Glucocorticoids: Molecular Mechanisms of Action

  • Diana Cruz-TopeteEmail author
  • John A. Cidlowski


Since their discovery in the 1940s, glucocorticoids remain one of the most widely prescribed drugs in the world to treat inflammatory and autoimmune disorders, including arthritis, multiple sclerosis, asthma, ulcerative colitis, eczema, and psoriasis. They are also used as potent immunosuppressants after an organ transplant, and in the treatment of hematological cancers. Although the clinical value of glucocorticoids has been known for almost 80 years, the molecular mechanisms underlying their systemic and tissue-specific actions are still a subject of intense investigation. In this chapter, we provide an overview of the mechanisms regulating glucocorticoid synthesis, secretion, bioavailability, physiological effects, and their signaling via the glucocorticoid receptor (GR). We briefly review the gene and protein structure of the glucocorticoid receptor and its isoforms, as well as the glucocorticoid receptor genomic and non-genomic mechanisms of action. Finally, we discuss in detail the current knowledge of glucocorticoid effects on the regulation of the inflammatory response from a molecular perspective.


Glucocorticoids Glucocorticoid receptors Genomic and non-genomic mechanisms Inflammation 


  1. 1.
    Miller WL, Auchus RJ (2011) The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 32(1):81–151. CrossRefPubMedGoogle Scholar
  2. 2.
    Oakley RH, Ren R, Cruz-Topete D, Bird GS, Myers PH, Boyle MC, Schneider MD, Willis MS, Cidlowski JA (2013) Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease. Proc Natl Acad Sci U S A 110(42):17035–17040. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cruz-Topete D, Myers PH, Foley JF, Willis MS, Cidlowski JA (2016) Corticosteroids are essential for maintaining cardiovascular function in male mice. Endocrinology 157(7):2759–2771. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Cain DW, Cidlowski JA (2015) Specificity and sensitivity of glucocorticoid signaling in health and disease. Best Pract Res Clin Endocrinol Metab 29(4):545–556. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sapolsky RM (2000) Stress hormones: good and bad. Neurobiol Dis 7(5):540–542. CrossRefPubMedGoogle Scholar
  6. 6.
    Sapolsky RM, Romero LM, Munck AU (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 21(1):55–89. CrossRefPubMedGoogle Scholar
  7. 7.
    Ramamoorthy S, Cidlowski JA (2016) Corticosteroids: mechanisms of action in health and disease. Rheum Dis Clin N Am 42(1):15–31, vii. CrossRefGoogle Scholar
  8. 8.
    Charmandari E, Chrousos GP, Lambrou GI, Pavlaki A, Koide H, Ng SS, Kino T (2011) Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man. PLoS One 6(9):e25612. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Coutinho AE, Chapman KE (2011) The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 335(1):2–13. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Macfarlane DP, Forbes S, Walker BR (2008) Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome. J Endocrinol 197(2):189–204. CrossRefPubMedGoogle Scholar
  11. 11.
    Whirledge SD, Oakley RH, Myers PH, Lydon JP, DeMayo F, Cidlowski JA (2015) Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization. Proc Natl Acad Sci U S A 112(49):15166–15171. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Wirth MM (2015) Hormones, stress, and cognition: the effects of glucocorticoids and oxytocin on memory. Adapt Hum Behav Physiol 1(2):177–201. CrossRefGoogle Scholar
  13. 13.
    Kadmiel M, Cidlowski JA (2013) Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci 34(9):518–530. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Di S, Malcher-Lopes R, Halmos KC, Tasker JG (2003) Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci 23(12):4850–4857CrossRefPubMedGoogle Scholar
  15. 15.
    Evanson NK, Tasker JG, Hill MN, Hillard CJ, Herman JP (2010) Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling. Endocrinology 151(10):4811–4819. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Orchinik M, Murray TF, Moore FL (1991) A corticosteroid receptor in neuronal membranes. Science 252(5014):1848–1851CrossRefPubMedGoogle Scholar
  17. 17.
    Hammond GL (2016) Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action. J Endocrinol 230(1):R13–R25. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Hammond GL, Smith CL, Paterson NA, Sibbald WJ (1990) A role for corticosteroid-binding globulin in delivery of cortisol to activated neutrophils. J Clin Endocrinol Metab 71(1):34–39. CrossRefPubMedGoogle Scholar
  19. 19.
    Hammond GL, Smith CL, Underhill DA (1991) Molecular studies of corticosteroid binding globulin structure, biosynthesis and function. J Steroid Biochem Mol Biol 40(4–6):755–762CrossRefPubMedGoogle Scholar
  20. 20.
    Tomlinson JW, Moore J, Cooper MS, Bujalska I, Shahmanesh M, Burt C, Strain A, Hewison M, Stewart PM (2001) Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines. Endocrinology 142(5):1982–1989. CrossRefPubMedGoogle Scholar
  21. 21.
    Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R, Thompson EB, Rosenfeld MG, Evans RM (1985) Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature 318(6047):635–641CrossRefPubMedGoogle Scholar
  22. 22.
    Weinberger C, Hollenberg SM, Ong ES, Harmon JM, Brower ST, Cidlowski J, Thompson EB, Rosenfeld MG, Evans RM (1985) Identification of human glucocorticoid receptor complementary DNA clones by epitope selection. Science 228(4700):740–742CrossRefPubMedGoogle Scholar
  23. 23.
    Weinberger C, Hollenberg SM, Rosenfeld MG, Evans RM (1985) Domain structure of human glucocorticoid receptor and its relationship to the v-erb-A oncogene product. Nature 318(6047):670–672CrossRefPubMedGoogle Scholar
  24. 24.
    Oakley RH, Cidlowski JA (2013) The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol 132(5):1033–1044. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kumar R, Thompson EB (2005) Gene regulation by the glucocorticoid receptor: structure: function relationship. J Steroid Biochem Mol Biol 94(5):383–394. CrossRefPubMedGoogle Scholar
  26. 26.
    Oakley RH, Cidlowski JA (2011) Cellular processing of the glucocorticoid receptor gene and protein: new mechanisms for generating tissue-specific actions of glucocorticoids. J Biol Chem 286(5):3177–3184. CrossRefPubMedGoogle Scholar
  27. 27.
    Bamberger CM, Bamberger AM, de Castro M, Chrousos GP (1995) Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest 95(6):2435–2441. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Oakley RH, Sar M, Cidlowski JA (1996) The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J Biol Chem 271(16):9550–9559CrossRefPubMedGoogle Scholar
  29. 29.
    Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E (2010) The human glucocorticoid receptor: molecular basis of biologic function. Steroids 75(1):1–12. CrossRefPubMedGoogle Scholar
  30. 30.
    Lewis-Tuffin LJ, Cidlowski JA (2006) The physiology of human glucocorticoid receptor beta (hGRbeta) and glucocorticoid resistance. Ann N Y Acad Sci 1069:1–9. CrossRefPubMedGoogle Scholar
  31. 31.
    Kino T, Manoli I, Kelkar S, Wang Y, Su YA, Chrousos GP (2009) Glucocorticoid receptor (GR) beta has intrinsic, GRalpha-independent transcriptional activity. Biochem Biophys Res Commun 381(4):671–675. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kino T, Su YA, Chrousos GP (2009) Human glucocorticoid receptor isoform beta: recent understanding of its potential implications in physiology and pathophysiology. Cell Mol Life Sci 66(21):3435–3448. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kelly A, Bowen H, Jee YK, Mahfiche N, Soh C, Lee T, Hawrylowicz C, Lavender P (2008) The glucocorticoid receptor beta isoform can mediate transcriptional repression by recruiting histone deacetylases. J Allergy Clin Immunol 121(1):203–208. e201. CrossRefPubMedGoogle Scholar
  34. 34.
    He B, Cruz-Topete D, Oakley RH, Xiao X, Cidlowski JA (2015) Human glucocorticoid receptor beta regulates gluconeogenesis and inflammation in mouse liver. Mol Cell Biol 36(5):714–730. CrossRefPubMedGoogle Scholar
  35. 35.
    de Lange P, Segeren CM, Koper JW, Wiemer E, Sonneveld P, Brinkmann AO, White A, Brogan IJ, de Jong FH, Lamberts SW (2001) Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells. Cancer Res 61(10):3937–3941PubMedGoogle Scholar
  36. 36.
    Krett NL, Pillay S, Moalli PA, Greipp PR, Rosen ST (1995) A variant glucocorticoid receptor messenger RNA is expressed in multiple myeloma patients. Cancer Res 55(13):2727–2729PubMedGoogle Scholar
  37. 37.
    Wang Z, Frederick J, Garabedian MJ (2002) Deciphering the phosphorylation “code” of the glucocorticoid receptor in vivo. J Biol Chem 277(29):26573–26580. CrossRefPubMedGoogle Scholar
  38. 38.
    Orti E, Hu LM, Munck A (1993) Kinetics of glucocorticoid receptor phosphorylation in intact cells. Evidence for hormone-induced hyperphosphorylation after activation and recycling of hyperphosphorylated receptors. J Biol Chem 268(11):7779–7784PubMedGoogle Scholar
  39. 39.
    Rogatsky I, Waase CL, Garabedian MJ (1998) Phosphorylation and inhibition of rat glucocorticoid receptor transcriptional activation by glycogen synthase kinase-3 (GSK-3). Species-specific differences between human and rat glucocorticoid receptor signaling as revealed through GSK-3 phosphorylation. J Biol Chem 273(23):14315–14321CrossRefPubMedGoogle Scholar
  40. 40.
    Rogatsky I, Logan SK, Garabedian MJ (1998) Antagonism of glucocorticoid receptor transcriptional activation by the c-Jun N-terminal kinase. Proc Natl Acad Sci U S A 95(5):2050–2055CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Beck IM, Vanden Berghe W, Gerlo S, Bougarne N, Vermeulen L, De Bosscher K, Haegeman G (2009) Glucocorticoids and mitogen- and stress-activated protein kinase 1 inhibitors: possible partners in the combat against inflammation. Biochem Pharmacol 77(7):1194–1205. CrossRefPubMedGoogle Scholar
  42. 42.
    Avenant C, Ronacher K, Stubsrud E, Louw A, Hapgood JP (2010) Role of ligand-dependent GR phosphorylation and half-life in determination of ligand-specific transcriptional activity. Mol Cell Endocrinol 327(1–2):72–88. CrossRefPubMedGoogle Scholar
  43. 43.
    Galliher-Beckley AJ, Williams JG, Collins JB, Cidlowski JA (2008) Glycogen synthase kinase 3beta-mediated serine phosphorylation of the human glucocorticoid receptor redirects gene expression profiles. Mol Cell Biol 28(24):7309–7322. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Webster JC, Jewell CM, Bodwell JE, Munck A, Sar M, Cidlowski JA (1997) Mouse glucocorticoid receptor phosphorylation status influences multiple functions of the receptor protein. J Biol Chem 272(14):9287–9293CrossRefPubMedGoogle Scholar
  45. 45.
    Chen W, Dang T, Blind RD, Wang Z, Cavasotto CN, Hittelman AB, Rogatsky I, Logan SK, Garabedian MJ (2008) Glucocorticoid receptor phosphorylation differentially affects target gene expression. Mol Endocrinol 22(8):1754–1766. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Deroo BJ, Rentsch C, Sampath S, Young J, DeFranco DB, Archer TK (2002) Proteasomal inhibition enhances glucocorticoid receptor transactivation and alters its subnuclear trafficking. Mol Cell Biol 22(12):4113–4123CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Wallace AD, Cidlowski JA (2001) Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids. J Biol Chem 276(46):42714–42721. CrossRefPubMedGoogle Scholar
  48. 48.
    Le Drean Y, Mincheneau N, Le Goff P, Michel D (2002) Potentiation of glucocorticoid receptor transcriptional activity by sumoylation. Endocrinology 143(9):3482–3489. CrossRefPubMedGoogle Scholar
  49. 49.
    Ito K, Yamamura S, Essilfie-Quaye S, Cosio B, Ito M, Barnes PJ, Adcock IM (2006) Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression. J Exp Med 203(1):7–13. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Vandevyver S, Dejager L, Van Bogaert T, Kleyman A, Liu Y, Tuckermann J, Libert C (2012) Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation. J Clin Invest 122(6):2130–2140. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Grad I, Picard D (2007) The glucocorticoid responses are shaped by molecular chaperones. Mol Cell Endocrinol 275(1–2):2–12. CrossRefPubMedGoogle Scholar
  52. 52.
    Dittmar KD, Pratt WB (1997) Folding of the glucocorticoid receptor by the reconstituted Hsp90-based chaperone machinery. The initial hsp90.p60.hsp70-dependent step is sufficient for creating the steroid binding conformation. J Biol Chem 272(20):13047–13054CrossRefPubMedGoogle Scholar
  53. 53.
    Pratt WB, Toft DO (1997) Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev 18(3):306–360. CrossRefPubMedGoogle Scholar
  54. 54.
    Pratt WB (1997) The role of the hsp90-based chaperone system in signal transduction by nuclear receptors and receptors signaling via MAP kinase. Annu Rev Pharmacol Toxicol 37:297–326. CrossRefPubMedGoogle Scholar
  55. 55.
    Holaska JM, Black BE, Love DC, Hanover JA, Leszyk J, Paschal BM (2001) Calreticulin is a receptor for nuclear export. J Cell Biol 152(1):127–140CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Biddie SC, John S, Hager GL (2010) Genome-wide mechanisms of nuclear receptor action. Trends Endocrinol Metab 21(1):3–9. CrossRefPubMedGoogle Scholar
  57. 57.
    Rogatsky I, Ivashkiv LB (2006) Glucocorticoid modulation of cytokine signaling. Tissue Antigens 68(1):1–12. CrossRefPubMedGoogle Scholar
  58. 58.
    Ratman D, Vanden Berghe W, Dejager L, Libert C, Tavernier J, Beck IM, De Bosscher K (2013) How glucocorticoid receptors modulate the activity of other transcription factors: a scope beyond tethering. Mol Cell Endocrinol 380(1–2):41–54. CrossRefPubMedGoogle Scholar
  59. 59.
    Buttgereit F, Scheffold A (2002) Rapid glucocorticoid effects on immune cells. Steroids 67(6):529–534CrossRefPubMedGoogle Scholar
  60. 60.
    Boldizsar F, Talaber G, Szabo M, Bartis D, Palinkas L, Nemeth P, Berki T (2010) Emerging pathways of non-genomic glucocorticoid (GC) signalling in T cells. Immunobiology 215(7):521–526. CrossRefPubMedGoogle Scholar
  61. 61.
    Samarasinghe RA, Witchell SF, DeFranco DB (2012) Cooperativity and complementarity: synergies in non-classical and classical glucocorticoid signaling. Cell Cycle 11(15):2819–2827. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Matthews L, Berry A, Ohanian V, Ohanian J, Garside H, Ray D (2008) Caveolin mediates rapid glucocorticoid effects and couples glucocorticoid action to the antiproliferative program. Mol Endocrinol 22(6):1320–1330. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Cain DW, Cidlowski JA (2017) Immune regulation by glucocorticoids. Nat Rev Immunol 17(4):233–247. CrossRefPubMedGoogle Scholar
  64. 64.
    McEwen BS, Biron CA, Brunson KW, Bulloch K, Chambers WH, Dhabhar FS, Goldfarb RH, Kitson RP, Miller AH, Spencer RL, Weiss JM (1997) The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res Brain Res Rev 23(1–2):79–133CrossRefPubMedGoogle Scholar
  65. 65.
    Yosef N, Shalek AK, Gaublomme JT, Jin H, Lee Y, Awasthi A, Wu C, Karwacz K, Xiao S, Jorgolli M, Gennert D, Satija R, Shakya A, Lu DY, Trombetta JJ, Pillai MR, Ratcliffe PJ, Coleman ML, Bix M, Tantin D, Park H, Kuchroo VK, Regev A (2013) Dynamic regulatory network controlling TH17 cell differentiation. Nature 496(7446):461–468. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Ayroldi E, Cannarile L, Migliorati G, Nocentini G, Delfino DV, Riccardi C (2012) Mechanisms of the anti-inflammatory effects of glucocorticoids: genomic and nongenomic interference with MAPK signaling pathways. FASEB J 26(12):4805–4820. CrossRefPubMedGoogle Scholar
  67. 67.
    Miyata M, Lee JY, Susuki-Miyata S, Wang WY, Xu H, Kai H, Kobayashi KS, Flavell RA, Li JD (2015) Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M. Nat Commun 6:6062. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Beaulieu E, Morand EF (2011) Role of GILZ in immune regulation, glucocorticoid actions and rheumatoid arthritis. Nat Rev Rheumatol 7(6):340–348. CrossRefPubMedGoogle Scholar
  69. 69.
    Livolsi A, Busuttil V, Imbert V, Abraham RT, Peyron JF (2001) Tyrosine phosphorylation-dependent activation of NF-kappa B. Requirement for p56 LCK and ZAP-70 protein tyrosine kinases. Eur J Biochem 268(5):1508–1515CrossRefPubMedGoogle Scholar
  70. 70.
    Yang N, Zhang W, Shi XM (2008) Glucocorticoid-induced leucine zipper (GILZ) mediates glucocorticoid action and inhibits inflammatory cytokine-induced COX-2 expression. J Cell Biochem 103(6):1760–1771. CrossRefPubMedGoogle Scholar
  71. 71.
    Cruz-Topete D, Cidlowski JA (2015) One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation 22(1–2):20–32. CrossRefPubMedGoogle Scholar
  72. 72.
    Bhattacharyya S, Brown DE, Brewer JA, Vogt SK, Muglia LJ (2007) Macrophage glucocorticoid receptors regulate Toll-like receptor 4-mediated inflammatory responses by selective inhibition of p38 MAP kinase. Blood 109(10):4313–4319. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Cronstein BN, Kimmel SC, Levin RI, Martiniuk F, Weissmann G (1992) A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc Natl Acad Sci U S A 89(21):9991–9995CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Atsuta J, Plitt J, Bochner BS, Schleimer RP (1999) Inhibition of VCAM-1 expression in human bronchial epithelial cells by glucocorticoids. Am J Respir Cell Mol Biol 20(4):643–650. CrossRefPubMedGoogle Scholar
  75. 75.
    Frankfurt O, Rosen ST (2004) Mechanisms of glucocorticoid-induced apoptosis in hematologic malignancies: updates. Curr Opin Oncol 16(6):553–563CrossRefPubMedGoogle Scholar
  76. 76.
    O'Neill LA, Golenbock D, Bowie AG (2013) The history of Toll-like receptors - redefining innate immunity. Nat Rev Immunol 13(6):453–460. CrossRefPubMedGoogle Scholar
  77. 77.
    Kumar A, Takada Y, Boriek AM, Aggarwal BB (2004) Nuclear factor-kappaB: its role in health and disease. J Mol Med (Berl) 82(7):434–448. CrossRefGoogle Scholar
  78. 78.
    Liden J, Delaunay F, Rafter I, Gustafsson J, Okret S (1997) A new function for the C-terminal zinc finger of the glucocorticoid receptor. Repression of RelA transactivation. J Biol Chem 272(34):21467–21472CrossRefPubMedGoogle Scholar
  79. 79.
    Ogawa S, Lozach J, Benner C, Pascual G, Tangirala RK, Westin S, Hoffmann A, Subramaniam S, David M, Rosenfeld MG, Glass CK (2005) Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 122(5):707–721. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Nissen RM, Yamamoto KR (2000) The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev 14(18):2314–2329CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Islam KN, Mendelson CR (2008) Glucocorticoid/glucocorticoid receptor inhibition of surfactant protein-A (SP-A) gene expression in lung type II cells is mediated by repressive changes in histone modification at the SP-A promoter. Mol Endocrinol 22(3):585–596. CrossRefPubMedGoogle Scholar
  82. 82.
    Ito K, Barnes PJ, Adcock IM (2000) Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol 20(18):6891–6903CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    McKay LI, Cidlowski JA (2000) CBP (CREB binding protein) integrates NF-kappaB (nuclear factor-kappaB) and glucocorticoid receptor physical interactions and antagonism. Mol Endocrinol 14(8):1222–1234. CrossRefPubMedGoogle Scholar
  84. 84.
    Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M (1995) Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 270(5234):286–290CrossRefPubMedGoogle Scholar
  85. 85.
    Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr (1995) Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 270(5234):283–286CrossRefPubMedGoogle Scholar
  86. 86.
    Vesely PW, Staber PB, Hoefler G, Kenner L (2009) Translational regulation mechanisms of AP-1 proteins. Mutat Res 682(1):7–12. CrossRefPubMedGoogle Scholar
  87. 87.
    Busillo JM, Cidlowski JA (2013) The five Rs of glucocorticoid action during inflammation: ready, reinforce, repress, resolve, and restore. Trends Endocrinol Metab 24(3):109–119. CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Gonzalez MV, Jimenez B, Berciano MT, Gonzalez-Sancho JM, Caelles C, Lafarga M, Munoz A (2000) Glucocorticoids antagonize AP-1 by inhibiting the activation/phosphorylation of JNK without affecting its subcellular distribution. J Cell Biol 150(5):1199–1208CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    De Bosscher K, Vanden Berghe W, Haegeman G (2001) Glucocorticoid repression of AP-1 is not mediated by competition for nuclear coactivators. Mol Endocrinol 15(2):219–227. CrossRefPubMedGoogle Scholar
  90. 90.
    Beck IM, Vanden Berghe W, Vermeulen L, Yamamoto KR, Haegeman G, De Bosscher K (2009) Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases. Endocr Rev 30(7):830–882. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Reily MM, Pantoja C, Hu X, Chinenov Y, Rogatsky I (2006) The GRIP1:IRF3 interaction as a target for glucocorticoid receptor-mediated immunosuppression. EMBO J 25(1):108–117. CrossRefPubMedGoogle Scholar
  92. 92.
    Geiss G, Jin G, Guo J, Bumgarner R, Katze MG, Sen GC (2001) A comprehensive view of regulation of gene expression by double-stranded RNA-mediated cell signaling. J Biol Chem 276(32):30178–30182CrossRefPubMedGoogle Scholar
  93. 93.
    Tarassishin L, Suh HS, Lee SC (2011) Interferon regulatory factor 3 plays an anti-inflammatory role in microglia by activating the PI3K/Akt pathway. J Neuroinflammation 8:187. CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Flammer JR, Dobrovolna J, Kennedy MA, Chinenov Y, Glass CK, Ivashkiv LB, Rogatsky I (2010) The type I interferon signaling pathway is a target for glucocorticoid inhibition. Mol Cell Biol 30(19):4564–4574. CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Cho IJ, Kim SG (2009) A novel mitogen-activated protein kinase phosphatase-1 and glucocorticoid receptor (GR) interacting protein-1-dependent combinatorial mechanism of gene transrepression by GR. Mol Endocrinol 23(1):86–99. CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Ayroldi E, Migliorati G, Bruscoli S, Marchetti C, Zollo O, Cannarile L, D’Adamio F, Riccardi C (2001) Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor kappaB. Blood 98(3):743–753CrossRefPubMedGoogle Scholar
  97. 97.
    Riccardi C, Bruscoli S, Ayroldi E, Agostini M, Migliorati G (2001) GILZ, a glucocorticoid hormone induced gene, modulates T lymphocytes activation and death through interaction with NF-kB. Adv Exp Med Biol 495:31–39CrossRefPubMedGoogle Scholar
  98. 98.
    Di Marco B, Massetti M, Bruscoli S, Macchiarulo A, Di Virgilio R, Velardi E, Donato V, Migliorati G, Riccardi C (2007) Glucocorticoid-induced leucine zipper (GILZ)/NF-kappaB interaction: role of GILZ homo-dimerization and C-terminal domain. Nucleic Acids Res 35(2):517–528. CrossRefPubMedGoogle Scholar
  99. 99.
    Smoak K, Cidlowski JA (2006) Glucocorticoids regulate tristetraprolin synthesis and posttranscriptionally regulate tumor necrosis factor alpha inflammatory signaling. Mol Cell Biol 26(23):9126–9135. CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Kim SW, Rhee HJ, Ko J, Kim YJ, Kim HG, Yang JM, Choi EC, Na DS (2001) Inhibition of cytosolic phospholipase A2 by annexin I. Specific interaction model and mapping of the interaction site. J Biol Chem 276(19):15712–15719. CrossRefPubMedGoogle Scholar
  101. 101.
    Dennis EA (1994) Diversity of group types, regulation, and function of phospholipase A2. J Biol Chem 269(18):13057–13060PubMedGoogle Scholar
  102. 102.
    Perretti M, Ahluwalia A (2000) The microcirculation and inflammation: site of action for glucocorticoids. Microcirculation 7(3):147–161CrossRefPubMedGoogle Scholar
  103. 103.
    Nakagawa M, Bondy GP, Waisman D, Minshall D, Hogg JC, van Eeden SF (1999) The effect of glucocorticoids on the expression of L-selectin on polymorphonuclear leukocyte. Blood 93(8):2730–2737PubMedGoogle Scholar
  104. 104.
    Mori N, Horie Y, Gerritsen ME, Anderson DC, Granger DN (1999) Anti-inflammatory drugs and endothelial cell adhesion molecule expression in murine vascular beds. Gut 44(2):186–195CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Wust S, van den Brandt J, Tischner D, Kleiman A, Tuckermann JP, Gold R, Luhder F, Reichardt HM (2008) Peripheral T cells are the therapeutic targets of glucocorticoids in experimental autoimmune encephalomyelitis. J Immunol 180(12):8434–8443CrossRefPubMedGoogle Scholar
  106. 106.
    Perretti M, D’Acquisto F (2009) Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat Rev Immunol 9(1):62–70. CrossRefPubMedGoogle Scholar
  107. 107.
    Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461CrossRefPubMedGoogle Scholar
  108. 108.
    Perretti M, Chiang N, La M, Fierro IM, Marullo S, Getting SJ, Solito E, Serhan CN (2002) Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor. Nat Med 8(11):1296–1302. CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Brewer JA, Khor B, Vogt SK, Muglia LM, Fujiwara H, Haegele KE, Sleckman BP, Muglia LJ (2003) T-cell glucocorticoid receptor is required to suppress COX-2-mediated lethal immune activation. Nat Med 9(10):1318–1322. CrossRefPubMedGoogle Scholar
  110. 110.
    Szatmari I, Nagy L (2008) Nuclear receptor signalling in dendritic cells connects lipids, the genome and immune function. EMBO J 27(18):2353–2362. CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Petrillo MG, Fettucciari K, Montuschi P, Ronchetti S, Cari L, Migliorati G, Mazzon E, Bereshchenko O, Bruscoli S, Nocentini G, Riccardi C (2014) Transcriptional regulation of kinases downstream of the T cell receptor: another immunomodulatory mechanism of glucocorticoids. BMC Pharmacol Toxicol 15:35. CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Lowenberg M, Verhaar AP, van den Brink GR, Hommes DW (2007) Glucocorticoid signaling: a nongenomic mechanism for T-cell immunosuppression. Trends Mol Med 13(4):158–163. CrossRefPubMedGoogle Scholar
  113. 113.
    Mittelstadt PR, Monteiro JP, Ashwell JD (2012) Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness. J Clin Invest 122(7):2384–2394. CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Elenkov IJ (2004) Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci 1024:138–146. CrossRefPubMedGoogle Scholar
  115. 115.
    Baschant U, Frappart L, Rauchhaus U, Bruns L, Reichardt HM, Kamradt T, Brauer R, Tuckermann JP (2011) Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells. Proc Natl Acad Sci U S A 108(48):19317–19322. CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Bruscoli S, Biagioli M, Sorcini D, Frammartino T, Cimino M, Sportoletti P, Mazzon E, Bereshchenko O, Riccardi C (2015) Lack of glucocorticoid-induced leucine zipper (GILZ) deregulates B-cell survival and results in B-cell lymphocytosis in mice. Blood 126(15):1790–1801. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular and Cellular PhysiologyLouisiana State University Health Sciences Center-ShreveportShreveportUSA
  2. 2.Molecular Endocrinology Group, Signal Transduction LaboratoryNational Institute of Environmental Health Sciences, NIH, RTPDurhamUSA

Personalised recommendations