Level of Expression and Functional Properties of Lymphocyte Corticosteroid Receptors as Biological Correlates of PTSD, Trauma-Exposure, or Resilience to PTSD

  • Gordana Matić
  • Danijela Vojnović Milutinović
  • Ivana Elaković
  • Jelena Nestorov
  • Danka Savić
Reference work entry


This chapter summarizes current research on glucocorticoid receptor (GR) functional alterations associated with trauma exposure, posttraumatic stress disorder (PTSD) psychopathology, and resilience and vulnerability to PTSD. Special attention is paid to hormone-binding activity of the receptor, the level of its expression, its ratio to mineralocorticoid receptor (MR), and the interactions of corticosteroid receptors with heat shock protein chaperones, Hsp90 and Hsp70.

Determinations of GR number (Bmax) and assessments of lymphocyte sensitivity to glucocorticoids in trauma-exposed individuals with and without PTSD have yielded rather inconsistent results. The contribution of most other factors determining tissue responsiveness to glucocorticoid hormones to PTSD pathophysiology is currently under investigation. Thus, increased GR protein level in peripheral lymphocytes from current and lifetime PTSD patients in comparison to trauma-exposed non-PTSD individuals (trauma controls) appeared to be a possible correlate of vulnerability to PTSD. Besides, PTSD patients displayed the lowest and trauma controls the highest fractional occupancy of the GR, suggesting that the receptor redox status may be a factor contributing to vulnerability/resilience to PTSD. Estimates of the GR hormone-binding potency (Bmax/KD ratio) and of strength of correlation between Bmax and KD pointed to deterioration of glucocorticoid signaling in the lymphocytes as a characteristic of PTSD patients. Lymphocyte MR protein level, MR/GR ratio, and Hsp90 and Hsp70 levels were found to be unaffected by traumatic events and past or current PTSD symptoms. However, the association of GR and Hsp90 expression levels appeared as a candidate marker of trauma exposure, while that of MR and Hsp70 levels of vulnerability to PTSD.


PTSD Trauma Corticosteroid receptors Glucocorticoid receptor Mineralocorticoid receptor Peripheral blood mononuclear cells Resilience to PTSD Vulnerability to PTSD, heat shock proteins 

List of Abbreviations


Maximal number of receptor sites per cell


Glucocorticoid receptor

HPA axis

Hypothalamic-pituitary-adrenocortical axis


Heat shock factor 1


Heat shock protein 70


Heat shock protein 90


Equilibrium dissociation constant


Mineralocorticoid receptor


Peripheral blood mononuclear cells


Post-traumatic stress disorder


  1. Altemus M, Dhabhar FS, Yang R. Immune function in PTSD. Ann N Y Acad Sci. 2006;1071:167–83.CrossRefPubMedGoogle Scholar
  2. Bachmann AW, Sedgley TL, Jackson RV, Gibson JN, Young RM, Torpy DJ. Glucocorticoid receptor polymorphisms and post-traumatic stress disorder. Psychoneuroendocrinology. 2005;30:297–306.CrossRefPubMedGoogle Scholar
  3. Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009;34 Suppl 1:S186–95.CrossRefPubMedGoogle Scholar
  4. Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299:1291–305.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Brkljačić J, Milutinović DV, Dundjerski J, Matić G. Mercury stimulates rat liver glucocorticoid receptor association with Hsp90 and Hsp70. J Biochem Mol Toxicol. 2004;18:257–60.CrossRefPubMedGoogle Scholar
  6. Brkljacic J, Tanic N, Milutinovic DV, Elakovic I, Jovanovic SM, Perisic T, et al. Validation of endogenous controls for gene expression studies in peripheral lymphocytes from war veterans with and without PTSD. BMC Mol Biol. 2010;11:26.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Crocoll A, Schneikert J, Hubner S, Martin E, Cato AC. BAG-1M: a potential specificity determinant of corticosteroid receptor action. Kidney Int. 2000;57:1265–9.CrossRefPubMedGoogle Scholar
  8. Čvoro A, Dundjerski J, Trajković D, Matić G. Association of the rat liver glucocorticoid receptor with Hsp90 and Hsp70 upon whole body hyperthermic stress. J Steroid Biochem Mol Biol. 1998;67:319–25.CrossRefPubMedGoogle Scholar
  9. Davies L, Karthikeyan N, Lynch JT, Sial EA, Gkourtsa A, Demonacos C, et al. Cross talk of signaling pathways in the regulation of the glucocorticoid receptor function. Mol Endocrinol. 2008;22:1331–44.CrossRefPubMedGoogle Scholar
  10. de Kloet CS, Vermetten E, Geuze E, Kavelaars A, Heijnen CJ, Westenberg HG. Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-pharmacological challenge tests, a review. J Psychiatr Res. 2006;40:550–67.CrossRefPubMedGoogle Scholar
  11. de Kloet CS, Vermetten E, Bikker A, Meulman E, Geuze E, Kavelaars A, et al. Leukocyte glucocorticoid receptor expression and immunoregulation in veterans with and without post-traumatic stress disorder. Mol Psychiatry. 2007;12:443–53.PubMedGoogle Scholar
  12. Dimitrov S, Lange T, Fehm HL, Born J. A regulatory role of prolactin, growth hormone, and corticosteroids for human T-cell production of cytokines. Brain Behav Immun. 2004;18:368–74.CrossRefPubMedGoogle Scholar
  13. Edwards DP, Estes PA, Fadok VA, Bona BJ, Onate S, Nordeen SK, et al. Heat shock alters the composition of heteromeric steroid receptor complexes and enhances receptor activity in vivo. Biochemistry. 1992;31:2482–91.CrossRefPubMedGoogle Scholar
  14. Elaković I, Perišić T, Čanković-Kadijević M, Matić G. Correlation between glucocorticoid receptor binding parameters, blood pressure, and body mass index in a healthy human population. Cell Biochem Funct. 2007;25:427–31.CrossRefPubMedGoogle Scholar
  15. Galigniana MD, Erlejman AG, Monte M, Gomez-Sanchez C, Piwien-Pilipuk G. The hsp90-FKBP52 complex links the mineralocorticoid receptor to motor proteins and persists bound to the receptor in early nuclear events. Mol Cell Biol. 2010;30:1285–98.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Gotovac K, Sabioncello A, Rabatic S, Berki T, Dekaris D. Flow cytometric determination of glucocorticoid receptor (GCR) expression in lymphocyte subpopulations: lower quantity of GCR in patients with post-traumatic stress disorder (PTSD). Clin Exp Immunol. 2003;131:335–9.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Grad I, Picard D. The glucocorticoid responses are shaped by molecular chaperones. Mol Cell Endocrinol. 2007;275:2–12.CrossRefPubMedGoogle Scholar
  18. Gross KL, Lu NZ, Cidlowski JA. Molecular mechanisms regulating glucocorticoid sensitivity and resistance. Mol Cell Endocrinol. 2009;300:7–16.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Harris AP, Holmes MC, de Kloet ER, Chapman KE, Seckl JR. Mineralocorticoid and glucocorticoid receptor balance in control of HPA axis and behaviour. Psychoneuroendocrinology. 2013;38:648–58.CrossRefPubMedGoogle Scholar
  20. Hauer D, Weis F, Papassotiropoulos A, Schmoeckel M, Beiras-Fernandez A, Lieke J, et al. Relationship of a common polymorphism of the glucocorticoid receptor gene to traumatic memories and posttraumatic stress disorder in patients after intensive care therapy. Crit Care Med. 2011;39:643–50.CrossRefPubMedGoogle Scholar
  21. Jones TJ, Li D, Wolf IM, Wadekar SA, Periyasamy S, Sanchez ER. Enhancement of glucocorticoid receptor-mediated gene expression by constitutively active heat shock factor 1. Mol Endocrinol. 2004;18:509–20.CrossRefPubMedGoogle Scholar
  22. Kellner M, Baker DG, Yassouridis A, Bettinger S, Otte C, Naber D, et al. Mineralocorticoid receptor function in patients with posttraumatic stress disorder. Am J Psychiatry. 2002;159:1938–40.CrossRefPubMedGoogle Scholar
  23. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the national comorbidity survey. Arch Gen Psychiatry. 1995;52:1048–60.CrossRefPubMedGoogle Scholar
  24. Kojika S, Sugita K, Inukai T, Saito M, Iijima K, Tezuka T, et al. Mechanisms of glucocorticoid resistance in human leukemic cells: implication of abnormal 90 and 70 kDa heat shock proteins. Leukemia. 1996;10:994–9.PubMedGoogle Scholar
  25. Matić G, Milutinović DV, Nestorov J, Elaković I, Jovanovic SM, Perišić T, et al. Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD. Prog Neuropsychopharmacol Biol Psychiatry. 2013;43:238–45.CrossRefPubMedGoogle Scholar
  26. Matić G, Vojnović Milutinović D, Nestorov J, Elaković I, Manitašević Jovanović S, Elzaedi YM, et al. Mineralocorticoid receptor and heat shock protein expression levels in peripheral lymphocytes from war trauma-exposed men with and without PTSD. Psychiatry Res. 2014;215:379–85.CrossRefPubMedGoogle Scholar
  27. Meijer OC, Karssen AM, de Kloet ER. Cell- and tissue-specific effects of corticosteroids in relation to glucocorticoid resistance: examples from the brain. J Endocrinol. 2003;178:13–8.CrossRefPubMedGoogle Scholar
  28. Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol. 2013;132:1033–44.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Okamoto K, Tanaka H, Makino Y, Makino I. Restoration of the glucocorticoid receptor function by the phosphodiester compound of vitamins C and E, EPC-K1 (l-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzo pyran-6-yl hydrogen phosphate] potassium salt), via a redox-dependent mechanism. Biochem Pharmacol. 1998;56:79–86.CrossRefPubMedGoogle Scholar
  30. Otte C, Muhtz C, Daneshkhah S, Yassouridis A, Kiefer F, Wiedemann K, et al. Mineralocorticoid receptor function in posttraumatic stress disorder after pretreatment with metyrapone. Biol Psychiatry. 2006;60:784–7.CrossRefPubMedGoogle Scholar
  31. Pratt WB, Toft DO. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev. 1997;18:306–60.PubMedGoogle Scholar
  32. Rao NA, McCalman MT, Moulos P, Francoijs KJ, Chatziioannou A, Kolisis FN, et al. Coactivation of GR and NFKB alters the repertoire of their binding sites and target genes. Genome Res. 2011;21:1404–16.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Richter K, Haslbeck M, Buchner J. The heat shock response: life on the verge of death. Mol Cell. 2010;40:253–66.CrossRefPubMedGoogle Scholar
  34. Rohleder N, Wolf JM, Wolf OT. Glucocorticoid sensitivity of cognitive and inflammatory processes in depression and posttraumatic stress disorder. Neurosci Biobehav Rev. 2010;35:104–14.CrossRefPubMedGoogle Scholar
  35. Savic D, Knezevic G, Damjanovic S, Spiric Z, Matic G. The role of personality and traumatic events in cortisol levels – where does PTSD fit in? Psychoneuroendocrinology. 2012;37:937–47.CrossRefPubMedGoogle Scholar
  36. Scammell JG, Denny WB, Valentine DL, Smith DF. Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three new world primates. Gen Comp Endocrinol. 2001;124:152–65.CrossRefPubMedGoogle Scholar
  37. Segman RH, Shefi N, Goltser-Dubner T, Friedman N, Kaminski N, Shalev AY. Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors. Mol Psychiatry. 2005;10:500–13.CrossRefPubMedGoogle Scholar
  38. Shalev AY, Videlock EJ, Peleg T, Segman R, Pitman RK, Yehuda R. Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part I: HPA axis responses. Int J Neuropsychopharmacol. 2008;11:365–72.CrossRefPubMedGoogle Scholar
  39. Silva CM, Powell-Oliver FE, Jewell CM, Sar M, Allgood VE, Cidlowski JA. Regulation of the human glucocorticoid receptor by long-term and chronic treatment with glucocorticoid. Steroids. 1994;59:436–42.CrossRefPubMedGoogle Scholar
  40. Simons Jr SS, Pratt WB. Glucocorticoid receptor thiols and steroid-binding activity. Methods Enzymol. 1995;251:406–22.CrossRefPubMedGoogle Scholar
  41. Su TP, Zhang L, Chung MY, Chen YS, Bi YM, Chou YH, et al. Levels of the potential biomarker p11 in peripheral blood cells distinguish patients with PTSD from those with other major psychiatric disorders. J Psychiatr Res. 2009;43:1078–85.CrossRefPubMedGoogle Scholar
  42. Svensson E, Vidovic K, Lassen C, Richter J, Olofsson T, Fioretos T, et al. Deregulation of the Wilms’ tumour gene 1 protein (WT1) by BCR/ABL1 mediates resistance to imatinib in human leukaemia cells. Leukemia. 2007;21:2485–94.CrossRefPubMedGoogle Scholar
  43. Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, et al. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004;25:831–66.CrossRefPubMedGoogle Scholar
  44. van Zuiden M, Geuze E, Willemen HL, Vermetten E, Maas M, Heijnen CJ, et al. Pre-existing high glucocorticoid receptor number predicting development of posttraumatic stress symptoms after military deployment. Am J Psychiatry. 2011;168:89–96.CrossRefPubMedGoogle Scholar
  45. van Zuiden M, Geuze E, Willemen HL, Vermetten E, Maas M, Amarouchi K, et al. Glucocorticoid receptor pathway components predict posttraumatic stress disorder symptom development: a prospective study. Biol Psychiatry. 2012;71:309–16.CrossRefPubMedGoogle Scholar
  46. Vanderbilt JN, Miesfeld R, Maler BA, Yamamoto KR. Intracellular receptor concentration limits glucocorticoid-dependent enhancer activity. Mol Endocrinol. 1987;1:68–74.CrossRefPubMedGoogle Scholar
  47. Vidovic A, Vilibic M, Sabioncello A, Gotovac K, Rabatic S, Folnegovic-Smalc V, et al. Circulating lymphocyte subsets, natural killer cell cytotoxicity, and components of hypothalamic-pituitary-adrenal axis in Croatian war veterans with posttraumatic stress disorder: cross-sectional study. Croat Med J. 2007;48:198–206.PubMedPubMedCentralGoogle Scholar
  48. von Kanel R, Hepp U, Kraemer B, Traber R, Keel M, Mica L, et al. Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder. J Psychiatr Res. 2007;41:744–52.CrossRefGoogle Scholar
  49. Wang Z, Frederick J, Garabedian MJ. Deciphering the phosphorylation “code” of the glucocorticoid receptor in vivo. J Biol Chem. 2002;277:26573–80.CrossRefPubMedGoogle Scholar
  50. Watson LC, Kuchenbecker KM, Schiller BJ, Gross JD, Pufall MA, Yamamoto KR. The glucocorticoid receptor dimer interface allosterically transmits sequence-specific DNA signals. Nat Struct Mol Biol. 2013;20:876–83.CrossRefPubMedPubMedCentralGoogle Scholar
  51. Wheler GH, Brandon D, Clemons A, Riley C, Kendall J, Loriaux DL, et al. Cortisol production rate in posttraumatic stress disorder. J Clin Endocrinol Metab. 2006;91:3486–9.CrossRefPubMedGoogle Scholar
  52. Yehuda R. Status of glucocorticoid alterations in post-traumatic stress disorder. Ann N Y Acad Sci. 2009;1179:56–69.CrossRefPubMedGoogle Scholar
  53. Yehuda R, LeDoux J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron. 2007;56:19–32.CrossRefPubMedGoogle Scholar
  54. Yehuda R, Boisoneau D, Lowy MT, Giller Jr EL. Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. Arch Gen Psychiatry. 1995;52:583–93.CrossRefPubMedGoogle Scholar
  55. Yehuda R, Golier JA, Yang RK, Tischler L. Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder. Biol Psychiatry. 2004;55:1110–6.CrossRefPubMedGoogle Scholar
  56. Yehuda R, Cai G, Golier JA, Sarapas C, Galea S, Ising M, et al. Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks. Biol Psychiatry. 2009;66:708–11.CrossRefPubMedGoogle Scholar
  57. Zhang L, Li H, Ursano RJ. Heat shock protein and posttraumatic stress disorder. In: Asea AAA, Pedersen BK, editors. Heat shock proteins and whole body physiology. Houten: Springer; 2010. p. 179–92.CrossRefGoogle Scholar
  58. Zieker J, Zieker D, Jatzko A, Dietzsch J, Nieselt K, Schmitt A, et al. Differential gene expression in peripheral blood of patients suffering from post-traumatic stress disorder. Mol Psychiatry. 2007;12:116–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Gordana Matić
    • 1
  • Danijela Vojnović Milutinović
    • 1
  • Ivana Elaković
    • 1
  • Jelena Nestorov
    • 1
  • Danka Savić
    • 2
  1. 1.Department of BiochemistryInstitute for Biological Research “Siniša Stanković”, University of BelgradeBelgradeSerbia
  2. 2.Laboratory for Theoretical and Condensed Matter PhysicsVinča Institute of Nuclear Sciences, University of BelgradeBelgradeSerbia

Personalised recommendations