Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

New insights into the cell- and tissue-specificity of glucocorticoid actions

Cellular & Molecular Immunology volume 18, pages 269–278 (2021)Cite this article

Subjects

Abstract

Glucocorticoids (GCs) are endogenous hormones that are crucial for the homeostasis of the organism and adaptation to the external environment. Because of their anti-inflammatory effects, synthetic GCs are also extensively used in clinical practice. However, almost all cells in the body are sensitive to GC regulation. As a result, these mediators have pleiotropic effects, which may be undesirable or detrimental to human health. Here, we summarize the recent findings that contribute to deciphering the molecular mechanisms downstream of glucocorticoid receptor activation. We also discuss the complex role of GCs in infectious diseases such as sepsis and COVID-19, in which the balance between pathogen elimination and protection against excessive inflammation and immunopathology needs to be tightly regulated. An understanding of the cell type- and context-specific actions of GCs from the molecular to the organismal level would help to optimize their therapeutic use.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Oster, H. et al. The functional and clinical significance of the 24-hour rhythm of circulating glucocorticoids. Endocr. Rev. 38, 3–45 (2017).

    PubMed  Google Scholar 

  2. Cole, T. J. et al. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. 9, 1608–1621 (1995).

    CAS  PubMed  Google Scholar 

  3. Vandewalle, J., Luypaert, A., De Bosscher, K. & Libert, C. Therapeutic mechanisms of glucocorticoids. Trends Endocrinol. Metab. 29, 42–54 (2018).

    CAS  PubMed  Google Scholar 

  4. Frei, E. 3rd et al. The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood 26, 642–656 (1965).

    PubMed  Google Scholar 

  5. Herr, I. & Pfitzenmaier, J. Glucocorticoid use in prostate cancer and other solid tumours: implications for effectiveness of cytotoxic treatment and metastases. Lancet Oncol. 7, 425–430 (2006).

    CAS  PubMed  Google Scholar 

  6. Holgate, S. T. & Polosa, R. Treatment strategies for allergy and asthma. Nat. Rev. Immunol. 8, 218–230 (2008).

    CAS  PubMed  Google Scholar 

  7. Dendoncker, K. & Libert, C. Glucocorticoid resistance as a major drive in sepsis pathology. Cytokine growth factor Rev. 35, 85–96 (2017).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. Cain, D. W. & Cidlowski, J. A. Immune regulation by glucocorticoids. Nat. Rev. Immunol. 17, 233–247 (2017).

    CAS  PubMed  Google Scholar 

  10. Kadmiel, M. & Cidlowski, J. A. Glucocorticoid receptor signaling in health and disease. Trends Pharmacol. Sci. 34, 518–530 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Meijsing, S. H. et al. DNA binding site sequence directs glucocorticoid receptor structure and activity. Science 324, 407–410 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hudson, W. H., Youn, C. & Ortlund, E. A. The structural basis of direct glucocorticoid-mediated transrepression. Nat. Struct. Mol. Biol. 20, 53–58 (2013).

    CAS  PubMed  Google Scholar 

  13. Timmermans, S., Souffriau, J. & Libert, C. A general introduction to glucocorticoid biology. Front. Immunol. 10, 1545 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  15. Kassel, O. et al. Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J. 20, 7108–7116 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lasa, M., Abraham, S. M., Boucheron, C., Saklatvala, J. & Clark, A. R. Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38. Mol. Cell. Biol. 22, 7802–7811 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Widen, C., Gustafsson, J. A. & Wikstrom, A. C. Cytosolic glucocorticoid receptor interaction with nuclear factor-kappa B proteins in rat liver cells. Biochemical J. 373, 211–220 (2003).

    CAS  Google Scholar 

  18. De Bosscher, K. et al. Glucocorticoids repress NF-kappaB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell. Proc. Natl Acad. Sci. USA 97, 3919–3924 (2000).

    PubMed  Google Scholar 

  19. De Bosscher, K., Vanden Berghe, W. & Haegeman, G. The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression. Endocr. Rev. 24, 488–522 (2003).

    PubMed  Google Scholar 

  20. Berrebi, D. et al. Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10. Blood 101, 729–738 (2003).

    CAS  PubMed  Google Scholar 

  21. 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).

    CAS  PubMed  Google Scholar 

  22. John, S. et al. Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat. Genet. 43, 264–268 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Franco, L. M. et al. Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses. J. Exp. Med. 216, 384–406 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Dejager, L. et al. Neutralizing TNFalpha restores glucocorticoid sensitivity in a mouse model of neutrophilic airway inflammation. Mucosal Immunol. 8, 1212–1225 (2015).

    CAS  PubMed  Google Scholar 

  25. Van Bogaert, T. et al. Tumor necrosis factor inhibits glucocorticoid receptor function in mice: a strong signal toward lethal shock. J. Biol. Chem. 286, 26555–26567 (2011).

    PubMed  PubMed Central  Google Scholar 

  26. Dendoncker, K. et al. TNF-alpha inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile. Proc. Natl Acad. Sci. USA 116, 12942–12951 (2019).

    CAS  PubMed  Google Scholar 

  27. Reichardt, H. M. et al. DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93, 531–541 (1998).

    CAS  PubMed  Google Scholar 

  28. Whirledge, S. & DeFranco, D. B. Glucocorticoid signaling in health and disease: insights from tissue-specific GR knockout mice. Endocrinology 159, 46–64 (2018).

    CAS  PubMed  Google Scholar 

  29. Wyllie, A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284, 555–556 (1980).

    CAS  PubMed  Google Scholar 

  30. Strehl, C., Ehlers, L., Gaber, T. & Buttgereit, F. Glucocorticoids-all-rounders tackling the versatile players of the immune system. Front. Immunol. 10, 1744 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Zacharchuk, C. M., Mercep, M., Chakraborti, P. K., Simons, S. S. Jr. & Ashwell, J. D. Programmed T lymphocyte death. Cell activation- and steroid-induced pathways are mutually antagonistic. J. Immunol. 145, 4037–4045 (1990).

    CAS  PubMed  Google Scholar 

  32. Liberman, A. C. et al. The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction. FASEB J. 21, 1177–1188 (2007).

    CAS  PubMed  Google Scholar 

  33. Jee, Y. K. et al. Repression of interleukin-5 transcription by the glucocorticoid receptor targets GATA3 signaling and involves histone deacetylase recruitment. J. Biol. Chem. 280, 23243–23250 (2005).

    CAS  PubMed  Google Scholar 

  34. Maneechotesuwan, K. et al. Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease. PLoS Med. 6, e1000076 (2009).

    PubMed  PubMed Central  Google Scholar 

  35. Liberman, A. C., Druker, J., Refojo, D., Holsboer, F. & Arzt, E. Glucocorticoids inhibit GATA-3 phosphorylation and activity in T cells. FASEB J. 23, 1558–1571 (2009).

    CAS  PubMed  Google Scholar 

  36. Hu, C. et al. Glucocorticoids modulate Th1 and Th2 responses in asthmatic mouse models by inhibition of Notch1 signaling. Int. Arch. allergy Immunol. 175, 44–52 (2018).

    CAS  PubMed  Google Scholar 

  37. Elenkov, I. J. Glucocorticoids and the Th1/Th2 balance. Ann. N. Y. Acad. Sci. 1024, 138–146 (2004).

    CAS  PubMed  Google Scholar 

  38. Banuelos, J., Cao, Y., Shin, S. C. & Lu, N. Z. Immunopathology alters Th17 cell glucocorticoid sensitivity. Allergy 72, 331–341 (2017).

    CAS  PubMed  Google Scholar 

  39. Shimba, A. et al. Glucocorticoids drive diurnal oscillations in T cell distribution and responses by inducing interleukin-7 receptor and CXCR4. Immunity 48, 286–298.e6 (2018).

    CAS  PubMed  Google Scholar 

  40. Cain, D. W. et al. Murine glucocorticoid receptors orchestrate B cell migration selectively between bone marrow and blood. J. Immunol. 205, 619–629 (2020).

    CAS  PubMed  Google Scholar 

  41. Burger, J. A. & Montserrat, E. Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling. Blood 121, 1501–1509 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Quatrini, L. et al. Endogenous glucocorticoids control host resistance to viral infection through the tissue-specific regulation of PD-1 expression on NK cells. Nat. Immunol. 19, 954–962 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Quatrini, L. et al. Glucocorticoids and the cytokines IL-12, IL-15 and IL-18 present in the tumor microenvironment induce PD-1 expression on human Natural Killer cells. J. Allergy clinical Immunol. https://doi.org/10.1016/j.jaci.2020.04.044 (2020).

  44. Xing, K., Gu, B., Zhang, P. & Wu, X. Dexamethasone enhances programmed cell death 1 (PD-1) expression during T cell activation: an insight into the optimum application of glucocorticoids in anti-cancer therapy. BMC Immunol. 16, 39 (2015).

    PubMed  PubMed Central  Google Scholar 

  45. Maeda, N. et al. Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells. J. Biol. Chem. 294, 19896–19906 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Tokunaga, A. et al. Selective inhibition of low-affinity memory CD8(+) T cells by corticosteroids. J. Exp. Med. 216, 2701–2713 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Rudak, P. T. et al. Stress-elicited glucocorticoid receptor signaling upregulates TIGIT in innate-like invariant T lymphocytes. Brain, Behav., Immun. 80, 793–804 (2019).

    CAS  Google Scholar 

  48. Ma, W. et al. Dexamethasone inhibits IL-12p40 production in lipopolysaccharide-stimulated human monocytic cells by down-regulating the activity of c-Jun N-terminal kinase, the activation protein-1, and NF-kappa B transcription factors. J. Immunol. 172, 318–330 (2004).

    CAS  PubMed  Google Scholar 

  49. Larsson, S. & Linden, M. Effects of a corticosteroid, budesonide, on production of bioactive IL-12 by human monocytes. Cytokine 10, 786–789 (1998).

    CAS  PubMed  Google Scholar 

  50. Visser, J. et al. Differential regulation of interleukin-10 (IL-10) and IL-12 by glucocorticoids in vitro. Blood 91, 4255–4264 (1998).

    CAS  PubMed  Google Scholar 

  51. Di Rosa, M., Radomski, M., Carnuccio, R. & Moncada, S. Glucocorticoids inhibit the induction of nitric oxide synthase in macrophages. Biochem. Biophys. Res. Commun. 172, 1246–1252 (1990).

    PubMed  Google Scholar 

  52. Lee, S. H. et al. Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide. J. Biol. Chem. 267, 25934–25938 (1992).

    CAS  PubMed  Google Scholar 

  53. Abraham, S. M. et al. Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J. Exp. Med. 203, 1883–1889 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Pfander, P., Fidan, M., Burret, U., Lipinski, L. & Vettorazzi, S. Cdk5 deletion enhances the anti-inflammatory potential of GC-mediated GR activation during inflammation. Front. Immunol. 10, 1554 (2019).

    PubMed  PubMed Central  Google Scholar 

  55. Tuckermann, J. P. et al. Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy. J. Clin. Investig. 117, 1381–1390 (2007).

    CAS  PubMed  Google Scholar 

  56. Bhattacharyya, S., Brown, D. E., Brewer, J. A., Vogt, S. K. & Muglia, L. J. Macrophage glucocorticoid receptors regulate Toll-like receptor 4-mediated inflammatory responses by selective inhibition of p38 MAP kinase. Blood 109, 4313–4319 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kleiman, A. et al. Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin-1 in macrophages. FASEB J. 26, 722–729 (2012).

    CAS  PubMed  Google Scholar 

  58. Yang, H. et al. Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity. Nat. Med. 25, 1428–1441 (2019).

    CAS  PubMed  Google Scholar 

  59. Hermoso, M. A., Matsuguchi, T., Smoak, K. & Cidlowski, J. A. Glucocorticoids and tumor necrosis factor alpha cooperatively regulate toll-like receptor 2 gene expression. Mol. Cell. Biol. 24, 4743–4756 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Lannan, E. A., Galliher-Beckley, A. J., Scoltock, A. B. & Cidlowski, J. A. Proinflammatory actions of glucocorticoids: glucocorticoids and TNFalpha coregulate gene expression in vitro and in vivo. Endocrinology 153, 3701–3712 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Mattiola, I. et al. The macrophage tetraspan MS4A4A enhances dectin-1-dependent NK cell-mediated resistance to metastasis. Nat. Immunol. 20, 1012–1022 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Irwin, M. R. & Cole, S. W. Reciprocal regulation of the neural and innate immune systems. Nat. Rev. Immunol. 11, 625–632 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Quatrini, L., Vivier, E. & Ugolini, S. Neuroendocrine regulation of innate lymphoid cells. Immunological Rev. 286, 120–136 (2018).

    CAS  Google Scholar 

  64. Ehrchen, J. et al. Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes. Blood 109, 1265–1274 (2007).

    CAS  PubMed  Google Scholar 

  65. Mozo, L., Suarez, A. & Gutierrez, C. Glucocorticoids up-regulate constitutive interleukin-10 production by human monocytes. Clin. Exp. Allergy 34, 406–412 (2004).

    CAS  PubMed  Google Scholar 

  66. Tu, G. W. et al. Glucocorticoid attenuates acute lung injury through induction of type 2 macrophage. J. Transl. Med. 15, 181 (2017).

    PubMed  PubMed Central  Google Scholar 

  67. Meers, G. K., Bohnenberger, H., Reichardt, H. M., Luhder, F. & Reichardt, S. D. Impaired resolution of DSS-induced colitis in mice lacking the glucocorticoid receptor in myeloid cells. PLoS ONE 13, e0190846 (2018).

    PubMed  PubMed Central  Google Scholar 

  68. Buechler, C. et al. Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J. Leukoc. Biol. 67, 97–103 (2000).

    CAS  PubMed  Google Scholar 

  69. Vallelian, F. et al. Glucocorticoid treatment skews human monocyte differentiation into a hemoglobin-clearance phenotype with enhanced heme-iron recycling and antioxidant capacity. Blood 116, 5347–5356 (2010).

    CAS  PubMed  Google Scholar 

  70. Giles, K. M. et al. Glucocorticoid augmentation of macrophage capacity for phagocytosis of apoptotic cells is associated with reduced p130Cas expression, loss of paxillin/pyk2 phosphorylation, and high levels of active Rac. J. Immunol. 167, 976–986 (2001).

    CAS  PubMed  Google Scholar 

  71. van der Goes, A., Hoekstra, K., van den Berg, T. K. & Dijkstra, C. D. Dexamethasone promotes phagocytosis and bacterial killing by human monocytes/macrophages in vitro. J. Leukoc. Biol. 67, 801–807 (2000).

    PubMed  Google Scholar 

  72. Le Tulzo, Y. et al. Monocyte human leukocyte antigen-DR transcriptional downregulation by cortisol during septic shock. Am. J. Respir. Crit. Care Med. 169, 1144–1151 (2004).

    PubMed  Google Scholar 

  73. Celada, A., McKercher, S. & Maki, R. A. Repression of major histocompatibility complex IA expression by glucocorticoids: the glucocorticoid receptor inhibits the DNA binding of the X box DNA binding protein. J. Exp. Med. 177, 691–698 (1993).

    CAS  PubMed  Google Scholar 

  74. Yona, S. & Gordon, S. Inflammation: glucocorticoids turn the monocyte switch. Immunol. Cell Biol. 85, 81–82 (2007).

    PubMed  Google Scholar 

  75. Cecconi, M., Evans, L., Levy, M. & Rhodes, A. Sepsis and septic shock. Lancet 392, 75–87 (2018).

    PubMed  Google Scholar 

  76. Perlstein, R. S., Whitnall, M. H., Abrams, J. S., Mougey, E. H. & Neta, R. Synergistic roles of interleukin-6, interleukin-1, and tumor necrosis factor in the adrenocorticotropin response to bacterial lipopolysaccharide in vivo. Endocrinology 132, 946–952 (1993).

    CAS  PubMed  Google Scholar 

  77. Rivier, C., Chizzonite, R. & Vale, W. In the mouse, the activation of the hypothalamic-pituitary-adrenal axis by a lipopolysaccharide (endotoxin) is mediated through interleukin-1. Endocrinology 125, 2800–2805 (1989).

    CAS  PubMed  Google Scholar 

  78. Ramachandra, R. N., Sehon, A. H. & Berczi, I. Neuro-hormonal host defence in endotoxin shock. Brain, Behav., Immun. 6, 157–169 (1992).

    CAS  Google Scholar 

  79. Cavaillon, J. M. & Adib-Conquy, M. Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit. Care 10, 233 (2006).

    PubMed  PubMed Central  Google Scholar 

  80. Adib-Conquy, M. et al. Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients. Crit. Care Med. 34, 2377–2385 (2006).

    CAS  PubMed  Google Scholar 

  81. Yoza, B. K. & McCall, C. E. Facultative heterochromatin formation at the IL-1 beta promoter in LPS tolerance and sepsis. Cytokine 53, 145–152 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    CAS  PubMed  Google Scholar 

  83. Porta, C. et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc. Natl Acad. Sci. USA 106, 14978–14983 (2009).

    CAS  PubMed  Google Scholar 

  84. Lopez-Collazo, E. & del Fresno, C. Pathophysiology of endotoxin tolerance: mechanisms and clinical consequences. Crit. Care 17, 242 (2013).

    PubMed  PubMed Central  Google Scholar 

  85. Quatrini, L. et al. Host resistance to endotoxic shock requires the neuroendocrine regulation of group 1 innate lymphoid cells. J. Exp. Med. 214, 3531–3541 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Li, C. C., Munitic, I., Mittelstadt, P. R., Castro, E. & Ashwell, J. D. Suppression of dendritic cell-derived IL-12 by endogenous glucocorticoids is protective in LPS-induced sepsis. PLoS Biol. 13, e1002269 (2015).

    PubMed  PubMed Central  Google Scholar 

  87. Sprung, C. L. et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N. Engl. J. Med. 311, 1137–1143 (1984).

    CAS  PubMed  Google Scholar 

  88. Bone, R. C. et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N. Engl. J. Med. 317, 653–658 (1987).

    CAS  PubMed  Google Scholar 

  89. Annane, D. et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288, 862–871 (2002).

    CAS  PubMed  Google Scholar 

  90. Sprung, C. L. et al. Hydrocortisone therapy for patients with septic shock. N. Engl. J. Med. 358, 111–124 (2008).

    CAS  PubMed  Google Scholar 

  91. Venkatesh, B. et al. Adjunctive glucocorticoid therapy in patients with septic shock. N. Engl. J. Med. 378, 797–808 (2018).

    CAS  PubMed  Google Scholar 

  92. Annane, D. et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N. Engl. J. Med. 378, 809–818 (2018).

    CAS  PubMed  Google Scholar 

  93. Rhodes, A. et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 43, 304–377 (2017).

    PubMed  Google Scholar 

  94. Biswas, S. K. & Lopez-Collazo, E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 30, 475–487 (2009).

    CAS  PubMed  Google Scholar 

  95. Brandish, P. E. et al. Development of anti-CD74 antibody-drug conjugates to target glucocorticoids to immune cells. Bioconjugate Chem. 29, 2357–2369 (2018).

    CAS  Google Scholar 

  96. Li, H. et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet 395, 1517–1520 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Chen, G. et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Investig. 130, 2620–2629 (2020).

    CAS  PubMed  Google Scholar 

  99. Ledford, H. How does COVID-19 kill? Uncertainty is hampering doctors’ ability to choose treatments. Nature 580, 311–312 (2020).

    CAS  PubMed  Google Scholar 

  100. Metselaar, J. M., Wauben, M. H., Wagenaar-Hilbers, J. P., Boerman, O. C. & Storm, G. Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes. Arthritis Rheum. 48, 2059–2066 (2003).

    CAS  PubMed  Google Scholar 

  101. Metselaar, J. M. et al. Liposomal targeting of glucocorticoids to synovial lining cells strongly increases therapeutic benefit in collagen type II arthritis. Ann. Rheum. Dis. 63, 348–353 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Oikarinen, A. & Autio, P. New aspects of the mechanism of corticosteroid-induced dermal atrophy. Clin. Exp. Dermatol. 16, 416–419 (1991).

    CAS  PubMed  Google Scholar 

  103. Oikarinen, A., Haapasaari, K. M., Sutinen, M. & Tasanen, K. The molecular basis of glucocorticoid-induced skin atrophy: topical glucocorticoid apparently decreases both collagen synthesis and the corresponding collagen mRNA level in human skin in vivo. Br. J. Dermatol. 139, 1106–1110 (1998).

    CAS  PubMed  Google Scholar 

  104. Perez, P. et al. Altered skin development and impaired proliferative and inflammatory responses in transgenic mice overexpressing the glucocorticoid receptor. FASEB J. 15, 2030–2032 (2001).

    CAS  PubMed  Google Scholar 

  105. Beer, H. D., Fassler, R. & Werner, S. Glucocorticoid-regulated gene expression during cutaneous wound repair. Vitam. Hormones. 59, 217–239 (2000).

    CAS  Google Scholar 

  106. Skoner, D. P. et al. Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate. Pediatrics 105, E23 (2000).

    CAS  PubMed  Google Scholar 

  107. Reid, I. R. Glucocorticoid-induced osteoporosis. Bailliere’s Best. Pract. Res. Clin. Endocrinol. Metab. 14, 279–298 (2000).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  109. Schacke, H., Docke, W. D. & Asadullah, K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol. Therapeutics 96, 23–43 (2002).

    CAS  Google Scholar 

  110. Schacke, H. et al. Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects. Proc. Natl Acad. Sci. USA 101, 227–232 (2004).

    PubMed  Google Scholar 

  111. Coghlan, M. J. et al. A novel antiinflammatory maintains glucocorticoid efficacy with reduced side effects. Mol. Endocrinol. 17, 860–869 (2003).

    CAS  PubMed  Google Scholar 

  112. Klassen, C. et al. Airway epithelial cells are crucial targets of glucocorticoids in a mouse model of allergic asthma. J. Immunol. 199, 48–61 (2017).

    CAS  PubMed  Google Scholar 

  113. Obradovic, M. M. S. et al. Glucocorticoids promote breast cancer metastasis. Nature 567, 540–544 (2019).

    CAS  PubMed  Google Scholar 

  114. Cui, B. et al. Targeting ROR1 inhibits epithelial-mesenchymal transition and metastasis. Cancer Res. 73, 3649–3660 (2013).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The SU laboratory received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Program under grant agreement no. 648768, the Agence Nationnale de la Recherche (ANR) (No. ANR-14-CE14-0009-01), and the ARC foundation (No. PGA120140200817). The SU laboratory is also supported by institutional grants from INSERM, CNRS, Aix-Marseille University and Marseille-Immunopole to the CIML. L.Q. has received funding from AIRC and from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement no. 800924.

Author information

Authors and Affiliations

  1. Department of Immunology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy

    Linda Quatrini

  2. Aix Marseille Univ, CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Marseille, France

    Sophie Ugolini

Authors
  1. Linda Quatrini
    View author publications

    Search author on:PubMed Google Scholar

  2. Sophie Ugolini
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to Linda Quatrini or Sophie Ugolini.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Quatrini, L., Ugolini, S. New insights into the cell- and tissue-specificity of glucocorticoid actions. Cell Mol Immunol 18, 269–278 (2021). https://doi.org/10.1038/s41423-020-00526-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41423-020-00526-2

Keywords

This article is cited by

Search

Advanced search

Quick links