Skip to main content
SpringerLink
Log in

Effects of aging and menopause on serum interleukin-6 levels and peripheral blood mononuclear cell cytokine production in healthy nonobese women

  • Published:
AGE Aims and scope Submit manuscript

Abstract

Inappropriate interleukin-6 production is thought to play a role in the development of several age-related conditions including atherosclerosis. This study aimed to determine whether aging affects circulating interleukin-6 (IL-6) levels. Healthy, nonobese women (n = 208, 44.5 ± 0.70 years, 22.4 ± 0.17 kg/m2) were categorized into four age groups (22–31, 32–41, 42–51, and 52–63 years; cross-sectional study). Cytokine levels in serum and those produced from peripheral blood mononuclear cell (PBMC) were measured. The oldest group had the highest circulating levels of IL-6 and oxidized low-density lipoprotein (ox-LDL) and higher PBMC production of IL-6, tumor necrosis factor-α (TNF-α), and interleukin-1 alpha (IL-1β). Additionally, significant interactions between age and menopause were found for serum IL-6 (P = 0.024), and TNF-α (P = 0.011) and IL-1β (P < 0.001) produced from PBMCs. Serum IL-6 levels positively correlated with age, waist–hip ratio (WHR), systolic blood pressure, circulating levels of TNF-α, IL-1β, and ox-LDL, and urinary 8-epi-prostaglandin F2α. Multiple stepwise regression models identified the following factors for contributing to serum IL-6 levels: serum IL-1β, menopause status, WHR, and serum TNF-α in mode I (R 2 = 0.302); serum IL-1β, age, serum TNF-α, and WHR (β = 0.197; P = 0.006) in model II (R 2 = 0.283). Sub-analysis was performed according to menopausal status. Serum IL-6 levels were positively associated with levels of IL-6, TNF-α, and IL-1β in PBMC supernatants (unstimulated) from postmenopausal women, whereas these were negatively associated in premenopausal women. In conclusion, circulating IL-6 levels may be interactively influenced by age and menopause. Additionally, estrogen deprivation after menopause may enhance PBMC cytokine production in postmenopausal women, resulting in increased IL-6 levels which are closely related to oxidative stress.

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

Similar content being viewed by others

References

  • Abrahamsen B, Bonnevie-Nielsen V, Ebbesen EN, Gram J, Beck-Nielsen H (2000) Cytokines and bone loss in a 5-year longitudinal study—hormone replacement therapy suppresses serum soluble interleukin-6 receptor and increases interleukin-1-receptor antagonist: the Danish Osteoporosis Prevention Study. J Bone Miner Res 15:1545–1554

    Article  PubMed  CAS  Google Scholar 

  • Ahluwalia N, Mastro AM, Ball R, Miles MP, Rajendra R, Handte G (2001) Cytokine production by stimulated mononuclear cells did not change with aging in apparently healthy, well-nourished women. Mech Ageing Dev 122:1269–1279

    Article  PubMed  CAS  Google Scholar 

  • Barton BE (1996) The biological effects of interleukin 6. Med Res Rev 16:87–109

    Article  PubMed  CAS  Google Scholar 

  • Brüünsgaard H, Pedersen AN, Schroll M, Skinhoj P, Pedersen BK (1999) Impaired production of proinflammatory cytokines in response to lipopolysaccharide (LPS) stimulation in elderly humans. Clin Exp Immunol 118:235–241

    Article  PubMed  Google Scholar 

  • Brüünsgaard H, Pedersen BK (2003) Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am 23:15–39

    Article  PubMed  Google Scholar 

  • Brüünsgaard H, Pedersen M, Pedersen BK (2001) Aging and proinflammatory cytokines. Curr Opin Hematol 8:131–136

    Article  PubMed  Google Scholar 

  • Cioffi M, Esposito K, Vietri MT et al (2002) Cytocine pattern in postmenopause. Maturitas 41:187–192

    Article  PubMed  CAS  Google Scholar 

  • Deshpande R, Khalili H, Pergolizzi RG, Michael SD, Chang MD (1997) Estradiol down-regulates LPS-induced cytokine production and NF-κB activation in murine macrophages. Am J Reprod Immunol 38:46–54

    Article  PubMed  CAS  Google Scholar 

  • Ershler WB (1993) Interleukin-6: a cytokine for gerontologists. J Am Geriatr Soc 41:176–181

    PubMed  CAS  Google Scholar 

  • Ershler WB, Keller ET (2000) Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 51:245–270

    Article  PubMed  CAS  Google Scholar 

  • Federico A, Morgillo F, Tuccillo C, Ciardiello F, Loguercio C (2007) Chronic inflammation and oxidative stress in human carcinogenesis. Int J Cancer 121:2381–2386

    Article  PubMed  CAS  Google Scholar 

  • Ferrucci L, Corsi A, Lauretani F et al (2005) The origins of age-related proinflammatory state. Blood 105:2294–2299

    Article  PubMed  CAS  Google Scholar 

  • Forsey RJ, Thompson JM, Ernerudh J et al (2003) Plasma cytokine profiles in elderly humans. Mech Ageing Dev 124:487–493

    Article  PubMed  CAS  Google Scholar 

  • Gameiro CM, Romão F, Castelo-Branco C (2010) Menopause and aging: changes in the immune system—a review. Maturitas 67:316–320

    Article  PubMed  CAS  Google Scholar 

  • Girasole G, Giuliani N, Modena AB, Passeri G, Pedrazzoni M (1990) Oestrogens prevent the increase of human serum soluble interleukin-6 receptor induced by ovariectomy in vivo and decrease its release in human osteoblastic cells in vitro. Clin Endocrinol 51:801–807

    Article  Google Scholar 

  • Giuliani N, Sansoni P, Girasole G et al (2001) Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes. Exp Gerontol 36:547–557

    Article  PubMed  CAS  Google Scholar 

  • Jang Y, Kim JY, Kim OY et al (2004) The −1131 T- > C polymorphism in the apolipoprotein A5 gene is associated with postprandial hypertriacylglycerolemia; elevated small, dense LDL concentrations; and oxidative stress in nonobese Korean men. Am J Clin Nutr 80:832–840

    PubMed  CAS  Google Scholar 

  • Jilka RL, Hangoc G, Girasole G et al (1992) Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 257:88–91

    Article  PubMed  CAS  Google Scholar 

  • Kallen KJ (2002) The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases. Biochim Biophys Acta 1592:323–343

    Article  PubMed  CAS  Google Scholar 

  • Kamada M, Irahara M, Maegawa M et al (2001) Postmenopausal changes in serum cytokine levels and hormone replacement therapy. Am J Obstet Gynecol 184:309–314

    Article  PubMed  CAS  Google Scholar 

  • Kim JY, Hyun YJ, Jang Y et al (2008) Lipoprotein-associated phospholipase A2 activity is associated with coronary artery disease and markers of oxidative stress: a case–control study. Am J Clin Nutr 88:630–637

    PubMed  CAS  Google Scholar 

  • Liu H, Liu K, Bodenner DL (2005) Estrogen receptor inhibits interleukin-6 gene expression by disruption of nuclear factor-κB transactivation. Cytokine 31:251–257

    Article  PubMed  CAS  Google Scholar 

  • Massy ZA, Kim Y, Guijarro C, Kasiske BL, Keane WF, O'Donnell MP (2000) Low-density lipoprotein-induced expression of interleukin-6, a marker of human mesangial cell inflammation: effects of oxidation and modulation by lovastatin. Biochem Biophys Res Commun 67:536–540

    Article  Google Scholar 

  • Migliaccio E, Giorgio M, Mele S et al (1999) The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402:309–313

    Article  PubMed  CAS  Google Scholar 

  • Napoli C, Martin-Padura I, de Nigris F et al (2003) Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet. Proc Natl Acad Sci USA 100:2112–2116

    Article  PubMed  CAS  Google Scholar 

  • Oka H, Ikeda S, Koga S, Miyahara Y, Kohno S (2008) Atorvastatin induces associated reductions in platelet P-selectin, oxidized low-density lipoprotein, and interleukin-6 in patients with coronary artery diseases. Heart Vessels 23:249–256

    Article  PubMed  Google Scholar 

  • Pantsulaia I, Trofimov S, Kobyliansky E, Livshits G (2002) Genetic and environmental influences on IL-6 and TNF-alpha plasma levels in apparently healthy general population. Cytokine 19:138–146

    Article  PubMed  CAS  Google Scholar 

  • Papanicolaou DA, Vgontzas AN (2000) Interleukin-6: the endocrine cytokine. J Clin Endocrinol Metab 85:1331–1332

    Article  PubMed  CAS  Google Scholar 

  • Poli V, Balena R, Fattori E et al (1994) Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J 13:1189–1196

    PubMed  CAS  Google Scholar 

  • Rachoń D, Myśliwska J, Suchecka-Rachoń K, Wieckiewicz J, Myśliwski A (2002) Effects of oestrogen deprivation on interleukin-6 production by peripheral blood mononuclear cells of postmenopausal women. J Endocrinol 172:387–395

    Article  PubMed  Google Scholar 

  • Ray P, Ghosh SK, Zhang DH, Ray A (1997) Repression of interleukin-6 gene expression by 17 b-estradiol: inhibition of the DNA-binding activity of the transcription factors NF-IL6 and NF-κB by the estrogen receptor. FEBS Lett 409:79–85

    Article  PubMed  CAS  Google Scholar 

  • Riancho JA, Zarrabeitia MT, Amado JA, Olmos JM, González-Macías J (1994) Age-related differences in cytokine secretion. Gerontology 40:8–12

    Article  PubMed  CAS  Google Scholar 

  • Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101:1767–1772

    PubMed  CAS  Google Scholar 

  • Roberts LJ 2nd, Morrow JD (2002) Products of the isoprostane pathway: unique bioactive compounds and markers of lipid peroxidation. Cell Mol Life Sci 59:808–820

    Article  PubMed  CAS  Google Scholar 

  • Roubenoff R, Harris TB, Abad LW, Wilson PW, Dallal GE, Dinarello CA (1998) Monocyte cytokine production in an elderly population: effect of age and inflammation. J Gerontol A Biol Sci Med Sci 53:M20–M26

    Article  PubMed  CAS  Google Scholar 

  • Scheidt-Nave C, Bismar H, Leidig-Bruckner G et al (2001) Serum interleukin 6 is a major predictor of bone loss in women specific to the first decade past menopause. J Clin Endocrinol Metab 86:2032–2042

    Article  PubMed  CAS  Google Scholar 

  • Shoelson SE, Lee J, Yuan M (2003) Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int J Obes Relat Metab Disord 27:S49–S52

    Article  PubMed  CAS  Google Scholar 

  • Singh U, Devaraj S, Jialal I (2005) Vitamin E, oxidative stress, and inflammation. Annu Rev Nutr 25:151–174

    Article  PubMed  CAS  Google Scholar 

  • Taddei S, Virdis A, Ghiadoni L et al (2001) Age-related reduction of NO availability and oxidative stress in humans. Hypertension 38:274–279

    PubMed  CAS  Google Scholar 

  • Tamura T, Udagawa N, Takahashi N et al (1993) Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci USA 90:11924–11928

    Article  PubMed  CAS  Google Scholar 

  • Thomas CE, Jackson RL, Ohlweiler DF, Ku G (1994) Multiple lipid oxidation products in low density lipoproteins induce interleukin-1 beta release from human blood mononuclear cells. J Lipid Res 35:417–427

    PubMed  CAS  Google Scholar 

  • Volpato S, Guralnik JM, Ferrucci L et al (2001) Cardiovascular disease, interleukin-6, and risk of mortality in older women: the women's health and aging study. Circulation 103:947–953

    PubMed  CAS  Google Scholar 

  • von Haehling S, Genth-Zotz S, Sharma R et al (2003) The relationship between age and production of tumour necrosis factor-alpha in healthy volunteers and patients with chronic heart failure. Int J Cardiol 90:197–204

    Article  Google Scholar 

  • Yasui T, Maegawa M, Tomita J et al (2007) Changes in serum cytokine concentrationsduring the menopausal transition. Maturitas 56:396–403

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank the research volunteers who participated in the studies described in this report. This study was supported by the National Research Foundation of Korea (M10642120002-06N4212-00210, 2010-0015017, 2010-0000317, and 2010-0011003), Republic of Korea. All the authors were involved in the development of the study protocol and the experimental design.

Author information

Authors and Affiliations

  1. Yonsei University Research Institute of Science for Aging, Yonsei University, Seoul, South Korea

    Oh Yoen Kim, Jey Sook Chae, Jean Kyung Paik, Yangsoo Jang & Jong Ho Lee

  2. National Research Laboratory for Clinical Nutrigenetics/Nutrigenomics, Department of Food and Nutrition, Yonsei University, Seoul, South Korea

    Oh Yoen Kim, Jey Sook Chae, Jean Kyung Paik, Hee Sun Seo & Jong Ho Lee

  3. Cardiology Division, Yonsei University College of Medicine, Seoul, South Korea

    Yangsoo Jang

  4. Cardiovascular Genome Center, Yonsei University College of Medicine, Seoul, South Korea

    Yangsoo Jang

  5. Severance Medical Research Institute, Yonsei University College of Medicine, Seoul, South Korea

    Yangsoo Jang

  6. Unit Cytokines and Inflammation, Institut Pasteur, 28 rue Dr, Roux, Paris, France

    Jean-Marc Cavaillon

  7. Department of Food and Nutrition, College of Human Ecology, Yonsei University, 134 Shinchon-Ding, Sudaemun-Gu, Seoul, 120-749, South Korea

    Jong Ho Lee

Authors
  1. Oh Yoen Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jey Sook Chae
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean Kyung Paik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hee Sun Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yangsoo Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-Marc Cavaillon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jong Ho Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jong Ho Lee.

Additional information

Oh Yoen Kim and Jey Sook Chae equally contributed to this work.

About this article

Cite this article

Kim, O.Y., Chae, J.S., Paik, J.K. et al. Effects of aging and menopause on serum interleukin-6 levels and peripheral blood mononuclear cell cytokine production in healthy nonobese women. AGE 34, 415–425 (2012). https://doi.org/10.1007/s11357-011-9244-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-011-9244-2

Keywords

Search

Navigation