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
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rhen, T. & Cidlowski, J. A. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N. Engl. J. Med. 353, 1711–1723 (2005).
Manenschijn, L., van den Akker, E. L., Lamberts, S. W. & van Rossum, E. F. Clinical features associated with glucocorticoid receptor polymorphisms. An overview. Ann. NY Acad. Sci. 1179, 179–198 (2009).
Charmandari, E., Kino, T. & Chrousos, G. P. Primary generalized familial and sporadic glucocorticoid resistance (Chrousos syndrome) and hypersensitivity. Endocr. Dev. 24, 67–85 (2013).
Walker, B. R. Glucocorticoids and cardiovascular disease. Eur. J. Endocrinol. 157, 545–559 (2007).
Spijker, A. T. & van Rossum, E. F. Glucocorticoid sensitivity in mood disorders. Neuroendocrinology 95, 179–186 (2012).
Chrousos, G. P. & Kino, T. Glucocorticoid action networks and complex psychiatric and/or somatic disorders. Stress 10, 213–219 (2007).
Chrousos, G. P. & Kino, T. Glucocorticoid signaling in the cell. Expanding clinical implications to complex human behavioral and somatic disorders. Ann. NY Acad. Sci. 1179, 153–166 (2009).
Biddie, S. C., Conway-Campbell, B. L. & Lightman, S. L. Dynamic regulation of glucocorticoid signalling in health and disease. Rheumatology (Oxford) 51, 403–412 (2012).
Stavreva, D. A. et al. Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nat. Cell Biol. 11, 1093–1102 (2009).
Nader, N., Chrousos, G. P. & Kino, T. Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications. FASEB J. 23, 1572–1583 (2009).
Lamia, K. A. et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480, 552–556 (2011).
Stahn, C. & Buttgereit, F. Genomic and nongenomic effects of glucocorticoids. Nat. Clin. Pract. Rheumatol. 4, 525–533 (2008).
Bamberger, C. M., Schulte, H. M. & Chrousos, G. P. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr. Rev. 17, 245–261 (1996).
Silverman, M. N. & Sternberg, E. M. Neuroendocrine-immune interactions in rheumatoid arthritis: mechanisms of glucocorticoid resistance. Neuroimmunomodulation 15, 19–28 (2008).
Barnes, P. J. Mechanisms and resistance in glucocorticoid control of inflammation. J. Steroid Biochem. Mol. Biol. 120, 76–85 (2010).
Ramamoorthy, S. & Cidlowski, J. A. Exploring the molecular mechanisms of glucocorticoid receptor action from sensitivity to resistance. Endocr. Dev. 24, 41–56 (2013).
Donn, R. et al. Use of gene expression profiling to identify a novel glucocorticoid sensitivity determining gene, BMPRII. FASEB J. 21, 402–414 (2007).
Galon, J. et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J. 16, 61–71 (2002).
John, S. et al. Interaction of the glucocorticoid receptor with the chromatin landscape. Mol. Cell 29, 611–624 (2008).
Oakley, R. H. & Cidlowski, J. A. Cellular processing of the glucocorticoid receptor gene and protein: new mechanisms for generating tissue-specific actions of glucocorticoids. J. Biol. Chem. 286, 3177–3184 (2011).
Hollenberg, S. M. et al. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature 318, 635–641 (1985).
Kino, T. et al. Glucocorticoid receptor (GR) β has intrinsic, GRα-independent transcriptional activity. Biochem. Biophys. Res. Commun. 381, 671–675 (2009).
Lewis-Tuffin, L. J., Jewell, C. M., Bienstock, R. J., Collins, J. B. & Cidlowski, J. A. Human glucocorticoid receptor β binds RU-486 and is transcriptionally active. Mol. Cell Biol. 27, 2266–2282 (2007).
Brogan, I. J. et al. Interaction of glucocorticoid receptor isoforms with transcription factors AP-1 and NF-κB: lack of effect of glucocorticoid receptor β. Mol. Cell Endocrinol. 157, 95–104 (1999).
Hecht, K. et al. Evidence that the β-isoform of the human glucocorticoid receptor does not act as a physiologically significant repressor. J. Biol. Chem. 272, 26659–26664 (1997).
Gougat, C. et al. Overexpression of the human glucocorticoid receptor α and β isoforms inhibits AP-1 and NF-κB activities hormone independently. J. Mol. Med. 80, 309–318 (2002).
Kelly, A. et al. The glucocorticoid receptor β isoform can mediate transcriptional repression by recruiting histone deacetylases. J. Allergy Clin. Immunol. 121, 203–208 (2008).
Rivers, C., Levy, A., Hancock, J., Lightman, S. & Norman, M. Insertion of an amino acid in the DNA-binding domain of the glucocorticoid receptor as a result of alternative splicing. J. Clin. Endocrinol. Metab. 84, 4283–4286 (1999).
Lu, N. Z. & Cidlowski, J. A. Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes. Mol. Cell 18, 331–342 (2005).
Grad, I. & Picard, D. The glucocorticoid responses are shaped by molecular chaperones. Mol. Cell Endocrinol. 275, 2–12 (2007).
Surjit, M. et al. Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor. Cell 145, 224–241 (2011).
Haller, J., Mikics, E. & Makara, G. B. The effects of non-genomic glucocorticoid mechanisms on bodily functions and the central neural system. A critical evaluation of findings. Front. Neuroendocrinol. 29, 273–291 (2008).
Croxtall, J. D., Choudhury, Q. & Flower, R. J. Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor-dependent, transcription-independent mechanism. Br. J. Pharmacol. 130, 289–298 (2000).
Bartholome, B. et al. Membrane glucocorticoid receptors (mGCR) are expressed in normal human peripheral blood mononuclear cells and up-regulated after in vitro stimulation and in patients with rheumatoid arthritis. FASEB J. 18, 70–80 (2004).
Buttgereit, F. & Scheffold, A. Rapid glucocorticoid effects on immune cells. Steroids 67, 529–534 (2002).
Boldizsar, F. et al. Emerging pathways of non-genomic glucocorticoid (GC) signalling in T cells. Immunobiology 215, 521–526 (2010).
Mikics, E., Kruk, M. R. & Haller, J. Genomic and non-genomic effects of glucocorticoids on aggressive behavior in male rats. Psychoneuroendocrinology 29, 618–635 (2004).
Keller-Wood, M. E. & Dallman, M. F. Corticosteroid inhibition of ACTH secretion. Endocr. Rev. 5, 1–24 (1984).
Hinz, B. & Hirschelmann, R. Rapid non-genomic feedback effects of glucocorticoids on CRF-induced ACTH secretion in rats. Pharm. Res. 17, 1273–1277 (2000).
De Bosscher, K., Vanden Berghe, W. & Haegeman, G. The interplay between the glucocorticoid receptor and nuclear factor-κB or activator protein-1: molecular mechanisms for gene repression. Endocr. Rev. 24, 488–522 (2003).
Barnes, P. J. Histone deacetylase-2 and airway disease. Ther. Adv. Respir. Dis. 3, 235–243 (2009).
Beck, I. M. et al. Altered subcellular distribution of MSK1 induced by glucocorticoids contributes to NF-κB inhibition. EMBO J. 27, 1682–1693 (2008).
De Bosscher, K., Vanden Berghe, W. & Haegeman, G. Cross-talk between nuclear receptors and nuclear factor κB. Oncogene 25, 6868–6886 (2006).
Beck, I. M. et al. Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases. Endocr. Rev. 30, 830–882 (2009).
Ayroldi, E. & Riccardi, C. Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action. FASEB J. 23, 3649–3658 (2009).
Chi, H. et al. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc. Natl Acad. Sci. USA 103, 2274–2279 (2006).
Ismaili, N. & Garabedian, M. J. Modulation of glucocorticoid receptor function via phosphorylation. Ann. NY Acad. Sci. 1024, 86–101 (2004).
Chinenov, Y. & Rogatsky, I. Glucocorticoids and the innate immune system: crosstalk with the toll-like receptor signaling network. Mol. Cell Endocrinol. 275, 30–42 (2007).
Smoak, K. & Cidlowski, J. A. Glucocorticoids regulate tristetraprolin synthesis and posttranscriptionally regulate tumor necrosis factor α inflammatory signaling. Mol. Cell Biol. 26, 9126–9135 (2006).
Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A. & Karin, M. Immunosuppression by glucocorticoids: inhibition of NF-κB activity through induction of IκB synthesis. Science 270, 286–290 (1995).
Chriguer, R. S. et al. Glucocorticoid sensitivity in young healthy individuals: in vitro and in vivo studies. J. Clin. Endocrinol. Metab. 90, 5978–5984 (2005).
Huizenga, N. A. et al. Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals. J. Clin. Endocrinol. Metab. 83, 47–54 (1998).
Huizenga, N. A. et al. A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo. J. Clin. Endocrinol. Metab. 83, 144–151 (1998).
van Rossum, E. F. et al. A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels. Diabetes 51, 3128–3134 (2002).
Hearing, S. D., Norman, M., Smyth, C., Foy, C. & Dayan, C. M. Wide variation in lymphocyte steroid sensitivity among healthy human volunteers. J. Clin. Endocrinol. Metab. 84, 4149–4154 (1999).
Smit, P. et al. Differential regulation of synthetic glucocorticoids on gene expression levels of glucocorticoid-induced leucine zipper and interleukin-2. J. Clin. Endocrinol. Metab. 90, 2994–3000 (2005).
Blackhurst, G., McElroy, P. K., Fraser, R., Swan, R. L. & Connell, J. M. Seasonal variation in glucocorticoid receptor binding characteristics in human mononuclear leucocytes. Clin. Endocrinol. (Oxf.) 55, 683–688 (2001).
Cardinal, J., Pretorius, C. J. & Ungerer, J. P. Biological and diurnal variation in glucocorticoid sensitivity detected with a sensitive in vitro dexamethasone suppression of cytokine production assay. J. Clin. Endocrinol. Metab. 95, 3657–3663 (2010).
Engeland, W. C., Shinsako, J., Winget, C. M., Vernikos-Danellis, J. & Dallman, M. F. Circadian patterns of stress-induced ACTH secretion are modified by corticosterone responses. Endocrinology 100, 138–147 (1977).
Heuser, I. J. et al. Age-associated changes of pituitary-adrenocortical hormone regulation in humans: importance of gender. Neurobiol. Aging 15, 227–231 (1994).
Wolf, O. T., Convit, A., de Leon, M. J., Caraos, C. & Qadri, S. F. Basal hypothalamo-pituitary-adrenal axis activity and corticotropin feedback in young and older men: relationships to magnetic resonance imaging-derived hippocampus and cingulate gyrus volumes. Neuroendocrinology 75, 241–249 (2002).
Kudielka, B. M., Schmidt-Reinwald, A. K., Hellhammer, D. H. & Kirschbaum, C. Psychological and endocrine responses to psychosocial stress and dexamethasone/corticotropin-releasing hormone in healthy postmenopausal women and young controls: the impact of age and a two-week estradiol treatment. Neuroendocrinology 70, 422–430 (1999).
Van Cauter, E., Leproult, R. & Kupfer, D. J. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J. Clin. Endocrinol. Metab. 81, 2468–2473 (1996).
Bauer, M. E. Stress, glucocorticoids and ageing of the immune system. Stress 8, 69–83 (2005).
Keane, P. M., Pearson, J. & Walker, W. H. Binding characteristics of transcortin in human plasma in normal individuals, pregnancy and liver disease. J. Endocrinol. 43, 571–579 (1969).
Tomlinson, J. W. et al. 11 β-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr. Rev. 25, 831–866 (2004).
Ferrari, P. The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension. Biochim. Biophys. Acta 1802, 1178–1187 (2010).
Tsujimura, S., Saito, K., Nawata, M., Nakayamada, S. & Tanaka, Y. Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis. Ann. Rheum. Dis. 67, 380–388 (2008).
Silva, C. M. et al. Regulation of the human glucocorticoid receptor by long-term and chronic treatment with glucocorticoid. Steroids 59, 436–442 (1994).
Charmandari, E. et al. Functional characterization of the natural human glucocorticoid receptor (hGR) mutants hGRαR477H and hGRαG679S associated with generalized glucocorticoid resistance. J. Clin. Endocrinol. Metab. 91, 1535–1543 (2006).
Hagendorf, A. et al. Expression of the human glucocorticoid receptor splice variants α, β, and P in peripheral blood mononuclear leukocytes in healthy controls and in patients with hyper- and hypocortisolism. J. Clin. Endocrinol. Metab. 90, 6237–6243 (2005).
Lewis-Tuffin, L. J. & Cidlowski, J. A. The physiology of human glucocorticoid receptor β (hGRβ) and glucocorticoid resistance. Ann. NY Acad. Sci. 1069, 1–9 (2006).
Gross, K. L., Lu, N. Z. & Cidlowski, J. A. Molecular mechanisms regulating glucocorticoid sensitivity and resistance. Mol. Cell Endocrinol. 300, 7–16 (2009).
Roger, T., Chanson, A. L., Knaup-Reymond, M. & Calandra, T. Macrophage migration inhibitory factor promotes innate immune responses by suppressing glucocorticoid-induced expression of mitogen-activated protein kinase phosphatase-1. Eur. J. Immunol. 35, 3405–3413 (2005).
Wallace, A. D. & Cidlowski, J. A. Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids. J. Biol. Chem. 276, 42714–42721 (2001).
Barnes, P. J. & Adcock, I. M. Glucocorticoid resistance in inflammatory diseases. Lancet 373, 1905–1917 (2009).
Lu, N. Z. & Cidlowski, J. A. Glucocorticoid receptor isoforms generate transcription specificity. Trends Cell Biol. 16, 301–307 (2006).
Feldman, K. et al. The rs4844880 polymorphism in the promoter region of the HSD11B1 gene associates with bone mineral density in healthy and postmenopausal osteoporotic women. Steroids 77, 1345–1351 (2012).
Melander, O. et al. Association between a variant in the 11 β-hydroxysteroid dehydrogenase type 2 gene and primary hypertension. J. Hum. Hypertens. 14, 819–823 (2000).
Mariniello, B. et al. Analysis of the 11 β-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) in human essential hypertension. Am. J. Hypertens. 18, 1091–1098 (2005).
van Rossum, E. F. et al. Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index. Clin. Endocrinol. (Oxf.) 59, 585–592 (2003).
Stevens, A. et al. Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype. J. Clin. Endocrinol. Metab. 89, 892–897 (2004).
Marti, A. et al. Meta-analysis on the effect of the N363S polymorphism of the glucocorticoid receptor gene (GRL) on human obesity. BMC Med. Genet. 7, 50 (2006).
Geelen, C. C. et al. BclI glucocorticoid receptor polymorphism is associated with greater body fatness: the Hoorn and CODAM studies. J. Clin. Endocrinol. Metab. 98, E595–E599 (2013).
Ukkola, O., Perusse, L., Chagnon, Y. C., Despres, J. P. & Bouchard, C. Interactions among the glucocorticoid receptor, lipoprotein lipase and adrenergic receptor genes and abdominal fat in the Quebec Family Study. Int. J. Obes. Relat. Metab. Disord. 25, 1332–1339 (2001).
Jewell, C. M. & Cidlowski, J. A. Molecular evidence for a link between the N363S glucocorticoid receptor polymorphism and altered gene expression. J. Clin. Endocrinol. Metab. 92, 3268–3277 (2007).
van den Akker, E. L. et al. Glucocorticoid receptor polymorphism affects transrepression but not transactivation. J. Clin. Endocrinol. Metab. 91, 2800–2803 (2006).
Russcher, H. et al. Increased expression of the glucocorticoid receptor-A translational isoform as a result of the ER22/23EK polymorphism. Mol. Endocrinol. 19, 1687–1696 (2005).
Yudt, M. R. & Cidlowski, J. A. Molecular identification and characterization of a and b forms of the glucocorticoid receptor. Mol. Endocrinol. 15, 1093–1103 (2001).
van Rossum, E. F. et al. The ER22/23EK polymorphism in the glucocorticoid receptor gene is associated with a beneficial body composition and muscle strength in young adults. J. Clin. Endocrinol. Metab. 89, 4004–4009 (2004).
Kuningas, M., Mooijaart, S. P., Slagboom, P. E., Westendorp, R. G. & van Heemst, D. Genetic variants in the glucocorticoid receptor gene (NR3C1) and cardiovascular disease risk. The Leiden 85-plus Study. Biogerontology 7, 231–238 (2006).
van Rossum, E. F. et al. Association of the ER22/23EK polymorphism in the glucocorticoid receptor gene with survival and C-reactive protein levels in elderly men. Am. J. Med. 117, 158–162 (2004).
Schaaf, M. J. & Cidlowski, J. A. AUUUA motifs in the 3'UTR of human glucocorticoid receptor α and β mRNA destabilize mRNA and decrease receptor protein expression. Steroids 67, 627–636 (2002).
Kino, T., Vottero, A., Charmandari, E. & Chrousos, G. P. Familial/sporadic glucocorticoid resistance syndrome and hypertension. Ann. NY Acad. Sci. 970, 101–111 (2002).
Donner, K. M., Hiltunen, T. P., Janne, O. A., Sane, T. & Kontula, K. Generalized glucocorticoid resistance caused by a novel two-nucleotide deletion in the hormone-binding domain of the glucocorticoid receptor gene NR3C1. Eur. J. Endocrinol. 168, K9–K18 (2013).
Ruiz, M. et al. Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance. Clin. Endocrinol. (Oxf.) 55, 363–371 (2001).
van Rossum, E. F. & Lamberts, S. W. Glucocorticoid resistance syndrome: A diagnostic and therapeutic approach. Best Pract Res. Clin. Endocrinol. Metab. 20, 611–626 (2006).
Charmandari, E., Kino, T., Ichijo, T. & Chrousos, G. P. Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder. J. Clin. Endocrinol. Metab. 93, 1563–1572 (2008).
Iida, S. et al. A patient with hypocortisolism and Cushing's syndrome-like manifestations: cortisol hyperreactive syndrome. J. Clin. Endocrinol. Metab. 70, 729–737 (1990).
Newfield, R. S. et al. Normocortisolemic Cushing's syndrome initially presenting with increased glucocorticoid receptor numbers. J. Clin. Endocrinol. Metab. 85, 14–21 (2000).
Feldstein, A. C., Elmer, P. J., Nichols, G. A. & Herson, M. Practice patterns in patients at risk for glucocorticoid-induced osteoporosis. Osteoporos. Int. 16, 2168–2174 (2005).
Sliwinska-Stanczyk, P. et al. The effect of methylprednisolone on proliferation of PBMCs obtained from steroid-sensitive and steroid-resistant rheumatoid arthritis patients. Scand. J. Rheumatol. 36, 167–171 (2007).
de Jong, P. H. et al. Response to glucocorticoids at 2 weeks predicts the effectiveness of DMARD induction therapy at 3 months: post hoc analyses from the tREACH study. Ann. Rheum. Dis. 72, 1659–1663 (2013).
Wang, F. F. et al. New insights into the role and mechanism of macrophage migration inhibitory factor in steroid-resistant patients with systemic lupus erythematosus. Arthritis Res. Ther. 14, R103 (2012).
Saag, K. G. et al. Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am. J. Med. 96, 115–123 (1994).
van Oosten, M. J. et al. Polymorphisms in the glucocorticoid receptor gene that modulate glucocorticoid sensitivity are associated with rheumatoid arthritis. Arthritis Res. Ther. 12, R159 (2010).
van Winsen, L. M. et al. A glucocorticoid receptor gene haplotype (TthIII1/ER22/23EK/9β) is associated with a more aggressive disease course in multiple sclerosis. J. Clin. Endocrinol. Metab. 94, 2110–2114 (2009).
Quax, R. A. et al. Glucocorticoid receptor gene polymorphisms and disease activity during pregnancy and the postpartum period in rheumatoid arthritis. Arthritis Res. Ther. 14, R183 (2012).
Chen, H. L. & Li, L. R. Glucocorticoid receptor gene polymorphisms and glucocorticoid resistance in inflammatory bowel disease: a meta-analysis. Dig. Dis. Sci. 57, 3065–3075 (2012).
Potocnik, U., Ferkolj, I., Glavac, D. & Dean, M. Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis. Genes Immun. 5, 530–539 (2004).
Aeberli, D. et al. Endogenous macrophage migration inhibitory factor modulates glucocorticoid sensitivity in macrophages via effects on MAP kinase phosphatase-1 and p38 MAP kinase. FEBS Lett. 580, 974–981 (2006).
Tantisira, K. G. et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N. Engl. J. Med. 365, 1173–1183 (2011).
van den Berge, M., Hiemstra, P. S. & Postma, D. S. Genetics of glucocorticoids in asthma. N. Engl. J. Med. 365, 2434–2435 (2011).
Tissing, W. J., Meijerink, J. P., den Boer, M. L. & Pieters, R. Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia. Leukemia 17, 17–25 (2003).
Hardy, R. S. et al. Differential expression, function and response to inflammatory stimuli of 11β-hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue-specific regulation of inflammation. Arthritis Res. Ther. 8, R108 (2006).
Schmidt, M. et al. Reduced capacity for the reactivation of glucocorticoids in rheumatoid arthritis synovial cells: possible role of the sympathetic nervous system? Arthritis Rheum. 52, 1711–1720 (2005).
Hardy, R. et al. Local and systemic glucocorticoid metabolism in inflammatory arthritis. Ann. Rheum. Dis. 67, 1204–1210 (2008).
Olsen, N. et al. A gene expression signature for recent onset rheumatoid arthritis in peripheral blood mononuclear cells. Ann. Rheum. Dis. 63, 1387–1392 (2004).
Stegk, J. P., Ebert, B., Martin, H. J. & Maser, E. Expression profiles of human 11β-hydroxysteroid dehydrogenases type 1 and type 2 in inflammatory bowel diseases. Mol. Cell Endocrinol. 301, 104–108 (2009).
Sai, S. et al. Differential regulation of 11β-hydroxysteroid dehydrogenase-1 by dexamethasone in glucocorticoid-sensitive and -resistant childhood lymphoblastic leukemia. Leuk. Res. 33, 1696–1698 (2009).
Yudoh, K., Matsuno, H., Nakazawa, F., Yonezawa, T. & Kimura, T. Increased expression of multidrug resistance of P-glycoprotein on Th1 cells correlates with drug resistance in rheumatoid arthritis. Arthritis Rheum. 42, 2014–2015 (1999).
Farrell, R. J. et al. High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy. Gastroenterology 118, 279–288 (2000).
Quax, R. A. et al. In vitro glucocorticoid sensitivity is associated with clinical glucocorticoid therapy outcome in rheumatoid arthritis. Arthritis Res. Ther. 14, R195 (2012).
Hearing, S. D., Norman, M., Probert, C. S., Haslam, N. & Dayan, C. M. Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes. Gut 45, 382–388 (1999).
Poznansky, M. C. et al. Resistance to methylprednisolone in cultures of blood mononuclear cells from glucocorticoid-resistant asthmatic patients. Clin. Sci. (Lond.) 67, 639–645 (1984).
Kay, A. B., Diaz, P., Carmicheal, J. & Grant, I. W. Corticosteroid-resistant chronic asthma and monocyte complement receptors. Clin. Exp. Immunol. 44, 576–580 (1981).
DeRijk, R. H., Eskandari, F. & Sternberg, E. M. Corticosteroid resistance in a subpopulation of multiple sclerosis patients as measured by ex vivo dexamethasone inhibition of LPS induced IL-6 production. J. Neuroimmunol. 151, 180–188 (2004).
Molijn, G. J. et al. Differential adaptation of glucocorticoid sensitivity of peripheral blood mononuclear leukocytes in patients with sepsis or septic shock. J. Clin. Endocrinol. Metab. 80, 1799–1803 (1995).
Sher, E. R. et al. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J. Clin. Invest. 93, 33–39 (1994).
Du, J. et al. Flow cytometry analysis of glucocorticoid receptor expression and binding in steroid-sensitive and steroid-resistant patients with systemic lupus erythematosus. Arthritis Res. Ther. 11, R108 (2009).
Gruber, G. et al. Levels of glucocorticoid receptor and its ligand determine sensitivity and kinetics of glucocorticoid-induced leukemia apoptosis. Leukemia 23, 820–823 (2009).
Eggert, M. et al. Expression analysis of the glucocorticoid receptor and the nuclear factor-κB subunit p50 in lymphocytes from patients with rheumatoid arthritis. J. Rheumatol. 29, 2500–2506 (2002).
Huisman, A. M. et al. Glucocorticoid receptor up-regulation in early rheumatoid arthritis treated with low dose prednisone or placebo. Clin. Exp. Rheumatol. 21, 217–220 (2003).
Huisman, A. M. et al. Glucocorticoid receptor downregulation in early diagnosed rheumatoid arthritis. Ann. NY Acad. Sci. 966, 64–67 (2002).
Schlaghecke, R., Kornely, E., Wollenhaupt, J. & Specker, C. Glucocorticoid receptors in rheumatoid arthritis. Arthritis Rheum. 35, 740–744 (1992).
Sidoroff, M. & Kolho, K. L. Glucocorticoid sensitivity in inflammatory bowel disease. Ann. Med. 44, 578–587 (2012).
Shimada, T., Hiwatashi, N., Yamazaki, H., Kinouchi, Y. & Toyota, T. Relationship between glucocorticoid receptor and response to glucocorticoid therapy in ulcerative colitis. Dis. Colon Rectum 40, S54–S58 (1997).
Kam, J. C., Szefler, S. J., Surs, W., Sher, E. R. & Leung, D. Y. Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J. Immunol. 151, 3460–3466 (1993).
Hamid, Q. A. et al. Increased glucocorticoid receptor β in airway cells of glucocorticoid-insensitive asthma. Am. J. Respir. Crit. Care Med. 159, 1600–1604 (1999).
Honda, M. et al. Expression of glucocorticoid receptor β in lymphocytes of patients with glucocorticoid-resistant ulcerative colitis. Gastroenterology 118, 859–866 (2000).
Sousa, A. R., Lane, S. J., Cidlowski, J. A., Staynov, D. Z. & Lee, T. H. Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor β-isoform. J. Allergy Clin. Immunol. 105, 943–950 (2000).
Fujishima, S., Takeda, H., Kawata, S. & Yamakawa, M. The relationship between the expression of the glucocorticoid receptor in biopsied colonic mucosa and the glucocorticoid responsiveness of ulcerative colitis patients. Clin. Immunol. 133, 208–217 (2009).
Goecke, A. & Guerrero, J. Glucocorticoid receptor β in acute and chronic inflammatory conditions: clinical implications. Immunobiology 211, 85–96 (2006).
Kozaci, D. L., Chernajovsky, Y. & Chikanza, I. C. The differential expression of corticosteroid receptor isoforms in corticosteroid-resistant and -sensitive patients with rheumatoid arthritis. Rheumatology (Oxford) 46, 579–585 (2007).
Pujols, L., Mullol, J. & Picado, C. α and β glucocorticoid receptors: relevance in airway diseases. Curr. Allergy Asthma Rep. 7, 93–99 (2007).
Hausmann, M., Herfarth, H., Scholmerich, J. & Rogler, G. Glucocorticoid receptor isoform expression does not predict steroid treatment response in IBD. Gut 56, 1328–1329 (2007).
Hori, T. et al. Expression of mRNA for glucocorticoid receptors in peripheral blood mononuclear cells of patients with Crohn's disease. J. Gastroenterol. Hepatol. 17, 1070–1077 (2002).
Vazquez-Tello, A., Halwani, R., Hamid, Q. & Al-Muhsen, S. Glucocorticoid receptor-β up-regulation and steroid resistance induction by IL-17 and IL-23 cytokine stimulation in peripheral mononuclear cells. J. Clin. Immunol. 33, 466–478 (2013).
Webster, J. C., Oakley, R. H., Jewell, C. M. & Cidlowski, J. A. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative β isoform: a mechanism for the generation of glucocorticoid resistance. Proc. Natl Acad. Sci. USA 98, 6865–6870 (2001).
Bamberger, C. M., Bamberger, A. M., de Castro, M. & Chrousos, G. P. Glucocorticoid receptor β, a potential endogenous inhibitor of glucocorticoid action in humans. J. Clin. Invest. 95, 2435–2441 (1995).
Oakley, R. H., Jewell, C. M., Yudt, M. R., Bofetiado, D. M. & Cidlowski, J. A. The dominant negative activity of the human glucocorticoid receptor β isoform. Specificity and mechanisms of action. J. Biol. Chem. 274, 27857–27866 (1999).
Haarman, E. G., Kaspers, G. J., Pieters, R., Rottier, M. M. & Veerman, A. J. Glucocorticoid receptor α, β and γ expression vs in vitro glucocorticoid resistance in childhood leukemia. Leukemia 18, 530–537 (2004).
Qian, X., Zhu, Y., Xu, W. & Lin, Y. Glucocorticoid receptor and heat shock protein 90 in peripheral blood mononuclear cells from asthmatics. Chin. Med. J. (Engl.) 114, 1051–1054 (2001).
Jaaskelainen, T., Makkonen, H. & Palvimo, J. J. Steroid up-regulation of FKBP51 and its role in hormone signaling. Curr. Opin. Pharmacol. 11, 326–331 (2011).
Chun, E. et al. Dexamethasone-induced FKBP51 expression in peripheral blood mononuclear cells could play a role in predicting the response of asthmatics to treatment with corticosteroids. J. Clin. Immunol. 31, 122–127 (2011).
Weigel, N. L. & Moore, N. L. Steroid receptor phosphorylation: a key modulator of multiple receptor functions. Mol. Endocrinol. 21, 2311–2319 (2007).
Mercado, N. et al. p38 mitogen-activated protein kinase-gamma inhibition by long-acting β2 adrenergic agonists reversed steroid insensitivity in severe asthma. Mol. Pharmacol. 80, 1128–1135 (2011).
Mercado, N. et al. Restoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthma. PLoS ONE 7, e41582 (2012).
Ayoub, S., Hickey, M. J. & Morand, E. F. Mechanisms of disease: macrophage migration inhibitory factor in SLE, RA and atherosclerosis. Nat. Clin. Pract. Rheumatol. 4, 98–105 (2008).
Rossi, A. G. et al. Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF). Potential role in asthma. J. Clin. Invest. 101, 2869–2874 (1998).
Adcock, I. M., Lane, S. J., Brown, C. R., Lee, T. H. & Barnes, P. J. Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma. J. Exp. Med. 182, 1951–1958 (1995).
McKay, L. I. & Cidlowski, J. A. Cross-talk between nuclear factor-κB and the steroid hormone receptors: mechanisms of mutual antagonism. Mol. Endocrinol. 12, 45–56 (1998).
Biddie, S. C. et al. Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol. Cell 43, 145–155 (2011).
Ledderose, C. et al. Corticosteroid resistance in sepsis is influenced by microRNA-124--induced downregulation of glucocorticoid receptor-α. Crit. Care Med. 40, 2745–2753 (2012).
Tessel, M. A., Benham, A. L., Krett, N. L., Rosen, S. T. & Gunaratne, P. H. Role for microRNAs in regulating glucocorticoid response and resistance in multiple myeloma. Horm. Cancer 2, 182–189 (2011).
Yang, A. et al. Aberrant microRNA-182 expression is associated with glucocorticoid resistance in lymphoblastic malignancies. Leuk. Lymphoma 53, 2465–2473 (2012).
Bonnans, C. et al. Glucocorticoid receptor-binding characteristics in severe asthma. Eur. Respir. J. 21, 985–988 (2003).
Gladman, D. D., Urowitz, M. B., Doris, F., Lewandowski, K. & Anhorn, K. Glucocorticoid receptors in systemic lupus erythematosus. J. Rheumatol. 18, 681–684 (1991).
Corrigan, C. J. et al. Glucocorticoid resistance in chronic asthma. Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro. Am. Rev. Respir. Dis. 144, 1016–1025 (1991).
Kirkham, B. W., Corkill, M. M., Davison, S. C. & Panayi, G. S. Response to glucocorticoid treatment in rheumatoid arthritis: in vitro cell mediated immune assay predicts in vivo responses. J. Rheumatol. 18, 821–825 (1991).
Franchimont, D. et al. Decreased corticosensitivity in quiescent Crohn's disease: an ex vivo study using whole blood cell cultures. Dig. Dis. Sci. 44, 1208–1215 (1999).
Limbourg, F. P. & Liao, J. K. Nontranscriptional actions of the glucocorticoid receptor. J. Mol. Med. 81, 168–174 (2003).
Walker, B. R. Cortisol—cause and cure for metabolic syndrome? Diabet. Med. 23, 1281–1288 (2006).
Phillips, D. I. et al. Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J. Clin. Endocrinol. Metab. 83, 757–760 (1998).
Stalder, T. et al. Cortisol in hair and the metabolic syndrome. J. Clin. Endocrinol. Metab. 98, 2573–2580 (2013).
Manenschijn, L. et al. High long-term cortisol levels, measured in scalp hair, are associated with a history of cardiovascular disease. J. Clin. Endocrinol. Metab. 98, 2078–2083 (2013).
Abraham, S. B., Rubino, D., Sinaii, N., Ramsey, S. & Nieman, L. K. Cortisol, obesity, and the metabolic syndrome: A cross-sectional study of obese subjects and review of the literature. Obesity (Silver Spring) 21, E105–E117 (2013).
van den Akker, E. L. et al. Glucocorticoid receptor gene and risk of cardiovascular disease. Arch. Intern. Med. 168, 33–39 (2008).
Otte, C. et al. Glucocorticoid receptor gene, low-grade inflammation, and heart failure: the Heart and Soul study. J. Clin. Endocrinol. Metab. 95, 2885–2891 (2010).
Reynolds, R. M. et al. Skeletal muscle glucocorticoid receptor density and insulin resistance. JAMA 287, 2505–2506 (2002).
Wake, D. J. et al. Local and systemic impact of transcriptional up-regulation of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity. J. Clin. Endocrinol. Metab. 88, 3983–3988 (2003).
Masuzaki, H. et al. Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice. J. Clin. Invest. 112, 83–90 (2003).
Morton, N. M. et al. Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 β-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes 53, 931–938 (2004).
Paulmyer-Lacroix, O., Boullu, S., Oliver, C., Alessi, M. C. & Grino, M. Expression of the mRNA coding for 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: an in situ hybridization study. J. Clin. Endocrinol. Metab. 87, 2701–2705 (2002).
Sandeep, T. C. et al. Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11 β-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone. Diabetes 54, 872–879 (2005).
Nelson, J. C. & Davis, J. M. DST studies in psychotic depression: a meta-analysis. Am. J. Psychiatry 154, 1497–1503 (1997).
Vreeburg, S. A. et al. Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Arch. Gen. Psychiatry 66, 617–626 (2009).
Adam, E. K. et al. Prospective prediction of major depressive disorder from cortisol awakening responses in adolescence. Psychoneuroendocrinology 35, 921–931 (2010).
Sarabdjitsingh, R. A. et al. Stress responsiveness varies over the ultradian glucocorticoid cycle in a brain-region-specific manner. Endocrinology 151, 5369–5379 (2010).
Young, E. A., Carlson, N. E. & Brown, M. B. Twenty-four-hour ACTH and cortisol pulsatility in depressed women. Neuropsychopharmacology 25, 267–276 (2001).
van Rossum, E. F. et al. Polymorphisms of the glucocorticoid receptor gene and major depression. Biol. Psychiatry 59, 681–688 (2006).
Lahti, J. et al. Glucocorticoid receptor gene haplotype predicts increased risk of hospital admission for depressive disorders in the Helsinki birth cohort study. J. Psychiatr. Res. 45, 1160–1164 (2011).
Binder, E. B. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology 34 (Suppl. 1), S186–S195 (2009).
Liu, Z. et al. Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression. Neurosci. Lett. 404, 358–362 (2006).
Hancock, W. W. Rationale for HDAC inhibitor therapy in autoimmunity and transplantation. Handb. Exp. Pharmacol. 206, 103–123 (2011).
Huang, L. Targeting histone deacetylases for the treatment of cancer and inflammatory diseases. J. Cell Physiol. 209, 611–616 (2006).
Choo, Q. Y., Ho, P. C., Tanaka, Y. & Lin, H. S. Histone deacetylase inhibitors MS-275 and SAHA induced growth arrest and suppressed lipopolysaccharide-stimulated NF-κB p65 nuclear accumulation in human rheumatoid arthritis synovial fibroblastic E11 cells. Rheumatology (Oxford) 49, 1447–1460 (2010).
Joosten, L. A., Leoni, F., Meghji, S. & Mascagni, P. Inhibition of HDAC activity by ITF2357 ameliorates joint inflammation and prevents cartilage and bone destruction in experimental arthritis. Mol. Med. 17, 391–396 (2011).
Nasu, Y. et al. Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model. Osteoarthritis Cartilage 16, 723–732 (2008).
Stosic-Grujicic, S., Stojanovic, I. & Nicoletti, F. MIF in autoimmunity and novel therapeutic approaches. Autoimmun. Rev. 8, 244–249 (2009).
US National Library of Medicine. ClinicalTrials.gov [online], (2013).
Clark, A. R. & Lasa, M. Crosstalk between glucocorticoids and mitogen-activated protein kinase signalling pathways. Curr. Opin. Pharmacol. 3, 404–411 (2003).
Nishikawa, M. et al. Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthritis Rheum. 48, 2670–2681 (2003).
Kyttaris, V. C. Kinase inhibitors: a new class of antirheumatic drugs. Drug Des. Devel. Ther. 6, 245–250 (2012).
Tsujimura, S., Saito, K., Nakayamada, S., Nakano, K. & Tanaka, Y. Clinical relevance of the expression of P-glycoprotein on peripheral blood lymphocytes to steroid resistance in patients with systemic lupus erythematosus. Arthritis Rheum. 52, 1676–1683 (2005).
De Bosscher, K., Haegeman, G. & Elewaut, D. Targeting inflammation using selective glucocorticoid receptor modulators. Curr. Opin. Pharmacol. 10, 497–504 (2010).
Quax, R. A., Peeters, R. P. & Feelders, R. A. Selective glucocorticoid receptor modulators: future of glucocorticoid immunosuppressive therapy? Endocrinology 152, 2927–2929 (2011).
Stahn, C., Lowenberg, M., Hommes, D. W. & Buttgereit, F. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol. Cell Endocrinol. 275, 71–78 (2007).
Morton, N. M. Obesity and corticosteroids: 11β-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease. Mol. Cell Endocrinol. 316, 154–164 (2010).
Alberts, P. et al. Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia 45, 1528–1532 (2002).
Hermanowski-Vosatka, A. et al. 11 β-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J. Exp. Med. 202, 517–527 (2005).
Rosenstock, J. et al. The 11-β-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy. Diabetes Care 33, 1516–1522 (2010).
Feig, P. U. et al. Effects of an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, MK-0916, in patients with type 2 diabetes mellitus and metabolic syndrome. Diabetes Obes. Metab. 13, 498–504 (2011).
Koetz, K. R., van Rossum, E. F., Ventz, M., Diederich, S. & Quinkler, M. BclI polymorphism of the glucocorticoid receptor gene is associated with increased bone resorption in patients on glucocorticoid replacement therapy. Clin. Endocrinol. (Oxf.) 78, 831–837 (2013).
Bergthorsdottir, R., Leonsson-Zachrisson, M., Oden, A. & Johannsson, G. Premature mortality in patients with Addison's disease: a population-based study. J. Clin. Endocrinol. Metab. 91, 4849–4853 (2006).
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Table 1
The human GRβ in inflammatory and non-inflammatory disorders (DOC 133 kb)
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrendo.2013.183
This article is cited by
-
The heart of Detroit study: a window into urban middle-aged and older African Americans’ daily lives to understand psychosocial determinants of cardiovascular disease risk
BMC Psychiatry (2023)
-
Two cases of infantile-onset primary generalized glucocorticoid hypersensitivity and the effect of mifepristone
BMC Pediatrics (2022)
-
DNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival
Nature Communications (2022)
-
Children with Down syndrome: association of Bcl-I polymorphism of nuclear receptor subfamily 3 group C member 1 gene with obesity
Pediatric Research (2022)
-
Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management
Nature Reviews Rheumatology (2022)