GILZ and IL-2 mRNA expression in peripheral blood mononuclear cells in vitro.
Figure 4: Factors modulating tissue glucocorticoid sensitivity in inflammation.
Figure 5: Correlation between in vitro and in vivo glucocorticoid sensitivity in patients with rheumatoid arthritis who were treated intramuscularly with glucocorticoids.

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R. A. Quax and R. A. Feelders contributed to all aspects of the article. L. Manenschijn contributed to researching data for the article and writing the article. J. W. Koper and E. F. C. van Rossum provided substantial contribution to discussion of the content and reviewed/edited the manuscript before submission. J. M. Hazes and S. W. J. Lamberts reviewed/edited the manuscript before submission.

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Correspondence to Richard A. Feelders.

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The human GRβ in inflammatory and non-inflammatory disorders (DOC 133 kb)

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Quax, R., Manenschijn, L., Koper, J. et al. Glucocorticoid sensitivity in health and disease. Nat Rev Endocrinol 9, 670–686 (2013). https://doi.org/10.1038/nrendo.2013.183

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