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  • Review Article
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Glucocorticoid sensitivity in health and disease

Nature Reviews Endocrinology volume 9, pages 670–686 (2013)Cite this article

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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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References

  1. Rhen, T. & Cidlowski, J. A. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N. Engl. J. Med. 353, 1711–1723 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. 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).

    Article  CAS  PubMed  Google Scholar 

  3. Charmandari, E., Kino, T. & Chrousos, G. P. Primary generalized familial and sporadic glucocorticoid resistance (Chrousos syndrome) and hypersensitivity. Endocr. Dev. 24, 67–85 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Walker, B. R. Glucocorticoids and cardiovascular disease. Eur. J. Endocrinol. 157, 545–559 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Spijker, A. T. & van Rossum, E. F. Glucocorticoid sensitivity in mood disorders. Neuroendocrinology 95, 179–186 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Chrousos, G. P. & Kino, T. Glucocorticoid action networks and complex psychiatric and/or somatic disorders. Stress 10, 213–219 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. 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).

    Article  CAS  PubMed  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

  9. Stavreva, D. A. et al. Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nat. Cell Biol. 11, 1093–1102 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lamia, K. A. et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480, 552–556 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Stahn, C. & Buttgereit, F. Genomic and nongenomic effects of glucocorticoids. Nat. Clin. Pract. Rheumatol. 4, 525–533 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. Silverman, M. N. & Sternberg, E. M. Neuroendocrine-immune interactions in rheumatoid arthritis: mechanisms of glucocorticoid resistance. Neuroimmunomodulation 15, 19–28 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Barnes, P. J. Mechanisms and resistance in glucocorticoid control of inflammation. J. Steroid Biochem. Mol. Biol. 120, 76–85 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Ramamoorthy, S. & Cidlowski, J. A. Exploring the molecular mechanisms of glucocorticoid receptor action from sensitivity to resistance. Endocr. Dev. 24, 41–56 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Donn, R. et al. Use of gene expression profiling to identify a novel glucocorticoid sensitivity determining gene, BMPRII. FASEB J. 21, 402–414 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Galon, J. et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J. 16, 61–71 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. John, S. et al. Interaction of the glucocorticoid receptor with the chromatin landscape. Mol. Cell 29, 611–624 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  Google Scholar 

  21. Hollenberg, S. M. et al. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature 318, 635–641 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kino, T. et al. Glucocorticoid receptor (GR) β has intrinsic, GRα-independent transcriptional activity. Biochem. Biophys. Res. Commun. 381, 671–675 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. Grad, I. & Picard, D. The glucocorticoid responses are shaped by molecular chaperones. Mol. Cell Endocrinol. 275, 2–12 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Surjit, M. et al. Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor. Cell 145, 224–241 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. 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).

    Article  CAS  PubMed  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

  35. Buttgereit, F. & Scheffold, A. Rapid glucocorticoid effects on immune cells. Steroids 67, 529–534 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Boldizsar, F. et al. Emerging pathways of non-genomic glucocorticoid (GC) signalling in T cells. Immunobiology 215, 521–526 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. Keller-Wood, M. E. & Dallman, M. F. Corticosteroid inhibition of ACTH secretion. Endocr. Rev. 5, 1–24 (1984).

    Article  CAS  PubMed  Google Scholar 

  39. Hinz, B. & Hirschelmann, R. Rapid non-genomic feedback effects of glucocorticoids on CRF-induced ACTH secretion in rats. Pharm. Res. 17, 1273–1277 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. 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).

    Article  CAS  PubMed  Google Scholar 

  41. Barnes, P. J. Histone deacetylase-2 and airway disease. Ther. Adv. Respir. Dis. 3, 235–243 (2009).

    Article  PubMed  Google Scholar 

  42. Beck, I. M. et al. Altered subcellular distribution of MSK1 induced by glucocorticoids contributes to NF-κB inhibition. EMBO J. 27, 1682–1693 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. De Bosscher, K., Vanden Berghe, W. & Haegeman, G. Cross-talk between nuclear receptors and nuclear factor κB. Oncogene 25, 6868–6886 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ayroldi, E. & Riccardi, C. Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action. FASEB J. 23, 3649–3658 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ismaili, N. & Garabedian, M. J. Modulation of glucocorticoid receptor function via phosphorylation. Ann. NY Acad. Sci. 1024, 86–101 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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).

    Article  CAS  PubMed  Google Scholar 

  51. 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).

    Article  CAS  PubMed  Google Scholar 

  52. 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).

    CAS  PubMed  Google Scholar 

  53. 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).

    CAS  PubMed  Google Scholar 

  54. 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).

    Article  CAS  PubMed  Google Scholar 

  55. 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).

    CAS  PubMed  Google Scholar 

  56. 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).

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  CAS  Google Scholar 

  58. 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).

    Article  CAS  PubMed  Google Scholar 

  59. 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).

    Article  CAS  PubMed  Google Scholar 

  60. Heuser, I. J. et al. Age-associated changes of pituitary-adrenocortical hormone regulation in humans: importance of gender. Neurobiol. Aging 15, 227–231 (1994).

    Article  CAS  PubMed  Google Scholar 

  61. 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).

    Article  CAS  PubMed  Google Scholar 

  62. 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).

    Article  CAS  PubMed  Google Scholar 

  63. 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).

    CAS  PubMed  Google Scholar 

  64. Bauer, M. E. Stress, glucocorticoids and ageing of the immune system. Stress 8, 69–83 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. 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).

    Article  CAS  PubMed  Google Scholar 

  66. Tomlinson, J. W. et al. 11 β-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr. Rev. 25, 831–866 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Ferrari, P. The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension. Biochim. Biophys. Acta 1802, 1178–1187 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. 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).

    Article  CAS  PubMed  Google Scholar 

  69. Silva, C. M. et al. Regulation of the human glucocorticoid receptor by long-term and chronic treatment with glucocorticoid. Steroids 59, 436–442 (1994).

    Article  CAS  PubMed  Google Scholar 

  70. 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).

    Article  CAS  PubMed  Google Scholar 

  71. 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).

    Article  CAS  PubMed  Google Scholar 

  72. 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).

    Article  CAS  PubMed  Google Scholar 

  73. Gross, K. L., Lu, N. Z. & Cidlowski, J. A. Molecular mechanisms regulating glucocorticoid sensitivity and resistance. Mol. Cell Endocrinol. 300, 7–16 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. 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).

    Article  CAS  PubMed  Google Scholar 

  75. Wallace, A. D. & Cidlowski, J. A. Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids. J. Biol. Chem. 276, 42714–42721 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Barnes, P. J. & Adcock, I. M. Glucocorticoid resistance in inflammatory diseases. Lancet 373, 1905–1917 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Lu, N. Z. & Cidlowski, J. A. Glucocorticoid receptor isoforms generate transcription specificity. Trends Cell Biol. 16, 301–307 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. 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).

    Article  CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  PubMed  Google Scholar 

  80. 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).

    Article  CAS  PubMed  Google Scholar 

  81. 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).

    Article  CAS  Google Scholar 

  82. Stevens, A. et al. Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype. J. Clin. Endocrinol. Metab. 89, 892–897 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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).

    Article  CAS  PubMed  Google Scholar 

  85. 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).

    Article  CAS  PubMed  Google Scholar 

  86. 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).

    Article  CAS  PubMed  Google Scholar 

  87. van den Akker, E. L. et al. Glucocorticoid receptor polymorphism affects transrepression but not transactivation. J. Clin. Endocrinol. Metab. 91, 2800–2803 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. 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).

    Article  CAS  PubMed  Google Scholar 

  89. 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).

    Article  CAS  PubMed  Google Scholar 

  90. 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).

    Article  CAS  PubMed  Google Scholar 

  91. 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).

    Article  CAS  PubMed  Google Scholar 

  92. 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).

    Article  CAS  PubMed  Google Scholar 

  93. 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).

    Article  CAS  PubMed  Google Scholar 

  94. Kino, T., Vottero, A., Charmandari, E. & Chrousos, G. P. Familial/sporadic glucocorticoid resistance syndrome and hypertension. Ann. NY Acad. Sci. 970, 101–111 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. 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).

    Article  CAS  PubMed  Google Scholar 

  96. 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).

    Article  CAS  Google Scholar 

  97. 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).

    Article  CAS  PubMed  Google Scholar 

  98. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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).

    Article  CAS  PubMed  Google Scholar 

  100. Newfield, R. S. et al. Normocortisolemic Cushing's syndrome initially presenting with increased glucocorticoid receptor numbers. J. Clin. Endocrinol. Metab. 85, 14–21 (2000).

    CAS  PubMed  Google Scholar 

  101. 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).

    Article  CAS  PubMed  Google Scholar 

  102. 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).

    Article  CAS  PubMed  Google Scholar 

  103. 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).

    Article  CAS  PubMed  Google Scholar 

  104. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 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).

    Article  CAS  PubMed  Google Scholar 

  106. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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).

    Article  CAS  PubMed  Google Scholar 

  108. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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).

    Article  CAS  PubMed  Google Scholar 

  110. 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).

    Article  CAS  PubMed  Google Scholar 

  111. 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).

    Article  CAS  PubMed  Google Scholar 

  112. Tantisira, K. G. et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N. Engl. J. Med. 365, 1173–1183 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. van den Berge, M., Hiemstra, P. S. & Postma, D. S. Genetics of glucocorticoids in asthma. N. Engl. J. Med. 365, 2434–2435 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. 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).

    Article  CAS  PubMed  Google Scholar 

  115. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 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).

    Article  CAS  PubMed  Google Scholar 

  117. Hardy, R. et al. Local and systemic glucocorticoid metabolism in inflammatory arthritis. Ann. Rheum. Dis. 67, 1204–1210 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 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).

    Article  CAS  PubMed  Google Scholar 

  120. 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).

    Article  CAS  PubMed  Google Scholar 

  121. 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).

    Article  CAS  PubMed  Google Scholar 

  122. 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).

    Article  CAS  PubMed  Google Scholar 

  123. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 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).

    Article  CAS  Google Scholar 

  126. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 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).

    Article  CAS  PubMed  Google Scholar 

  128. 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).

    CAS  PubMed  Google Scholar 

  129. Sher, E. R. et al. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J. Clin. Invest. 93, 33–39 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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).

    Article  CAS  PubMed  Google Scholar 

  132. 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).

    CAS  PubMed  Google Scholar 

  133. 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).

    CAS  PubMed  Google Scholar 

  134. Huisman, A. M. et al. Glucocorticoid receptor downregulation in early diagnosed rheumatoid arthritis. Ann. NY Acad. Sci. 966, 64–67 (2002).

    Article  CAS  PubMed  Google Scholar 

  135. Schlaghecke, R., Kornely, E., Wollenhaupt, J. & Specker, C. Glucocorticoid receptors in rheumatoid arthritis. Arthritis Rheum. 35, 740–744 (1992).

    Article  CAS  PubMed  Google Scholar 

  136. Sidoroff, M. & Kolho, K. L. Glucocorticoid sensitivity in inflammatory bowel disease. Ann. Med. 44, 578–587 (2012).

    Article  CAS  PubMed  Google Scholar 

  137. 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).

    Article  CAS  PubMed  Google Scholar 

  138. 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).

    CAS  PubMed  Google Scholar 

  139. 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).

    Article  CAS  PubMed  Google Scholar 

  140. Honda, M. et al. Expression of glucocorticoid receptor β in lymphocytes of patients with glucocorticoid-resistant ulcerative colitis. Gastroenterology 118, 859–866 (2000).

    Article  CAS  PubMed  Google Scholar 

  141. 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).

    Article  CAS  PubMed  Google Scholar 

  142. 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).

    Article  CAS  PubMed  Google Scholar 

  143. Goecke, A. & Guerrero, J. Glucocorticoid receptor β in acute and chronic inflammatory conditions: clinical implications. Immunobiology 211, 85–96 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. 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).

    Article  CAS  Google Scholar 

  145. Pujols, L., Mullol, J. & Picado, C. α and β glucocorticoid receptors: relevance in airway diseases. Curr. Allergy Asthma Rep. 7, 93–99 (2007).

    Article  CAS  PubMed  Google Scholar 

  146. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 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).

    Article  CAS  PubMed  Google Scholar 

  148. 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).

    Article  CAS  PubMed  Google Scholar 

  149. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 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).

    Article  CAS  PubMed  Google Scholar 

  152. 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).

    Article  CAS  PubMed  Google Scholar 

  153. 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).

    CAS  Google Scholar 

  154. 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).

    Article  CAS  PubMed  Google Scholar 

  155. 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).

    Article  CAS  PubMed  Google Scholar 

  156. Weigel, N. L. & Moore, N. L. Steroid receptor phosphorylation: a key modulator of multiple receptor functions. Mol. Endocrinol. 21, 2311–2319 (2007).

    Article  CAS  PubMed  Google Scholar 

  157. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 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).

    Article  CAS  PubMed  Google Scholar 

  160. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. 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).

    Article  CAS  PubMed  Google Scholar 

  162. 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).

    Article  CAS  PubMed  Google Scholar 

  163. Biddie, S. C. et al. Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol. Cell 43, 145–155 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 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).

    Article  CAS  PubMed  Google Scholar 

  165. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Yang, A. et al. Aberrant microRNA-182 expression is associated with glucocorticoid resistance in lymphoblastic malignancies. Leuk. Lymphoma 53, 2465–2473 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Bonnans, C. et al. Glucocorticoid receptor-binding characteristics in severe asthma. Eur. Respir. J. 21, 985–988 (2003).

    Article  CAS  PubMed  Google Scholar 

  168. Gladman, D. D., Urowitz, M. B., Doris, F., Lewandowski, K. & Anhorn, K. Glucocorticoid receptors in systemic lupus erythematosus. J. Rheumatol. 18, 681–684 (1991).

    CAS  PubMed  Google Scholar 

  169. 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).

    Article  CAS  PubMed  Google Scholar 

  170. 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).

    CAS  PubMed  Google Scholar 

  171. 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).

    Article  CAS  PubMed  Google Scholar 

  172. Limbourg, F. P. & Liao, J. K. Nontranscriptional actions of the glucocorticoid receptor. J. Mol. Med. 81, 168–174 (2003).

    Article  CAS  PubMed  Google Scholar 

  173. Walker, B. R. Cortisol—cause and cure for metabolic syndrome? Diabet. Med. 23, 1281–1288 (2006).

    Article  CAS  PubMed  Google Scholar 

  174. 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).

    CAS  PubMed  Google Scholar 

  175. Stalder, T. et al. Cortisol in hair and the metabolic syndrome. J. Clin. Endocrinol. Metab. 98, 2573–2580 (2013).

    Article  CAS  PubMed  Google Scholar 

  176. 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).

    Article  CAS  PubMed  Google Scholar 

  177. 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).

    Article  CAS  Google Scholar 

  178. van den Akker, E. L. et al. Glucocorticoid receptor gene and risk of cardiovascular disease. Arch. Intern. Med. 168, 33–39 (2008).

    Article  CAS  PubMed  Google Scholar 

  179. 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).

    Article  CAS  PubMed  Google Scholar 

  180. Reynolds, R. M. et al. Skeletal muscle glucocorticoid receptor density and insulin resistance. JAMA 287, 2505–2506 (2002).

    Article  CAS  PubMed  Google Scholar 

  181. 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).

    Article  CAS  PubMed  Google Scholar 

  182. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. 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).

    Article  CAS  PubMed  Google Scholar 

  184. 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).

    CAS  PubMed  Google Scholar 

  185. 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).

    Article  CAS  PubMed  Google Scholar 

  186. Nelson, J. C. & Davis, J. M. DST studies in psychotic depression: a meta-analysis. Am. J. Psychiatry 154, 1497–1503 (1997).

    Article  CAS  PubMed  Google Scholar 

  187. 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).

    Article  CAS  PubMed  Google Scholar 

  188. Adam, E. K. et al. Prospective prediction of major depressive disorder from cortisol awakening responses in adolescence. Psychoneuroendocrinology 35, 921–931 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Sarabdjitsingh, R. A. et al. Stress responsiveness varies over the ultradian glucocorticoid cycle in a brain-region-specific manner. Endocrinology 151, 5369–5379 (2010).

    Article  CAS  PubMed  Google Scholar 

  190. Young, E. A., Carlson, N. E. & Brown, M. B. Twenty-four-hour ACTH and cortisol pulsatility in depressed women. Neuropsychopharmacology 25, 267–276 (2001).

    Article  CAS  PubMed  Google Scholar 

  191. van Rossum, E. F. et al. Polymorphisms of the glucocorticoid receptor gene and major depression. Biol. Psychiatry 59, 681–688 (2006).

    Article  CAS  PubMed  Google Scholar 

  192. 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).

    Article  PubMed  Google Scholar 

  193. 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).

    Article  CAS  PubMed  Google Scholar 

  194. Liu, Z. et al. Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression. Neurosci. Lett. 404, 358–362 (2006).

    Article  CAS  PubMed  Google Scholar 

  195. Hancock, W. W. Rationale for HDAC inhibitor therapy in autoimmunity and transplantation. Handb. Exp. Pharmacol. 206, 103–123 (2011).

    Article  CAS  PubMed  Google Scholar 

  196. Huang, L. Targeting histone deacetylases for the treatment of cancer and inflammatory diseases. J. Cell Physiol. 209, 611–616 (2006).

    Article  CAS  PubMed  Google Scholar 

  197. 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).

    Article  CAS  Google Scholar 

  198. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. 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).

    Article  CAS  PubMed  Google Scholar 

  200. Stosic-Grujicic, S., Stojanovic, I. & Nicoletti, F. MIF in autoimmunity and novel therapeutic approaches. Autoimmun. Rev. 8, 244–249 (2009).

    Article  CAS  PubMed  Google Scholar 

  201. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  202. Clark, A. R. & Lasa, M. Crosstalk between glucocorticoids and mitogen-activated protein kinase signalling pathways. Curr. Opin. Pharmacol. 3, 404–411 (2003).

    Article  CAS  PubMed  Google Scholar 

  203. 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).

    Article  CAS  PubMed  Google Scholar 

  204. Kyttaris, V. C. Kinase inhibitors: a new class of antirheumatic drugs. Drug Des. Devel. Ther. 6, 245–250 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. 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).

    Article  CAS  PubMed  Google Scholar 

  206. De Bosscher, K., Haegeman, G. & Elewaut, D. Targeting inflammation using selective glucocorticoid receptor modulators. Curr. Opin. Pharmacol. 10, 497–504 (2010).

    Article  CAS  PubMed  Google Scholar 

  207. Quax, R. A., Peeters, R. P. & Feelders, R. A. Selective glucocorticoid receptor modulators: future of glucocorticoid immunosuppressive therapy? Endocrinology 152, 2927–2929 (2011).

    Article  CAS  PubMed  Google Scholar 

  208. 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).

    Article  CAS  PubMed  Google Scholar 

  209. 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).

    Article  CAS  PubMed  Google Scholar 

  210. Alberts, P. et al. Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia 45, 1528–1532 (2002).

    Article  CAS  PubMed  Google Scholar 

  211. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. 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).

    Article  CAS  PubMed  Google Scholar 

  214. 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).

    Article  CAS  Google Scholar 

  215. 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).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, 's-Gravendijkwal 230, Rotterdam, 3015 CE, Netherlands

    Rogier A. Quax, Laura Manenschijn, Jan W. Koper, Steven W. J. Lamberts, Elisabeth F. C. van Rossum & Richard A. Feelders

  2. Department of Rheumatology, Erasmus Medical Center, 's-Gravendijkwal 230, Rotterdam, 3015 CE, Netherlands

    Johanna M. Hazes

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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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Supplementary Table 1

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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  • DOI: https://doi.org/10.1038/nrendo.2013.183

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