Skip to main content
SpringerLink
Log in

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

  • Reference work entry
  • First Online:
Comprehensive Guide to Post-Traumatic Stress Disorders

  • 144 Accesses

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 1,099.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 1,199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

Bmax :

Maximal number of receptor sites per cell

GR:

Glucocorticoid receptor

HPA axis:

Hypothalamic-pituitary-adrenocortical axis

HSF1:

Heat shock factor 1

Hsp70:

Heat shock protein 70

Hsp90:

Heat shock protein 90

KD :

Equilibrium dissociation constant

MR:

Mineralocorticoid receptor

PBMCs:

Peripheral blood mononuclear cells

PTSD:

Post-traumatic stress disorder

References

  • Altemus M, Dhabhar FS, Yang R. Immune function in PTSD. Ann N Y Acad Sci. 2006;1071:167–83.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • Grad I, Picard D. The glucocorticoid responses are shaped by molecular chaperones. Mol Cell Endocrinol. 2007;275:2–12.

    Article  PubMed  Google Scholar 

  • Gross KL, Lu NZ, Cidlowski JA. Molecular mechanisms regulating glucocorticoid sensitivity and resistance. Mol Cell Endocrinol. 2009;300:7–16.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Pratt WB, Toft DO. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev. 1997;18:306–60.

    PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • Richter K, Haslbeck M, Buchner J. The heat shock response: life on the verge of death. Mol Cell. 2010;40:253–66.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Simons Jr SS, Pratt WB. Glucocorticoid receptor thiols and steroid-binding activity. Methods Enzymol. 1995;251:406–22.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Vanderbilt JN, Miesfeld R, Maler BA, Yamamoto KR. Intracellular receptor concentration limits glucocorticoid-dependent enhancer activity. Mol Endocrinol. 1987;1:68–74.

    Article  PubMed  Google Scholar 

  • 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.

    PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Wang Z, Frederick J, Garabedian MJ. Deciphering the phosphorylation “code” of the glucocorticoid receptor in vivo. J Biol Chem. 2002;277:26573–80.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Yehuda R. Status of glucocorticoid alterations in post-traumatic stress disorder. Ann N Y Acad Sci. 2009;1179:56–69.

    Article  PubMed  Google Scholar 

  • Yehuda R, LeDoux J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron. 2007;56:19–32.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Chapter  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, 142 Despot Stefan Boulevard, 11060, Belgrade, Serbia

    Gordana Matić, Danijela Vojnović Milutinović, Ivana Elaković & Jelena Nestorov

  2. Laboratory for Theoretical and Condensed Matter Physics, Vinča Institute of Nuclear Sciences, University of Belgrade, 522, 11001, Belgrade, Serbia

    Danka Savić

Authors
  1. Gordana Matić
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Danijela Vojnović Milutinović
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ivana Elaković
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jelena Nestorov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Danka Savić
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gordana Matić .

Editor information

Editors and Affiliations

  1. Faculty of Society and Health, Buckinghamshire New University, Uxbridge, Middlesex, United Kingdom

    Colin R. Martin

  2. FactyofLifeSci&Med,Diabts&NutrnSciRshDiv, King’s College London, London, United Kingdom

    Victor R. Preedy

  3. DepartofBiomedicalSci,SchoolofLifeScienc, University of Westminster, London, United Kingdom

    Vinood B. Patel

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this entry

Cite this entry

Matić, G., Milutinović, D.V., Elaković, I., Nestorov, J., Savić, D. (2016). Level of Expression and Functional Properties of Lymphocyte Corticosteroid Receptors as Biological Correlates of PTSD, Trauma-Exposure, or Resilience to PTSD. In: Martin, C., Preedy, V., Patel, V. (eds) Comprehensive Guide to Post-Traumatic Stress Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-08359-9_3

Download citation

Publish with us

Policies and ethics

Search

Navigation