Synergistic Effects of Ageing and Stress on Neutrophil Function

  • Janet M. Lord
  • Anna C. Phillips
  • Wiebke Arlt


Although ageing is a complex process, we now know much of what happens with age at the cellular and tissue level. In contrast, our understanding of how the various age-related changes interact to result in frailty and pathology is incomplete. For example, ageing is accompanied by a loss of immune function (Immunesenescence), an increase in the level of circulating proinflammatory cytokines (Inflammaging), a decline in adrenal androgen production (Adrenopause) whilst concurrently peripheral glucocorticoid availability increases. In this article we propose that these changes in combination increase the susceptibility of older adults to the adverse effects of physical and emotional stress, exacerbating the age-related decline in immune competence and exposing the older individual to increased risk of infections. We have focused upon the effects of stress and ageing on neutrophil function, an element of the immune system that has received less attention from immunogerontologists, despite the primary role of neutrophils in fighting bacterial infections and the major contribution of such infections to agerelated morbidity and mortality. We propose that physical and emotional stressors elicit an exaggerated response in older adults that synergises with the age-related loss of neutrophil function, to compromise antibacterial mechanisms. Moreover, the molecular basis of this effect may lie with the significant changes in tissue concentrations of cortisol and dehydroepiandrosterone in peripheral target cells including the immune compartment.


Chronic Stress Neutrophil Function Glycyrrhetinic Acid Severe Congenital Neutropenia DHEA Supplementation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bonomo RA (2002) Resistant pathogens in respiratory tract infections in older people. J Am Geriatr Soc 50:S236–S241PubMedCrossRefGoogle Scholar
  2. 2.
    Fein AM (1999) Pneumonia in the elderly: Overview of diagnostic and therapeutic approaches. Clin Infect Dis 28:726–729PubMedCrossRefGoogle Scholar
  3. 3.
    Gavazzi G, Krause KH (2002) Ageing and infection. Lancet Infect Dis 2:659–666PubMedCrossRefGoogle Scholar
  4. 4.
    Martin GS, Mannino DM, Moss M (2006) The effect of age on the development and outcome of adult sepsis. Crit Care Med 34:15–21PubMedCrossRefGoogle Scholar
  5. 5.
    Liang SY, Mackowiak PA (2007) Infections in the elderly. Clin Geriatr Med 23:441–456PubMedCrossRefGoogle Scholar
  6. 6.
    Rajagopalan S, Yoshikawa TT (2000) Tuberculosis in long-term-care facilities. Infect Control Hosp Epidemiol 21:611–615PubMedCrossRefGoogle Scholar
  7. 7.
    Laube S (2004) Skin infections and ageing. Ageing Res Rev 3:69–89PubMedCrossRefGoogle Scholar
  8. 8.
    Butcher SK, Killampalli V, Chahal H, Kaya AE, Lord JM (2003) Effect of age on susceptibility to post-traumatic infection in the elderly. Biochem Soc Trans 31:449–451PubMedCrossRefGoogle Scholar
  9. 9.
    Pittman J (2007) Effect of aging on wound healing—Current concepts. J Wound Ostomy Continence Nurs 34:412–415PubMedGoogle Scholar
  10. 10.
    Cohen F, Kemeny ME, Kearney KA, Zegans LS, Neuhaus JM, Conant MA (1999) Persistent stress as a predictor of genital herpes recurrence. Arch Intern Med 159:2430–2436PubMedCrossRefGoogle Scholar
  11. 11.
    Lien L, Haavet OR, Thoresen M, Heyerdahl S, Bjertness E (2007) Mental health problems, negative life events, perceived pressure and the frequency of acute infections among adolescents—Results from a cross-sectional, multicultural, population-based study. Acta Paediatr 96:301–306PubMedCrossRefGoogle Scholar
  12. 12.
    Keynes WM (1994) Medical response to mental stress. J Royal Soc Med 87:536–539Google Scholar
  13. 13.
    Leserman J (2003) The effects of stressful life events, coping, and cortisol on HIV infection. CNS Spectr 8:25–30PubMedGoogle Scholar
  14. 14.
    Phillips AC, Carroll D, Bums VE, Ring C, Macleod J, Drayson M (2006) Bereavement and marriage are associated with antibody response to influenza vaccination in the elderly. Brain Behav Immun 20:279–289PubMedCrossRefGoogle Scholar
  15. 15.
    Glaser R, Kiecolt-Glaser JK (1997) Chronic stress modulates the virus-specific immune response to latent herpes simplex virus type 1. Ann Behav Med 19:78–82PubMedCrossRefGoogle Scholar
  16. 16.
    Kiecolt-Glaser JK, Glaser R, Gravenstein S, Malarkey WB, Sheridan J (1996) Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc Natl Acad Sci USA 93:3043–3047PubMedCrossRefGoogle Scholar
  17. 17.
    Clausing P, Bocker T, Diekgerdes J, Gartner K, Guttner J, Haemisch A, Veckenstedt A, Weimer A (1994) Social isolation modifies the response of mice to experimental mengo virus infection. J Exp Anim Sci 36:37–54PubMedGoogle Scholar
  18. 18.
    Radek KA, Elias P, Gallo RL (2007) Psychological and physiological stress increases susceptibility to skin infection by Group A Streptococcus due to glucocorticoid-mediated changes in innate immune function. J Invest Dermatol 127:S72Google Scholar
  19. 19.
    Pressman SD, Cohen S, Miller GE, Barkin A, Rabin BS (2005) Loneliness, social network size, and immune response to influenza vaccination in college freshmen. J Health Psychol 24:297–306CrossRefGoogle Scholar
  20. 20.
    Phillips AC, Burns VE, Carroll D, Ring C, Drayson M (2005) The association between life events, social support, and antibody status following thymus-dependent and thymus-independent vaccinations in healthy young adults. Brain Behav Immun 19:325–333PubMedCrossRefGoogle Scholar
  21. 21.
    Cohen S (2005) The Pittsburgh common cold studies: Psychosocial predictors of susceptibility to respiratory infectious illness. Int J Behav Med 12:123–131PubMedCrossRefGoogle Scholar
  22. 22.
    Glaser R, Kiecolt-Glaser JK (2005) Science and society—Stress-induced immune dysfunction: implications for health. Nat Rev Immunol 5:243–251PubMedCrossRefGoogle Scholar
  23. 23.
    Papia G, McLellan BA, El Helou P, Loiue M, Rachlis A, Szalai JP, Simor AE (1999) Infection in hospitalized trauma patients: incidence, risk factors and complications. J Trauma 47:923–927PubMedCrossRefGoogle Scholar
  24. 24.
    Caplan ES, Hoyt NJ (1985) Identification and treatment of infections in multiply traumatised patients. Am J Med 79:68–76PubMedCrossRefGoogle Scholar
  25. 25.
    Bhattacharrya T, Iorio R, Healy WL (2002) Rate of and risk factors for acute inpatient mortality after othropaedic surgery. J Bone Joint Surg Am 84:562–572Google Scholar
  26. 26.
    Nichols RL, Smith JW, Klein DB, Trunkey DD, Cooper RH, Adinolfi MF, Mills J (1984). Risk of infection after penetrating abdominal trauma. N Engl J Med 311:1065–1070PubMedCrossRefGoogle Scholar
  27. 27.
    Savill JS, Wyllie AH, Henson JE, Walport MJ, Henson PM, Haslett C (1989) Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages. J Clin Invest 83:865–875PubMedCrossRefGoogle Scholar
  28. 28.
    Scheel-Toellner D, Wang KQ, Webb PR, Wong SH, Craddock R, Assi LK, Salmon M, Lord JM (2004) Early events in spontaneous neutrophil apoptosis. Biochem Soc Trans 32:461–464PubMedCrossRefGoogle Scholar
  29. 29.
    Brach MA, deVos S, Gruss H-J, Herrmann F (1992) Prolongation of survival of human polymorphonuclear neutrophils by granulocyte-macropahge colony stimulating factor is caused by inhibition of programmed cell death. Blood 80:2920–2924PubMedGoogle Scholar
  30. 30.
    Scheel-Toellner D, Pilling D, Akbar AN, Hardie D, Lombardi G, Salmon M, Lord JM (1999) Inhibition of T cell apoptosis by IFN-beta rapidly reverses nuclear translocation of protein kinase C-delta. Eur J Immunol 29:2603–2612PubMedCrossRefGoogle Scholar
  31. 31.
    Esparza B, Sanchez H, Ruiz M, Barranquero M, Sabino E, Merino F (1996) Neutrophil function in elderly persons assessed by flow cytometry. Immunol Invest 25:185–190PubMedCrossRefGoogle Scholar
  32. 32.
    MacGregor RR, Shalit M (1990) Neutrophil function in healthy elderly subjects. J Gerontol 45:M55–M60PubMedGoogle Scholar
  33. 33.
    Rao KMK (1996) Age-related decline in ligand-induced actin polymerisation in human leukocytes and platelets. J Gerontol 41:561–566Google Scholar
  34. 34.
    Butcher SK, Chahal H, Nayak L, Sinclair A, Henriquez NV, Sapey E, O’Mahony D, Lord JM (2001) Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J. Leukocyte Biol 70:881–886PubMedGoogle Scholar
  35. 35.
    Fulop T, Komaromi I, Foris G Worum I, Leovey A (1986) Age-dependent variations of intralysosomal enzyme release from human PMN leukocytes under various stimuli. Immunobiology 171:302–310PubMedGoogle Scholar
  36. 36.
    Lipschitz DA, Udupa KB, Milton KY, Thompson CO (1984) Effect of age on hematopoieisis in man. Blood 63:502–509PubMedGoogle Scholar
  37. 37.
    Wenisch C, Patruta S, Daxbock F, Krause R, Horl W (2000) Effect of age on human neutrophil function. J Leukocyte Biol 67:40–45PubMedGoogle Scholar
  38. 38.
    Corberand J, Ngyen F, Laharrague P, Fontanilles AM, Gleyzes B, Gyrard E, Senegas C (1981) Polymorphonuclear functions and aging in humans. J Am Geriatr Soc 29:391–397PubMedGoogle Scholar
  39. 39.
    Whitelaw DA, Rayner BL, Wilcox PA (1992) Community acquired bacteremia in the elderly—a prospective study of 121 cases. J Am Geriatr Soc 40:996–1004PubMedGoogle Scholar
  40. 40.
    Fulop T, Larbi A, Douziech N, Fortin C, Guerard K-L, Lesur O, Khalil A, Dupuis G (2004) Signal transduction and functional changes in neutrophils with aging. Aging Cell 3:217–226PubMedCrossRefGoogle Scholar
  41. 41.
    Fortin CF, Larbi A, Lesur O, Douziech N, Fulop T. Jr (2006) Impairment of SHP-1 downregulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions. J Leukocyte Biol 79:1061–1072PubMedCrossRefGoogle Scholar
  42. 42.
    Emanuelli G, Lanzio M, Anfossi T, Romano S, Anfossi G, Calcamuggi G (1986) Influence of age on polymorphonuclear leukocytes in vitro: phagocytic activity in healthy human subjects. Gerontology 32:308–316PubMedGoogle Scholar
  43. 43.
    Fulop T, Foris G, Worum I, Leovey A (1985) Age-dependent alterations of Fc gamma receptor-mediated effector functions of human polymorphonuclear leucocytes, editors. Clin Exp Immunol 61:425–432PubMedGoogle Scholar
  44. 44.
    Mege JL, Capo C, Michel B, Gastaut JL, Bongrand P (1988) Phagocytic cell function in aged subjects. Neurobiol Aging 9:217–220PubMedCrossRefGoogle Scholar
  45. 45.
    McCourt M, Wang JH, Sookhai S, Redmond HP (1999) Proinflammatory mediators stimulate neutrophil-directed angiogenesis. Arch Surg 134:1325–1331PubMedCrossRefGoogle Scholar
  46. 46.
    Irwin M (1993) Stress-Induced Immune Suppression Role of the Autonomic Nervous System. Ann N Y Acad Sci 697:203–218PubMedCrossRefGoogle Scholar
  47. 47.
    Parrillo JE, Fauci AS (1979) Mechanisms of glucocorticoid action on immune processes. Annu Rev Pharmacol Toxicol 19:179–201PubMedCrossRefGoogle Scholar
  48. 48.
    Arlt W, Hewison M (2004) Hormones and immune function: implications of aging. Aging Cell 3:209–216PubMedCrossRefGoogle Scholar
  49. 49.
    Araneo B, Daynes R (1995) Dehydroepiandrosterone functions as more than an antiglucocorticoid in preserving immunocompetence after thermal injury. Endocrinology 136:393–401PubMedCrossRefGoogle Scholar
  50. 50.
    Daynes RA Dudley DJ Araneo BA (1990) Regulation of murine lymphokine production in vivo. II. Dehydroepiandrosterone is a natural enhancer of interleukin 2 synthesis by helper T cells. Eur J Immunol 20:793–802PubMedCrossRefGoogle Scholar
  51. 51.
    Padgett DA, MacCallum RC, Loria RM, Sheridan JF (2000) Androstenediol-induced restoration of responsiveness to influenza vaccination in mice. J Gerontol A Biol Sci Med Sci 55:B418–B424PubMedGoogle Scholar
  52. 52.
    Suzuki T, Suzuki N, Daynes RA, Engleman EG (1991) Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells. Clin Immunol Immunop 61:202–211CrossRefGoogle Scholar
  53. 53.
    Baulieu EE, Thomas G, Legrain S, Lahlou N, Roger M, Debuire B, Faucounau V, Girard L, Hervy MP, Latour F, Leaud MC, Mokrane A, Pitti-Ferrandi H, Trivalle C, de Lacharriere O, Nouveau S, Rakoto-Arison B, Souberbielle JC, Raison J, Le Bouc Y, Raynaud A, Girerd X, Forette F (2000) Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: Contribution of the DHEAge Study to a sociobiomedical issue. Proc Natl Acad Sci USA 97:4279–4284PubMedCrossRefGoogle Scholar
  54. 54.
    Arlt W, Callies F, Koehler I, van Vlijmen JC, Fassnacht M, Strasburger CJ, Seibel MJ, Huebler D, Ernst M, Oettel M, Reincke M, Schulte HM, Allolio B (2001) Dehydroepiandrosterone supplementation in healthy men with an age-related decline of dehydroepiandrosterone secretion. J Clin Endocrinol Metab 86:4686–4692PubMedCrossRefGoogle Scholar
  55. 55.
    Percheron G, Hogrel JY, Denot-Ledunois S, Fayet G, Forette F, Baulieu EE, Fardeau M, Marini JF (2003) Effect of 1-year oral administration of dehydroepiandrosterone to 60-to 80-year-old individuals on muscle function and cross-sectional area—A double-blind placebocontrolled trial. Arch Intern Med 163:720–727PubMedCrossRefGoogle Scholar
  56. 56.
    Nair KS, Smith G (2007) DHEA and testosterone in the elderly—reply. N Engl J Med Med 356:637Google Scholar
  57. 57.
    Viswanathan K, Dhabar FS (2005) Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. Proc Natl Acad Sci USA 102:5808–5813PubMedCrossRefGoogle Scholar
  58. 58.
    Harmsen AG, Turney TH (1985) Inhibition of in vivo neutrophil accumulation by stress. Inflammation 9:9–20PubMedCrossRefGoogle Scholar
  59. 59.
    Arber N, Berliner S, Arber L, Lipshitz A, Sinai Y, Zajicek G, Eilat Y, Pinkhas J, Aronson M (1992) The state of leukocyte adhesiveness-aggregation in the peripheral blood is more sensitive than the white blood cell count for the detection of acute mental stress. J Psychosom Res 36:37–46PubMedCrossRefGoogle Scholar
  60. 60.
    Arber N, Berliner S, Tamir A, Liberman E, Segal G, Pinkhas J, Aronson M (1991) The state of leukocyte adhesiveness-aggregation in the peripheral blood –a new and indepenednet marker of mental. Stress Medicine 7:75–78CrossRefGoogle Scholar
  61. 61.
    Steptoe A, Magid K, Edwards S, Brydon L, Hong Y, Erusalimsky J (2003) The influence of psychological stress and socioeconomic status on platelet activation in men. Atherosclerosis 168:57–63PubMedCrossRefGoogle Scholar
  62. 62.
    Lyte M, Baissa B, Nelson S (1991) Neuroendocrine examination of the social-conflict stressinduced enhancement of phagocytosis in mice. Faseb J. 5:A1386Google Scholar
  63. 63.
    Kang DH, Coe CL, McCarthy DO (1996) Academic examinations significantly impact immune responses, but not lung function, in healthy and well-managed asthmatic adolescents. Brain Behav Immun 10:164–181PubMedCrossRefGoogle Scholar
  64. 64.
    Kang DH, Coe CL, Karaszewski J, McCarthy DO (1998) Relationship of social support to stress responses and immune function in healthy and asthmatic adolescents. Res Nurs Health 21:117–128PubMedCrossRefGoogle Scholar
  65. 65.
    Kang DH, McCarthy DO (1994) The effect of psychosocial stress on neutrophil superoxide release. Res Nurs Health 17:363–370PubMedCrossRefGoogle Scholar
  66. 66.
    Campisi J, Leem TH, Fleshner M (2002) Acute stress decreases inflammation at the site of infection: A role for nitric oxide. Physiol Behav 77:291–299PubMedCrossRefGoogle Scholar
  67. 67.
    Ring C, Carroll D, Willemsen G, Cooke J, Ferraro A, Drayson M (1999) Secretory immunoglobulin A and cardiovascular activity during mental arithmetic and paced breathing. Psychophysiology 36:602–609PubMedCrossRefGoogle Scholar
  68. 68.
    Segerstrom SC, Miller GE (2004) Psychological stress and the human immune system: A meta-analytic study of 30 years of inquiry. Psychol Bull 130:601–630PubMedCrossRefGoogle Scholar
  69. 69.
    Reiche EMV, Morimoto HK, Nunes SOV (2006) Stress and depression-induced immune dysfunction: Implications for the development and progression of cancer. Int Rev Psychiatry 17:515–527CrossRefGoogle Scholar
  70. 70.
    Peake JM (2002) Exercise-induced alterations in neutrophil degranulation and respiratory burst activity: possible mechanisms of action. Exerc Immunol Rev 8:49–100PubMedGoogle Scholar
  71. 71.
    Butcher SK Killampalli V, Lascelles D, Wang K, Alpar E, Lord JM (2005) Raised cortisol: DHEAS ratios in the elderly after injury: Potential impact upon neutrophil function and immunity. Aging Cell 4:319–324PubMedCrossRefGoogle Scholar
  72. 72.
    Padgett DA, Glaser R (2003) How stress influences the immune response. Trends Immunol 24:444–448PubMedCrossRefGoogle Scholar
  73. 73.
    Weyts FAA, Flik G, Verburg-van Kemenade BML (1998) Cortisol inhibits apoptosis in carp neutrophilic granulocytes. Dev Comp Immunol 22:563–572PubMedCrossRefGoogle Scholar
  74. 74.
    Zhang XH, Moilanen E, Kankaanranta H (2001) Beclomethasone, budesonide and fluticasone propionate inhibit human neutrophil apoptosis. Eur J Pharmacol 431:365–371PubMedCrossRefGoogle Scholar
  75. 75.
    Dror Y, Ward AC, Touw IP, Freedman MH (2000) Combined corticosteroid/granulocyte colony-stimulating factor (G-CSF) therapy in the treatment of severe congenital neutropenia unresponsive to G-CSF: Activated glucocorticoid receptors synergize with G-CSF signals. Exp Hematol 28:1381–1389PubMedCrossRefGoogle Scholar
  76. 76.
    Davis KA, Fabian TC, Ragsdale DN, Trenthem LL, Croce NA, Proctor KG (2001) Combination therapy that targets secondary pulmonary changes after abdominal trauma. Shock 15:479–484PubMedCrossRefGoogle Scholar
  77. 77.
    Egger G, Aigner R, Glasner A, Hofer HP, Mitterhammer H, Zelzer S (2004) Blood polymorphonuclear leukocyte migration as a predictive marker for infections in severe trauma: comparison with various inflammation parameters. Intensive Care Med 30:331–334PubMedCrossRefGoogle Scholar
  78. 78.
    Egger G, Burda A, Mitterhammer H, Baumann G, Bratschitsch G, Glasner A (2003) Impaired blood polymorphonuclear leukocyte migration and infection risk in severe trauma. J Infect 47:148–154PubMedCrossRefGoogle Scholar
  79. 79.
    Bekesi G Kakucs R, Varbiro S, Racz K, Sprintz D, Feher J, Szekacs B (2000) In vitro effects of different steroid hormones on superoxide anion production of human neutrophil granulocytes. Steroids 65:889–894PubMedCrossRefGoogle Scholar
  80. 80.
    Wood DJ, Ions GK, Quinby JM, Gale DW, Stevens J (1992) Factors which influence mortality after subcapital hip fracture. J Bone Joint Surg 74:199–202Google Scholar
  81. 81.
    Dai YT, Wu SC, Weng R (2002) Unplanned hospital readmission and its predictors in patients with chronic conditions. J Formos Med Assoc 101:779–785PubMedGoogle Scholar
  82. 82.
    Khasraghi FA, Lee EJ, Christmas C, Wenz JF (2003) The economic impact of medical complications in geriatric patients with hip fracture. Orthopedics 26:49–53PubMedGoogle Scholar
  83. 83.
    Butcher SK, Killampalli V, Chahal H, Alpar EK, Lord JM (2003) Effect of age on susceptibility to post-traumatic infection in the elderly. Biochem Soc Trans 31:449–451PubMedCrossRefGoogle Scholar
  84. 84.
    Graham JE, Christian LM, Kiecolt-Glaser JK (2006) Stress, age, and immune function: Toward a lifespan approach. J Behav Med 29:389–400PubMedCrossRefGoogle Scholar
  85. 85.
    Laughlin GA, Barrett-Connor E (2000) Sexual dimorphism in the influence of advanced aging on adrenal hormone levels: The Rancho Bernardo Study. J J Clin Endocrinol Metab 85:3561–3568CrossRefGoogle Scholar
  86. 86.
    Orentreich N, Brind JL, Vogelman JH, Andres R, Baldwin H (1992) Long-term longitudinal measurements of plasma dehydroepiandosterone sulfate in normal men. J Clin Endocrinol Metab 75:1002–1004PubMedCrossRefGoogle Scholar
  87. 87.
    Arlt W (2004) Dehydroepiandrosterone and ageing. Best Practice Res. J Clin Endocrinol Metab 18:363–380Google Scholar
  88. 88.
    Arlt W, Martens JWM, Song MS, Wang JT, Auchus RJ, Miller WL (2002) Molecular evolution of adrenarche: Structural and functional analysis of P450c17 from four primate species. Endocrinology 143:4665–4672PubMedCrossRefGoogle Scholar
  89. 89.
    Smail PJ, Faiman C, Hobson WC, Fuller GB, Winter JSD (1982) Further studies on adrenarche in non-human primates. Endocrinology 111:844–848PubMedGoogle Scholar
  90. 90.
    Parker CR, Mixon RL, Brissie RM, Grizzle WE (1997) Aging alters zonation in the adrenal cortex of men. J Clin Endocrinol Metab 82:3898–3901PubMedCrossRefGoogle Scholar
  91. 91.
    Hornsby PJ (2002) Aging of the human adrenal cortex. Ageing Res Rev 1:229–242PubMedCrossRefGoogle Scholar
  92. 92.
    Liu CH, Laughlin GA, Fischer UG, Yen SSC (1990) Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in post-menopausal women—evidence for a reduced 17,20-Desmolase enzymatic activity. J Clin Endocrinol Metab 71:900–906PubMedGoogle Scholar
  93. 93.
    Parker CR, Slayden SM, Azziz R, Crabbe SL, Hines GA, Boots LR, Bae S (2000) Effects of aging on adrenal function in the human: responsiveness and sensitivity of adrenal androgens and cortisol to adrenocorticotropin in premenopausal and postmenopausal women. J Clin Endocrinol Metab 85:48–54PubMedCrossRefGoogle Scholar
  94. 94.
    Kudielka BM, Hellhammer J, Hellhammer DH, Wolf OT, Pirke KM, Varadi E, Pilz J, Kirschbaum C (1998) Sex differences in endocrine and psychological responses to psychosocial stress in healthy elderly subjects and the impact of a 2-week dehydroepiandrosterone treatment. J Clin Endocrinol Metab 83:1756–1761PubMedCrossRefGoogle Scholar
  95. 95.
    Arlt W, Hammer F, Sanning P, Butcher SK, Lord JM, Allolio B, Annane D, Stewart PM (2006) Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock. J Clin Endocrinol Metab 91:2548–2554PubMedCrossRefGoogle Scholar
  96. 96.
    Meikle AW, Dorchuck RW, Araneo BA, Stringham JD, Evans TG, Spruance SL, Daynes RA (1992) The presence of dehydroepiandrosterone-specific receptor binding complex in murine T-cells. J Steroid Biochem Mol Biol 42:293–304PubMedCrossRefGoogle Scholar
  97. 97.
    Okabe T, Haji M, Takayanagi R, Adachi M, Imasaki K, Kurimoto F, Watanabe T, Nawata H (1995) Up-regulation of high affinity dehydroepiandrosterone binding activity by dehydroepiandrosterone in activated human T lymphocytes. J Clin Endocrinol Metab 80:2993–2996PubMedCrossRefGoogle Scholar
  98. 98.
    Liu DM, Dillon JS (2002) Dehydroepiandrosterone activates endothelial cell nitric-oxide synthase by a specific plasma membrane receptor coupled to G alpha(i2,3). J Biol Chem 277:21379–21388PubMedCrossRefGoogle Scholar
  99. 99.
    Liu DM, Si HW, Reynolds KA, Zhen W, Jia ZQ, Dillon JS (2007) Dehydroepiandrosterone protects vascular endothelial cells against apoptosis through a G alpha(i) protein-dependent activation of phosphatidylinositol 3-kinase/Akt and regulation of antiapoptotic Bcl-2 expression. Endocrinology 148:3068–3076PubMedCrossRefGoogle Scholar
  100. 100.
    Loria RM, Padgett DA, Huynh PN (1996) Regulation of the immune response by dehydroepiandrosterone and its metabolites. J Endocrinol 150:S209–S220PubMedGoogle Scholar
  101. 101.
    Zhou ZF, Speiser PW (1999) Regulation of HSD17B1 and SRD5A1 in lymphocytes. Mol Genet Metab 68:410–417PubMedCrossRefGoogle Scholar
  102. 102.
    Zhou ZF, Shackleton CHL, Pahwa S, White PC, Speiser PW (1998) Prominent sex steroid metabolism in human lymphocytes. Mol Cell Endocrinol 138:61–69PubMedCrossRefGoogle Scholar
  103. 103.
    Schmidt M, Kreutz M, Loffler G, Scholmerich J, Straub RH (2000) Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages. J Endocrinol 164:161–169PubMedCrossRefGoogle Scholar
  104. 104.
    Hammer F, Drescher DG, Schneider SB, Quinkler M, Stewart PM, Allolio B, Arlt W (2005) Sex steroid metabolism in human peripheral blood mononuclear cells changes with aging. J Clin Endocrinol Metab 90:6283–6289PubMedCrossRefGoogle Scholar
  105. 105.
    Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM (2004) 11 beta-hydroxysteroid dehydrogenase type 1: A tissue-specific regulator of glucocorticoid response. Endocr Rev 25:831–866PubMedCrossRefGoogle Scholar
  106. 106.
    Draper N, Walker EA, Bujalska IJ, Tomlinson JW, Chalder SM, Arlt W, Lavery GG, Bedendo O, Ray DW, Laing I, Malunowicz E, White PC, Hewison M, Mason PJ, Connell JM, Shackleton CHL, Stewart PM (2003) Mutations in the genes encoding 11 beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nat Genet 34:434–439PubMedCrossRefGoogle Scholar
  107. 107.
    Lavery GG, Walker EA, Draper N, Jeyasuria P, Marcos J, Shackleton CHL, Parker KL, White PC, Stewart PM (2006) Hexose-6-phosphate dehydrogenase knock-out mice lack 11 beta-hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation. J Biol Chem 281:6546–6551PubMedCrossRefGoogle Scholar
  108. 108.
    Cooper MS, Bujalska I, Rabbitt E, Walker EA, Bland R, SHEPPARD MC, Hewison M, Stewart PM (2001) Modulation of 11 beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: An autocrine switch from glucocorticoid inactivation to activation. J Bone Miner Res 16:1037–1044PubMedCrossRefGoogle Scholar
  109. 109.
    Tomlinson JW, Moore J, Cooper MS, Bujalska I, Shahmanesh M, Burt C, Strain A, Hewison M, Stewart PM (2001) Regulation of expression of 11 beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines. Endocrinology 142:1982–1989PubMedCrossRefGoogle Scholar
  110. 110.
    Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panouraia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and antiinflammaging: A systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92–105PubMedCrossRefGoogle Scholar
  111. 111.
    Murakami K, Nakagawa T, Shozu M, Uchide K, Koike K, Inoue M (1999) Changes with aging of steroidal levels in the cerebrospinal fluid of women. Maturitas 33:71–80PubMedCrossRefGoogle Scholar
  112. 112.
    Sandeep TC, Yau JLW, MacLullich AMJ, Noble J, Deary IJ, Walker BR, Seckl JR (2004) 11 beta-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proc Natl Acad Sci USA 101:6734–6739PubMedCrossRefGoogle Scholar
  113. 113.
    Thieringer R, Le Grand CB, Carbin L, Cai TQ, Wong BM, Wright SD, Hermanowski-Vosatka A (2001) 11 beta-hydroxysteroid dehydrogenase type 1 is induced in human monocytes upon differentiation to macrophages. J Immunol 167:30–35PubMedGoogle Scholar
  114. 114.
    Freeman L, Hewison M, Hughes SV, Evans KN, Hardie D, Means TK, Chakraverty R (2005) Expression of 11 beta-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells. Blood 106:2042–2049PubMedCrossRefGoogle Scholar
  115. 115.
    Kasuya Y, Yokokawa A, Takashima S, Shibasaki H, Furuta T (2005) Use of 11 alpha-deuterium labeled cortisol as a tracer for assessing reduced 11 beta-HSD2 activity in vivo following glycyrrhetinic acid ingestion in a human subject. Steroids 70:117–125PubMedCrossRefGoogle Scholar
  116. 116.
    Tornatore KM, Logue G, Venuto RC, Davis PJ (1994) Pharmacokinetics of methylprednisolone in elderly and young healthy males. J Am Geriatr Soc 42:1118–1122PubMedGoogle Scholar
  117. 117.
    Asadullah K, Schacke H, Cato AC (2002) Dichotomy of glucocorticoid action in the immune system. Trends Immunol 23:120–122PubMedCrossRefGoogle Scholar
  118. 118.
    Rook GAW, Hernandez-Pando R, Lightman SL (1994) Hormones, peripherally activated hormones and regulation of the TH1/TH2 balance. Immunol Today 15:301–303PubMedCrossRefGoogle Scholar
  119. 119.
    Hernandez-Pando R, Streber MDL, Orozco H, Arriaga K, Pavon L, Al Nakhli SA, Rook GAW (1998) The effects of androstenediol and dehydroepiandrosterone on the course and cytokine profile of tuberculosis in BALB/c mice. Immunology 95:234–241PubMedCrossRefGoogle Scholar
  120. 120.
    Blauer KL, Poth M, Rogers WM, Bernton EW (1991) Dehydroepiandrosterone antagonizes the suppressive effects of dexamethasone in lymphocyte proliferation. Endocrinology 129:3174–3179PubMedCrossRefGoogle Scholar
  121. 121.
    Canning MO, Grotenhuis K, de Wit HJ, Drexhage HA (2000) Opposing effects of dehydroepiandrosterone and dexamethasone on the generation of monocyte-derived dendritic cells. Eur J Endocrinol 143:687–695PubMedCrossRefGoogle Scholar
  122. 122.
    Solerte SB, Fioravanti M, Vignati G, Giustina A, Cravello L, Ferrari E (1999) Dehydroepiandrosterone sulfate enhances natural killer cell cytotoxicity in humans via locally generated immunoreactive insulin-like growth factor I. J Clin Endocrinol Metab 84:3260–3267PubMedCrossRefGoogle Scholar
  123. 123.
    Straub RH, Konecna L, Hrach S, Rothe G, Kreutz M, Scholmerich J, Falk W, Lang B (1998) Serum dehydroepiandrosterone (DIEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: Possible link between endocrinosenescence and immunosenescence. J Clin Endocrinol Metab 83:2012–2017PubMedCrossRefGoogle Scholar
  124. 124.
    Gordon CM, LeBoff MS, Glowacki J (2001) Adrenal and gonadal steroids inhibit IL-6 secretion by human marrow cells. Cytokine 16:178–186PubMedCrossRefGoogle Scholar
  125. 125.
    Coles AJ, Thompson S, Cox AL, Curran S, Gurnell EM, Chatterjee VK (2005) Dehydroepiandrosterone replacement in patients with Addison’s disease has a bimodal effect on regulatory (CD4(+)CD25(hi) and CD4(+)FoxP3(+)) T cells. Eur J Immunol 35:3694–3703PubMedCrossRefGoogle Scholar
  126. 126.
    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-induced hemorrhage. Arch Surg 133:1281–1287PubMedCrossRefGoogle Scholar
  127. 127.
    Barkhausen T, Westphal BM, Puetz C, Krettek C, van Griensven M (2006) Dehydroepiandrosterone administration modulates endothelial and neutrophil adhesion molecule expression in vitro. Crit Care 10:R109 –R119PubMedCrossRefGoogle Scholar
  128. 128.
    Catania RA, Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH (1999) Dehydroepiandrosterone restores immune function following trauma-haemorrhage by a direct effect on T lymphocytes. Cytokine 11:443–450PubMedCrossRefGoogle Scholar
  129. 129.
    Gu S, Ripp SL, Prough RA, Geoghegan TE (2003) Dehydroepiandrosterone affects the expression of multiple genes in rat liver including 11 beta-hydroxysteroid dehydrogenase type 1: A cDNA array analysis. Mol Pharmacol 63:722–731PubMedCrossRefGoogle Scholar
  130. 130.
    Apostolova G, Schweizer RAS, Balazs Z, Kostadinova RM, Odermatt A (2005) Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue. Am J Physiol Endocrinol Metab 288:E957–E964PubMedCrossRefGoogle Scholar
  131. 131.
    Whorwood CB, Donovan SJ, Wood PJ, Phillips DIW (2001) Regulation of glucocorticoid receptor alpha and beta isoforms and type I 11 beta-hydroxysteroid dehydrogenase expression in human skeletal muscle cells: A key role in the pathogenesis of insulin resistance? J Clin Endocrinol Metab 86:2296–2308PubMedCrossRefGoogle Scholar
  132. 132.
    Butcher SK, Lord JM (2004) Stress responses and innate immunity: aging as a contributory factor. Aging Cell 3:151–160PubMedCrossRefGoogle Scholar
  133. 133.
    Esterling BA, KiecoltGlaser JK, Glaser R (1996) Psychosocial modulation of cytokineinduced natural killer cell activity in older adults. Psychosomatic Med 58:264–272Google Scholar
  134. 134.
    Glaser R, Sheridan J, Malarkey WB, MacCallum RC, Kiecolt-Glaser JK (2000) Chronic stress modulates the immune response to a pneumococcal pneumonia vaccine. Psychosom Med 62:804–807PubMedGoogle Scholar
  135. 135.
    Kiecolt-Glaser JK, Marucha PT, Malarkey WB, Mercado AM, Glaser R (1995) Slowing of wound healing by psychological stress. Lancet 346:1194–1196PubMedCrossRefGoogle Scholar
  136. 136.
    Vedhara K, McDermott MP, Evans TG, Treanor JJ, Plummer S, Tallon D, Cruttenden KA, Schifitto G (2002) Chronic stress in nonelderly caregivers - Psychological, endocrine and immune implications. J Psychosom Res 53:1153–1161PubMedCrossRefGoogle Scholar
  137. 137.
    Kiecolt-Glaser JK, Glaser R, Gravenstein S, Malarkey WB, Sheridan J (1996) Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc Natl Acad Sci USA 93:3043–3047PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Janet M. Lord
    • 1
  • Anna C. Phillips
    • 2
  • Wiebke Arlt
    • 3
  1. 1.MRC Centre for Immune Regulation, Division of Immunity and InfectionBirmingham University Medical SchoolBirminghamUK
  2. 2.School of Sport and Exercise ScienceBirmingham University Medical SchoolBirminghamUK
  3. 3.Division of Medical SciencesUniversity of BirminghamBirminghamUK

Personalised recommendations