Skip to main content
SpringerLink
Log in

Dehydroepiandrosterone: a modulator of cellular immunity and heat shock protein 70 production during polymicrobial sepsis

  • Experimental
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

Objective

DHEA is an immunomodulatory steroid hormone that improves survival during systemic inflammation. A DHEA-induced modulation of heat shock protein response may be an alternative mechanism contributing to the beneficial effects of this hormone. We investigated the effect of DHEA administration on survival, cellular immune functions, and HSP-70 production in septic mice.

Design and setting

Randomized animal study, level I trauma center, university research laboratory.

Subjects

Male NMRI mice.

Interventions

Mice were subjected to sham operation (laparotomy, LAP) or sepsis (cecal ligation and puncture, CLP) with or without administration of either saline 0.9% (LAP, CLP) or 20 mg/kg DHEA subcutaneously (LAP/DHEA, CLP/DHEA). Survival was monitored over a 48-h period. Splenocyte apoptosis rate (AnnexinV binding), splenocyte proliferation ([3H]thymidine incorporation), TNF-α plasma concentration (ELISA), and HSP-70 concentration (ELISA) in tissue extracts from liver, lung, and spleen were monitored 48 h after onset of sepsis.

Results

DHEA administration improved the survival of septic mice (78% vs. 50%). This effect was paralleled by increased splenocyte proliferation, decreased cellular apoptosis rate of splenocytes, and attenuation of TNF-α release. Furthermore, an increased HSP-70 concentration was observed in lungs and spleens of DHEA-treated septic animals.

Conclusions

DHEA-treatment decreased the mortality rate of septic mice. This was accompanied by improved cellular immune functions and an augmented heat shock response (HSP-70) of lungs and spleens. Further studies are required to demonstrate a direct relationship between the improved survival and the observed alterations in the immune system in DHEA-treated animals.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Loria RM, Padgett DA (1992) Androstenediol regulates systemic resistance against lethal viral infections in mice. Arch Virol 127:103–114

    Article  PubMed  CAS  Google Scholar 

  2. Ben-Nathan D, Padgett DA, Loria RM (1999) Androstendiol and dehydroepiandrosterone protect mice against lethal bacterial infection and lipopolysaccaride toxicity. J Med Microbiol 48:425–434

    PubMed  CAS  Google Scholar 

  3. Padgett DA, Loria RM, Sheridan JF (1997) Endocrine regulation of the immune response to influenza virus infection with a metabolite of DHEA – androstenediol. J Neuroimmunol 78:203–214

    Article  PubMed  CAS  Google Scholar 

  4. Oberbeck R, Dahlweid M, Koch M, van Griensven M, Emmendörfer A, Tscherne H, Pape HC (2001) Dehydroepiandrosterone decreases mortality and improves cellular immune function during polymicrobial sepsis. Crit Care Med 29:380–384

    Article  PubMed  CAS  Google Scholar 

  5. Sakakura Y, Nakagawa Y, Ohzeki T (2006) Differential effect of DHEA on mitogen-induced proliferation of T and B lymphocytes. J Steroid Biochem Mol Biol 99:115–120

    Article  PubMed  CAS  Google Scholar 

  6. Powell JM, Sonnenfeld G (2006) The effects of dehydroepiandrosterone (DHEA) on in vitro spleen cell proliferation and cytokine production. J Interferon Cytokine Res 26:34–39

    Article  PubMed  CAS  Google Scholar 

  7. Suzuki T, Shimizu T, Szalay L, Choudry MA, Rue LW 3rd, Bland KI, Chaudry IH (2006) Androstenediol ameliorates alterations in immune cells cytokine production capacity in a two-hit model of trauma-hemorrhage and sepsis. Cytokine 34:76–84

    Article  PubMed  CAS  Google Scholar 

  8. Angele MK, Catania RA, Ayala A, Cioffi WG, Bland KI, Chaudry IH (1998) Dehydroepiandrosterone: an inexpensive steroid hormone that decreases the mortality due to sepsis following trauma-hemorrhage. Arch Surg 133:1281–1288

    Article  PubMed  CAS  Google Scholar 

  9. Dannenberg HD, Alpert G, Lustig S, Ben-Nathan D (1992) Dehydroepiandrosterone protects mice from endotoxin toxicity and reduces tumor necrosis factor production. Antimicrob Agents Chemother 36:2275–2279

    Google Scholar 

  10. Griensven M van, Dahlweid FM, Giannoudis PV, Wittwer T, Böttcher F, Breddin M, Pape HC (2002) Dehydroepiandrosterone modulates the activity and the expression of lymphocyte subpopulations induced by cecal ligation and puncture. Shock 18:445–449

    Article  Google Scholar 

  11. Oberbeck R, Nickel E, van Griensven M, Tschernig T, Wittwer T, Schmitz D, Pape HC (2002) The effect of dehydroepiandrosterone on hemorrhage-induced suppression of cellular immune functions. Intensive Care Med 28:963–968

    Article  PubMed  Google Scholar 

  12. Hildebrand F, Pape HC, Hoevel P, Krettek C, van Griensven M (2003) The importance of cytokines in the pathogenesis of polymicrobial sepsis and dehydroepiandrosterone treatment in a rodent model. Shock 20:338–346

    Article  PubMed  CAS  Google Scholar 

  13. Kiang JG, Tsokos GC (1998) Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacol Ther 80:183–201

    Article  PubMed  CAS  Google Scholar 

  14. Voss MR, Stallone JN, Li M, Cornelussen RNM, Knuefermann P, Knowlton AA (2003) Gender differences in the expression of heat shock proteins: the effect of estrogen. Am J Physiol 285:H687–H692

    CAS  Google Scholar 

  15. Schroeder S, Bischoff J, Lehmann LE, Hering R, von Spiegel T, Putensen C, Hoeft A, Stüber F (1999) Endotoxin inhibits heat shock protein 70 expression in peripheral blood mononuclear cells of patients with severe sepsis. Intensive Care Med 25:52–57

    Article  PubMed  CAS  Google Scholar 

  16. Morikawa A, Kato T, Sugiyama N, Koide N, Yokochi T (1998) Altered expression of constitutive and inducible type heat shock proteins in response to D-galactosamine-sensitized mice to lipopolysaccaride as an experimental endotoxic shock model. FEMS Immunol Med Microbiol 21:37–45

    PubMed  CAS  Google Scholar 

  17. Da-Zhong X, Qi L, Gregory M, Deitch E (1996) Effect of heat shock and endotoxin stress on enterocyte viability apoptosis and function varies based on whether the cells are exposed to heat shock or endotoxin first. Arch Surg 131:1222–1228

    Google Scholar 

  18. Jäättelä M (1999) Heat shock proteins as cellular lifeguards. Ann Med 31:261–271

    Article  PubMed  Google Scholar 

  19. Jarrar D, Chaudry IH, Wang P (1999) Organ dysfunction following hemorrhage and sepsis: mechanisms and therapeutic approaches. Int J Mol Med 4:575–583

    PubMed  CAS  Google Scholar 

  20. Koh Y, Lim CM, Kim MJ, Shim TS, Lee SD (1999) Heat shock response decreases endotoxin-induced acute lung injury in rats. Respirology 4:325–330

    Article  PubMed  CAS  Google Scholar 

  21. Singleton KD, Serkova N, Beckey VE, Wischmeyer E (2005) Glutamine attenuates lung injury and improves survival after sepsis: role of enhanced heat shock protein expression. Crit Care Med 33:1206–1213

    Article  PubMed  CAS  Google Scholar 

  22. Tang P, Gannon MJ, Andrew A, Miller D (1995) Evidence of estrogenic regulation of heat shock protein expression in human endometrium and steroid-responsive cell lines. Eur J Endoncrinol 133:598–605

    CAS  Google Scholar 

  23. Voss MR, Stallone JN, Li M, Cornelussen RN, Knuefermann P, Knowlton AA (2003) Gender differences in the expression of heat shock proteins: the effect of estrogens. Am J Physiol 285:H687–H692

    CAS  Google Scholar 

  24. Heufelder AE, Wenzel BE, Bahn RS (1993) Glucocorticoids modulate the synthesis and expression of a 72 kDa heat shock protein in cultured Graves'retroocular fibroblasts. Acta Endocrinol (Copenh) 128:41–50

    CAS  Google Scholar 

  25. Svec F, Porter JR (1998) The actions of exogenous dehydroepiandrosterone in experimental animals and humans. Proc Soc Exp Biol Med 218:174–191

    PubMed  CAS  Google Scholar 

  26. Baker CC, Chaudry IH, Gaines HO, Baue AE (1983) Evaluation of factors affecting mortality rate after sepsis in murine cecal ligation and puncture model. Surgery 94:331–342

    PubMed  CAS  Google Scholar 

  27. Exton MS, v. Hörsten S, Schulte M, Vöge J, Strubel T, Donath S, Nagel E, Westermann J, Schedlowski M (1988) Behaviourally conditioned immunosupression using cyclosporine A. J Neuroimmunol 88:182–191

    Article  Google Scholar 

  28. Fleshner M, Nguyen KT, Cotter CS, Watkins LR, Maier SF (1998) Acute stressor suppresses acquired immunity and potentiates innate immunity. Am J Physiol 275:R870–R878

    PubMed  CAS  Google Scholar 

  29. Oberbeck R (2004) Therapeutic implications of immune endocrine interactions in the critically ill patients. Curr Drug Targets 4:129–139

    CAS  Google Scholar 

  30. Catania RA, Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH (1999) Dheydroepiandrosterone restored immune function following trauma hemorrhage by a direct effect on T-lymphocytes. Cytokine 11:443–450

    Article  PubMed  CAS  Google Scholar 

  31. Blauer KL, Poth M, Roger WM, Bernton EW (1991) Dehydroepiandrosterone antagonizes the suppressive effects of dexamethasone on lymphocyte proliferation. Endocrinology 129:3174–3179

    PubMed  CAS  Google Scholar 

  32. Jarrar D, Kuebler JF, Wang P, Bland KI, Chaudry IH (2001) DHEA: a novel adjunct for the treatment of male trauma patients. Trends Mol Med 7:81–85

    Article  PubMed  CAS  Google Scholar 

  33. Cohen JJ (1993) Apoptosis. Immunol Today 14:126–130

    Article  PubMed  CAS  Google Scholar 

  34. Takabashi H, Nakajima A, Sekihara A (2004) Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) inhibit the apoptosis in human peripheral blood lymphocytes. J Steroid Biochem Mol Biol 88:261–268

    Article  CAS  Google Scholar 

  35. Hampl R, Vondra K (2006) Natural antiglucocorticoids. Vnitr Lek 52:973–978

    PubMed  CAS  Google Scholar 

  36. Blauer KL, Poth M, Rogers WM, Bernton EW (1991) DHEA antagonizes the suppressive effects of dexamethasone on lymphocyte proliferation. Endocrinology 129:3174–3179

    Article  PubMed  CAS  Google Scholar 

  37. Browne ES, Wright BE, Porter JR, Svec F (1992) DHEA: antiglucocorticoid action in mice. Am J Med Sci 303:366–371

    Article  PubMed  CAS  Google Scholar 

  38. Williams JR (2000) The effects of DHEA on carcinogenesis, obesity, the immune system, and aging. Lipids 35:325–331

    Article  PubMed  CAS  Google Scholar 

  39. Herr I, Gassler N, Friess H, Büchler MW (2007) Regulation of differential pro- and anti-apoptotic signaling by glucocorticoids. Apoptosis 12:271–291

    Article  PubMed  CAS  Google Scholar 

  40. Szalay L, Shimizu T, Suzuki T, Hseih YH, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH (2006) Androstenediol administration after trauma-hemorrhage attenuates inflammatory response, reduces organ damage, and improves survival following sepsis. Am J Physiol 291:G260–G266

    CAS  Google Scholar 

  41. Jarrar D, Wang P, Cioffi WG, Bland KI, Chaudry IH (2000) Mechanisms of salutary effects of dehydroepiandrosterone after trauma-hemorrhage: direct or indirect effects on cardiac and hepatocellular function. Arch Surg 135:416–422

    Article  PubMed  CAS  Google Scholar 

  42. Singleton KD, Serkova N, Beckey VE, Wischmeyer PE (2005) Glutamine attenuates lung injury and improves survival of sepsis: role of enhanced heat shock protein expression. Crit Care Med 33:1206–1213

    Article  PubMed  CAS  Google Scholar 

  43. Villar J, Ribeiro SP, Brendan J, Mulen M, Post M, Slutsky A (1994) Induction of the heat shock response reduces the mortality rate and organ damage in a sepsis-induced acute lung injury model. Crit Care Med 22:914–921

    Article  PubMed  CAS  Google Scholar 

  44. Hotchkiss R, Nunnally I, Lindquist S, Taulien J, Perdrizet G, Karl I (1993) Hyperthermia protects mice against the lethal effects of endotoxin. Am J Physiol 265:R1447–R1457

    PubMed  CAS  Google Scholar 

  45. Ribeiro SP, Villar J, Downey GP, Edelson JD, Slutsky AS (1994) Sodium arsenite induces heat shock protein-72 kilodalton expression in the lungs and protects rats against sepsis. Crit Care Med 22:922–929

    Article  PubMed  CAS  Google Scholar 

  46. Ryan AJ, Flanagan SW, Moseley PL, Gisolfi CV (1992) Acute heat stress protects rats against endotoxin shock. J Appl Physiol 73:1517–1522

    PubMed  CAS  Google Scholar 

  47. Bruemmer-Smith S, Stüber F, Schroeder S (2001) Protective functions of intracellular heat-shock protein (HSP) 70-expression in patients with severe sepsis. Intensive Care Med 27:1835–1841

    Article  PubMed  CAS  Google Scholar 

  48. DeMaio A (1999) Heat shock proteins: facts, thoughts, and dreams. Shock 11:1–12

    Article  CAS  Google Scholar 

  49. Chen D, Pan J, Du B, Sun D (2005) Induction of the heat shock response in vivo inhibits NF-kappa B activity and protects murine liver from endotoxemia-induced injury. J Clin Immunol 25:452–461

    Article  PubMed  CAS  Google Scholar 

  50. Ostberg JR, Kaplan KC, Repasky EA (2002) Induction of stress proteins in a panel of mouse tissues by fever-range whole body hyperthermia. Int J Hyperthermia 18:552–562

    Article  PubMed  CAS  Google Scholar 

  51. Ofenstein JP, Heidemann S, Juett-Wilstermann A, Sarnaik A (2000) Expression of stress proteins HSP 72 & HSP 32 in response to endotoxemia. Ann Clin Lab Sci 30:92–98

    PubMed  CAS  Google Scholar 

  52. Flohé S, Dominguez Fernandez E, Ackermann M, Hirsch T, Borgermann J, Schade FU (1999) Endotoxin tolerance in rats: expression of TNF-α, IL-6, IL-10, VCAM, and HSP 70 in lung and liver during endotoxin shock. Cytokine 11:796–804

    Article  PubMed  Google Scholar 

  53. Shi Y, Tu Z, Tang D, Liu M, Wang K, Calderwood S, Xiao X (2006) The inhibition of LPS-induced production of the inflammatory cytokines by HSP 70 involves inactivation of the NF-kappa B pathway but not the MAPK pathways. Shock 26:277–284

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Trauma Surgery, University Hospital of Essen, Hufelandstrasse 55, 45147, Essen, Germany

    Reiner Oberbeck, Hanno Deckert, Jörg Bangen & Daniel Schmitz

  2. Department of Orthopedic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa., USA

    Phillip Kobbe

Authors
  1. Reiner Oberbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hanno Deckert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jörg Bangen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Phillip Kobbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Schmitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reiner Oberbeck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oberbeck, R., Deckert, H., Bangen, J. et al. Dehydroepiandrosterone: a modulator of cellular immunity and heat shock protein 70 production during polymicrobial sepsis. Intensive Care Med 33, 2207–2213 (2007). https://doi.org/10.1007/s00134-007-0851-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-007-0851-4

Keywords

Search

Navigation