, Volume 3, Issue 5, pp 271–290 | Cite as

Age-related changes in Type 1 and Type 2 cytokine production in humans



Although aging is accompanied by several changes in immune function, altered T cell function represents the most consistent and dramatic change. Since cytokines modulate the immune response, it has been postulated that these age-associated changes in T cell function may be due to alterations in cytokine production. Data from murine studies generally support an age-related shift from a Th1-like (IL-2, IFN-γ) to a Th2-like (IL-4, IL-6,IL-10) cytokine response; however, whether or not such an age-related shift to a Type 2 cytokine response occurs in humans is not certain. This review of over 60 studies in humans, in which Type 1 and Type 2 cytokines were evaluated either alone or together, suggests that age-associated changes in cytokine production are inconsistent. Further, these age-associated changes in cytokine production do not always induce a shift to a Type 2 cytokine response. Importantly, these studies highlight that the stimulus used to induce cytokines influences both the level and pattern of immune response. Additional comprehensive evaluations in human studies are both critical and necessary to clearly identify the impact of altered cytokine production on age-related changes in immune function.

aging cell-mediated response humans humoral response immunity Type 1 cytokines Type 2 cytokines 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adibzadeh M, Pohla H, Rehbein A and Pawelec G (1995) Longterm culture of monoclonal human T lymphocytes: models for immunosenescence? Mech Ageing Dev 83: 171-183PubMedCrossRefGoogle Scholar
  2. Albright JW, Zuiga-Pflcker JC and Albright JF (1995) Transcriptional control of IL-2 and IL-4 in T cells of young and old mice. Cell Immunol 164: 170-175PubMedCrossRefGoogle Scholar
  3. Al-Rayes H, Pachas W, Mirza N, Ahern DJ, Geha RS and Vercelli D (1992) IgE regulation and lymphokine patterns in aging humans. J Allerg Clin Immunol 90: 630-636CrossRefGoogle Scholar
  4. Barcellini W, Borghi MO, Sguotti C, Palmieri R, Frasca D, Meroni PL, Doria G and Zanussi C (1988) Heterogeneity of immune responsiveness in healthy elderly subjects. Clin Immunol Immunopath 47: 142-151CrossRefGoogle Scholar
  5. Beharka AA, Meydani M, Wu D, Leka LS, Meydani A and Meydani SN (2001) Interleukin-6 production does not increase with age. J Gerontol Biol Sci 56A: B81-B88Google Scholar
  6. Bernstein ED and Murasko DM (1998) Effect of age on cytokine production in humans. Age 21: 137-151CrossRefGoogle Scholar
  7. Bernstein ED, Gardner EM, Abrutyn E, Gross P and Murasko DM (1998) Cytokine production after influenza vaccination in a healthy elderly population. Vaccine 16: 1722-1731PubMedCrossRefGoogle Scholar
  8. Bodnar Z, Steger MM, Saurwein-Teissl M, Maczek C and Grubeck-Loebenstein B (1997) Cytokine production in response to stimulation with tetanus toxoid, mycobacterium tuberculosis and influenza antigens in peripheral blood mononuclear cells and T cell lines from healthy elderlies. Intern Arch Allergy Immunol 112: 323-330Google Scholar
  9. Born J, Uthgenannt D, Dodt C, Nunninghoff D, Ringvolt E, Wagner T and Fehm HL (1995) Cytokine production and lymphocyte subpopulations in aged humans. An assessment during nocturnal sleep. Mech Ageing Dev 84: 113-126PubMedCrossRefGoogle Scholar
  10. Bruunsgaard H, Pedersen AN, Schroll M, Skinhoj P and Pedersen BK (2000) Proliferative responses of blood mononuclear cells (BMNC) in a cohort of elderly humans: role of lymphocyte phenotype and cytokine production. Clin Exp Immunol 119: 433-440PubMedCrossRefGoogle Scholar
  11. Cakman I, Rohwer J, Schutz RM, Kirchner H and Rink L (1996) Dysregulation between TH1 and TH2 T cell subpopulations in the elderly. Mech Ageing Dev 87: 197-209PubMedCrossRefGoogle Scholar
  12. Candore G, DiLorenzo G, Melluso M, Cigna D, Colucci AT, Modica MA and Caruso C (1993): γ-interferon, interleukin-4 and interleukin-6 vitro production in old subjects. Autoimmunity 16: 275-280PubMedGoogle Scholar
  13. Castle S, Uyemura K, Wong W, Modlin R and Effros R (1997) Evidence of enhanced type 2 immune response and impaired upregulation of a type 1 response in frail elderly nursing home residents. Mech Ageing Dev 94: 7-16PubMedCrossRefGoogle Scholar
  14. Castle SC, Uyemura K, Crawford W, Wong W, Klaustermeyer WB and Makinodan T (1999) Age-related impaired proliferation of peripheral blood mononuclear cells is associated with an increase in both IL-10 and IL-12. Exp Gerontol 34: 243-252PubMedCrossRefGoogle Scholar
  15. Cohen HJ (1999) Oncology and aging: General principles of cancer in the elderly In: Hazard WR et al. (eds) Principles of Geriatric Medicine and Gerontology: 117-130. McGraw-Hill, New YorkGoogle Scholar
  16. Ershler WB (1993) Interleukin-6: a cytokine for gerontologists. J Am Ger Soc 41: 176-181Google Scholar
  17. Ershler WB, Sun WH, Binkley N, Gravenstein S, Volk MJ, Kamoske G, Klopp RG, Roecker EB, Daynes RA and Weindruch R (1993) Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and vitro production is modifiable by dietary restriction. Lymph Cytokine Res 12: 225-230Google Scholar
  18. Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, Monti D, Franceschi C and Paganelli R (1993) Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 23: 2375-2378PubMedGoogle Scholar
  19. Gillis S, Kozak R, Durante M and Weksler ME (1981) Immunological studies of aging. Decreased production of and response to T cell growth factor by lymphocytes from aged humans. J Clin Invest 67: 937-942PubMedGoogle Scholar
  20. Hessen MT, Kaye D and Murasko DM (1991) Heterogeneous effects of exogenous lymphokines on lymphoproliferation of elderly subjects. Mech Aging Dev 58: 61-73PubMedCrossRefGoogle Scholar
  21. Hobbs MV, Weigle WO, Noonan DJ, Torbett BE, McEvilly RJ, Koch RJ, Cardenas GJ and Ernst DN (1993) Patterns of cytokine gene expression by CD4+ T cells from young and old mice. J Immunol 150: 3602-3614PubMedGoogle Scholar
  22. Hobbs MV, Weigle WO and Ernst D (1994) Interleukin-10 production by splenic CD4+ cells and cell subsets from young and old mice. Cell Immunol 154: 264-272PubMedCrossRefGoogle Scholar
  23. Holbrook NJ, Chopra RK, McCoy MT, Nagel JE, Powers DC, Adler WH and Schneider EL (1989) Expression of interleukin-2 and the interleukin-2 receptor in aging rats. Cell Immunol 120: 1-9PubMedCrossRefGoogle Scholar
  24. James K, Premchand N, Skibinska A, Skibinski G, Nicol M and Mason JI (1997) IL-6, DHEA and the ageing process. Mech Ageing Dev 93: 15-24PubMedCrossRefGoogle Scholar
  25. Kania DM, Binkley N, Checovich M, Havighurst T, Schilling M and Ershler WB (1995) Elevated plasma levels of interleukin-6 in postmenopausal women do not correlate with bone density. J Am Ger Soc 43: 236-239Google Scholar
  26. Karanfilov CI, Liu B, Fox CC, Lakshmanan RR and Whisler RL (1999) Age-related defects in Th1 and Th2 cytokine production by human T cells can be dissociated from altered frequencies of CD45RA+ and CD45RO+ T cell subsets. Mech Ageing Dev 109: 97-112PubMedCrossRefGoogle Scholar
  27. Kuby J (1997) Immunology. New York, WH Freeman and Company.Google Scholar
  28. Ligthart GJ, Coberand JX, Geertzen HGM, Meinders AE, Knook DL and Hijmins W (1990) Necessity of the assessment of health status in human immunogerontological studies: evaluation of the SENIEUR protocol. Mech Ageing Dev 55: 89-105PubMedCrossRefGoogle Scholar
  29. Lio D, D'Anna C, Gervasi F, Scola L, Potestio M, DiLorenzo G, Listi F, Colombo A, Candore G, Caruso C (1998) Interleukin-12 release by mitogen-stimulated mononuclear cells in the elderly. Mech Ageing Dev 102: 211-219PubMedCrossRefGoogle Scholar
  30. Lio D, Balistreri CR, Candore G, D'Anna C, DiLorenzo G, Gervasi F, Listi F, Scola L and Caruso C (2000) In vitro treatment with interleukin-2 normalizes type-1 cytokine production by lymphocytes from elderly. Immunopharmacol Immunotoxicol 22: 195-203PubMedGoogle Scholar
  31. Llorente L, Richaud-Patin Y, Alvarado C, Vidaller A and Jakez-Ocampo J (1997) Autoantibody production in healthy elderly people is not promoted by interleukin-10 although this cytokine is expressed in them by a peculiar CD8+CD3+ large granular cell subpopulation. Scand J Immunol 45: 401-407PubMedCrossRefGoogle Scholar
  32. Lombard PR and Steiner G (1992) Preliminary report on cytokine determination in human synovial fluids: a consensus study of the European Workshop for Rheumatology Research. Clin Exp Rheumat 10: 515-520Google Scholar
  33. Lung TL, Saurwein-Teissi M, Parson W, Schonitzer D and Grubeck-Loebenstein B (2000) Unimpaired dendritic cells can be derived from monocytes in old age and can mobilize residual function in senescent T cells. Vaccine 18: 1606-1612PubMedCrossRefGoogle Scholar
  34. McElhaney JE, Beattie BL, Devine R, Grynoch R, Toth EL and Bleackley RC (1990) Age-related decline in interleukin 2 production in response to influenza vaccine. J Am Ger Soc 38: 652-658Google Scholar
  35. McElhaney JE, Meneilly GS, Beattie BL, Helgason CD, Lee SF, Devine RD and Bleackley RC (1992) The effect of influenza vaccination on IL2 production in healthy elderly: implications for current vaccination practices. J Gerontol 47: M3-M8PubMedGoogle Scholar
  36. McElhaney JE, Meneilly GS, Pinkoski MJ, Lechelt KE and Bleackley RC (1995) Vaccine-related determinants of the interleukin-2 response to influenza vaccination in healthy young and elderly adults. Vaccine 13: 6-10PubMedCrossRefGoogle Scholar
  37. Miller RA (1996) The aging immune system: primer and prospectus. Science 273: 70-74PubMedGoogle Scholar
  38. Molteni M, Della Bella S, Mascagni B, Coppola C, De Micheli V, Zulian C, Birindelli S, Vanoli M and Scorza R (1994) Secretion of cytokines upon allogeneic stimulation: effect of aging. J Biol Regul Homeostatic Agents 8: 41-47Google Scholar
  39. Murasko DM, Weiner P and Kaye D (1987) Decline in mitogen induced proliferation in the increasing age. Clin Exp Immunol 70: 440-448PubMedGoogle Scholar
  40. Murasko DM and Goonewardene IM (1990) T-cell function in aging: mechanisms of decline. Ann Rev Gerontol Geriat 10: 71-96Google Scholar
  41. Murasko DM, Nelson BJ, Matour D, Goonewardene IM and Kaye D (1991) Heterogeneity of changes in lymphoproliferative ability with increasing age. Exper Gerontol 26: 269-279CrossRefGoogle Scholar
  42. Murasko DM, Bernstein ED, Gardner EM, Gross P, Munk G, Dran S and Abrutyn E (2001) Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly. Exp Gerontol 37: 427-439CrossRefGoogle Scholar
  43. Mysliwska J, Bryl E, Foerster J and Mysliwski A (1998) Increase of interleukin 6 and decrease of interleukin 2 production during the ageing process are influenced by the health status. Mech Ageing Dev 100: 313-328PubMedCrossRefGoogle Scholar
  44. Nagel JE, Chopra RK, Chrest FJ, McCoy MT, Schneider EL, Holbrook NJ and Adler WH (1988) Decreased proliferation, interleukin 2 synthesis, and interleukin 2 receptor expression are accompanied by decreased mRNA expression in phytohemagglutinin-stimulated cells from elderly donors. J Clin Invest 81: 1096-1102PubMedCrossRefGoogle Scholar
  45. Nijhuis EW, Remarque EJ, Hinloopen B, Van Der Pouw-Kraan T, Van Lier RA, Ligthart GJ and Nagelkerken L (1994) Age-related increase in the fraction of CD27-CD4+ T cells and IL-4 production as a feature of CD4+ T cell differentiation in vivo. Clin Exp Immunol 96: 528-534PubMedCrossRefGoogle Scholar
  46. Orson FM, Saadeh CK, Lewis DE and Nelson DL (1989) Interleukin 2 receptor expression by T cells in human aging. Cell Immunol 124: 278-291PubMedCrossRefGoogle Scholar
  47. Peterson PK, Chao CC, Carson P, Hu S, Nichol K and Janoff EN (1994) Levels of tumor necrosis factor, interleukin 6, interleukin 10, and transforming growth factor are normal in the serum of the healthy elderly. Clin Infect Dis 19: 1158-1159PubMedGoogle Scholar
  48. Quyang Q, Cicek G, Westendorp RGJ, Cools HJM, Van der Klis RJ and Remarque EJ (2000) Reduced IFNγ production in elderly people following vitro stimulation with influenza vaccine and endotoxin. Mech Ageing Dev 121: 131-137Google Scholar
  49. Rabinowich H, Goses Y, Reshef T and Klajman A (1985) Interleukin-2 production and activity in aged humans. Mech Ageing Dev 32: 213-226PubMedCrossRefGoogle Scholar
  50. Reiner SL and Locksley RM (1995) The regulation of immunity to Leishmania major. Ann Rev Immunol 13: 151-179CrossRefGoogle Scholar
  51. Sakata-Kaneko S, Wakatsuki Y, Matsunaga Y, Usui T and Kita T (2000) Altered Th1/Th2 commitment in human CD4+ T cells with ageing. Clin Exp Immunol 120: 267-273PubMedCrossRefGoogle Scholar
  52. Salkind AR (1994) Influence of age on the production of Fos and Jun by influenza virus-exposed T cells. J Leuk Biol 56: 817-820Google Scholar
  53. Saurwein-Teissi M, Blasko I, Zisterer K, Neuman B, Lang B and Grubeck-Loebenstein B (2000) An imbalance between pro-and anti-inflammatory cytokines, a characteristic feature of old age. Cytokine 12: 1160-1161CrossRefGoogle Scholar
  54. Scheffer C, Zawotzky R and Rink L (2000) Interferon-γ levels finally become stable with increasing age as revealed by using an ELISA corresponding to the bioactivity. Mech Ageing Dev 121: 47-58PubMedCrossRefGoogle Scholar
  55. Schwab R, Pfeffer LM, Szabo P, Gamble D, Schnurr CM and Weksler ME (1990) Defective expression of high affinity IL-2 receptors on activated T cells from aged humans. Intern Immunol 2: 239-246Google Scholar
  56. Shearer GM (1997) Th1/Th2 changes in aging. Mech Ageing Dev 94: 1-5PubMedCrossRefGoogle Scholar
  57. Sindermann J, Kruse A, Frercks HJ, Schultz RM and Kirchner H (1993) Investigations of the lymphokine system in elderly individuals. Mech Ageing Dev 70: 149-159PubMedCrossRefGoogle Scholar
  58. Song LJ, Nagel JE, Chrest FJ, Collins GD and Adler WH (1992) Comparison of CD3 and CD2 activation pathways in T cells from young and elderly adults. Aging 4: 307-315PubMedGoogle Scholar
  59. Song L, Kim YH, Chopra RK, Proust JJ, Nagel JE, Nordin AA and Adler WH (1993) Age-related effects in T cell activation and proliferation. Exp Gerontol 28: 313-321PubMedCrossRefGoogle Scholar
  60. Vallejo AN, Brandes JC, Weyand CM and Goronzy JJ (1999) Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence. J Immunol 162: 6572-6579PubMedGoogle Scholar
  61. Weifeng C, Schulin L, Xinomei G and Xuewen F (1986) The capacity of lymphocyte production by peripheral blood lymphocytes from aged humans. Immunolog Invest 15: 575-583Google Scholar
  62. Weyand CM, Brandes JC, Schmidt D, Fulbright JW and Goronzy JJ (1998) Functional properties of CD4+ CD28-T cells in the aging immune system. Mech Ageing Dev 102: 131-147PubMedCrossRefGoogle Scholar
  63. Wu D, Meydani SN, Sastre J, Hayek M and Meydani M (1994) In vitro glutathione supplementation enhances interleukin-2 production and mitogenic response of peripheral blood mononuclear cells from young and old subjects. J Nutr 124: 655-663PubMedGoogle Scholar
  64. Xu X, Beckman I and Bradley J (1993) Age-related changes in the expression of IL-2 and high-affinity IL-2-binding sites. Intern Arch Allergy Immunol 102: 224-231Google Scholar
  65. Yen CJ, Lin SL, Huang KT and Lin RH (2000) Age-associated changes in interferon-γ and interleukin-4 secretion by purified human CD4+ and CD8+ T cells. J Biomed Sci 7: 317-321PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  1. 1.Department of Microbiology and ImmunologyMCP Hahnemann University School of MedicinePhiladelphiaUSA

Personalised recommendations