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. 1996 Mar;64(3):769–774. doi: 10.1128/iai.64.3.769-774.1996

Lipopolysaccharide-induced lethality and cytokine production in aged mice.

K Tateda 1, T Matsumoto 1, S Miyazaki 1, K Yamaguchi 1
PMCID: PMC173836  PMID: 8641780

Abstract

This study was designed to define the lipopolysaccharide (LPS) sensitivity of aged mice in terms of lethality and cytokine production and to determine down-regulating responses of corticosterone and interleukin 10 (IL-10). The 50% lethal doses of LPS in young (6- to 7-week-old) and aged (98- to 102-week-old) mice were 601 and 93 microg per mouse (25.6 and 1.6 mg per kg of body weight), respectively. Aged mice were approximately 6.5-fold more sensitive to the lethal toxicity of LPS in micrograms per mouse (16-fold more sensitive in milligrams per kilogram) than young mice. Levels in sera of tumor necrosis factor-alpha (TNF-alpha) IL-1alpha, and IL-6 after intraperitoneal injection of 100 microg of LPS peaked at 1.5, 3, and 3 h, respectively, and declined thereafter in both groups of mice. However, the peak values of these cytokines were significantly higher in aged than in young mice (P < 0.05). Gamma interferon (IFN-gamma) was detectable at 3 h, and sustained high levels were still detected after 12 h in both age groups. Although there were no significant differences in levels of IFN-gamma in sera from both groups, aged mice showed higher IFN-gamma levels throughout the 3- to 12-h study period. Administration of increasing doses of LPS revealed that aged mice had a lower threshold to IL-1alpha production than young mice. In addition, aged mice were approximately 4-fold more sensitive to the lethal toxicity of exogenous TNF in units per mouse (10-fold more sensitive in units per kilogram) than young mice. With regard to down-regulating factors, corticosterone amounts were similar at basal levels and no differences in kinetics after the LPS challenge were observed, whereas IL-10 levels in sera were significantly higher in aged mice at 1.5 and 3 h than in young mice (P < 0.01). These results indicate that aged mice are more sensitive to the lethal toxicities of LPS and TNF than young mice. We conclude that a relatively activated, or primed, state for LPS-induced cytokine production, in spite of full down-regulating responses by corticosterone and IL- 10, may explain at least in part LPS sensitivity in aged mice.

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Selected References

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  1. Alexander H. R., Doherty G. M., Buresh C. M., Venzon D. J., Norton J. A. A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. J Exp Med. 1991 Apr 1;173(4):1029–1032. doi: 10.1084/jem.173.4.1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bertini R., Bianchi M., Ghezzi P. Adrenalectomy sensitizes mice to the lethal effects of interleukin 1 and tumor necrosis factor. J Exp Med. 1988 May 1;167(5):1708–1712. doi: 10.1084/jem.167.5.1708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Besedovsky H. O., del Rey A., Klusman I., Furukawa H., Monge Arditi G., Kabiersch A. Cytokines as modulators of the hypothalamus-pituitary-adrenal axis. J Steroid Biochem Mol Biol. 1991;40(4-6):613–618. doi: 10.1016/0960-0760(91)90284-c. [DOI] [PubMed] [Google Scholar]
  4. Besedovsky H., del Rey A., Sorkin E., Dinarello C. A. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science. 1986 Aug 8;233(4764):652–654. doi: 10.1126/science.3014662. [DOI] [PubMed] [Google Scholar]
  5. Beutler B., Krochin N., Milsark I. W., Luedke C., Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986 May 23;232(4753):977–980. doi: 10.1126/science.3754653. [DOI] [PubMed] [Google Scholar]
  6. Beutler B., Milsark I. W., Cerami A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. doi: 10.1126/science.3895437. [DOI] [PubMed] [Google Scholar]
  7. Black P. H. Immune system-central nervous system interactions: effect and immunomodulatory consequences of immune system mediators on the brain. Antimicrob Agents Chemother. 1994 Jan;38(1):7–12. doi: 10.1128/aac.38.1.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bogdan C., Paik J., Vodovotz Y., Nathan C. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem. 1992 Nov 15;267(32):23301–23308. [PubMed] [Google Scholar]
  9. Bone R. C. The pathogenesis of sepsis. Ann Intern Med. 1991 Sep 15;115(6):457–469. doi: 10.7326/0003-4819-115-6-457. [DOI] [PubMed] [Google Scholar]
  10. Bradley S. F., Vibhagool A., Kunkel S. L., Kauffman C. A. Monokine secretion in aging and protein malnutrition. J Leukoc Biol. 1989 Jun;45(6):510–514. doi: 10.1002/jlb.45.6.510. [DOI] [PubMed] [Google Scholar]
  11. Bruley-Rosset M., Vergnon I. Interleukin-1 synthesis and activity in aged mice. Mech Ageing Dev. 1984 Mar;24(3):247–264. doi: 10.1016/0047-6374(84)90111-8. [DOI] [PubMed] [Google Scholar]
  12. Chen Y., Bradley S. F. Aging and eliciting agents: effect on murine peritoneal macrophage monokine bioactivity. Exp Gerontol. 1993 Mar-Apr;28(2):145–159. doi: 10.1016/0531-5565(93)90004-w. [DOI] [PubMed] [Google Scholar]
  13. Chopra R. K., Holbrook N. J., Powers D. C., McCoy M. T., Adler W. H., Nagel J. E. Interleukin 2, interleukin 2 receptor, and interferon-gamma synthesis and mRNA expression in phorbol myristate acetate and calcium ionophore A23187-stimulated T cells from elderly humans. Clin Immunol Immunopathol. 1989 Nov;53(2 Pt 1):297–308. doi: 10.1016/0090-1229(89)90058-5. [DOI] [PubMed] [Google Scholar]
  14. Daynes R. A., Araneo B. A., Ershler W. B., Maloney C., Li G. Z., Ryu S. Y. Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative. J Immunol. 1993 Jun 15;150(12):5219–5230. [PubMed] [Google Scholar]
  15. Doherty G. M., Lange J. R., Langstein H. N., Alexander H. R., Buresh C. M., Norton J. A. Evidence for IFN-gamma as a mediator of the lethality of endotoxin and tumor necrosis factor-alpha. J Immunol. 1992 Sep 1;149(5):1666–1670. [PubMed] [Google Scholar]
  16. Effros R. B., Svoboda K., Walford R. L. Influence of age and caloric restriction on macrophage IL-6 and TNF production. Lymphokine Cytokine Res. 1991 Oct;10(5):347–351. [PubMed] [Google Scholar]
  17. Ernst D. N., Weigle W. O., Noonan D. J., McQuitty D. N., Hobbs M. V. The age-associated increase in IFN-gamma synthesis by mouse CD8+ T cells correlates with shifts in the frequencies of cell subsets defined by membrane CD44, CD45RB, 3G11, and MEL-14 expression. J Immunol. 1993 Jul 15;151(2):575–587. [PubMed] [Google Scholar]
  18. Ershler W. B., Sun W. H., Binkley N., Gravenstein S., Volk M. J., Kamoske G., Klopp R. G., Roecker E. B., Daynes R. A., Weindruch R. Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction. Lymphokine Cytokine Res. 1993 Aug;12(4):225–230. [PubMed] [Google Scholar]
  19. Fagiolo U., Cossarizza A., Scala E., Fanales-Belasio E., Ortolani C., Cozzi E., Monti D., Franceschi C., Paganelli R. Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol. 1993 Sep;23(9):2375–2378. doi: 10.1002/eji.1830230950. [DOI] [PubMed] [Google Scholar]
  20. Foster K. D., Conn C. A., Kluger M. J. Fever, tumor necrosis factor, and interleukin-6 in young, mature, and aged Fischer 344 rats. Am J Physiol. 1992 Feb;262(2 Pt 2):R211–R215. doi: 10.1152/ajpregu.1992.262.2.R211. [DOI] [PubMed] [Google Scholar]
  21. Frey E. A., Miller D. S., Jahr T. G., Sundan A., Bazil V., Espevik T., Finlay B. B., Wright S. D. Soluble CD14 participates in the response of cells to lipopolysaccharide. J Exp Med. 1992 Dec 1;176(6):1665–1671. doi: 10.1084/jem.176.6.1665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gardner I. D. The effect of aging on susceptibility to infection. Rev Infect Dis. 1980 Sep-Oct;2(5):801–810. doi: 10.1093/clinids/2.5.801. [DOI] [PubMed] [Google Scholar]
  23. Gérard C., Bruyns C., Marchant A., Abramowicz D., Vandenabeele P., Delvaux A., Fiers W., Goldman M., Velu T. Interleukin 10 reduces the release of tumor necrosis factor and prevents lethality in experimental endotoxemia. J Exp Med. 1993 Feb 1;177(2):547–550. doi: 10.1084/jem.177.2.547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Heinzel F. P. The role of IFN-gamma in the pathology of experimental endotoxemia. J Immunol. 1990 Nov 1;145(9):2920–2924. [PubMed] [Google Scholar]
  25. Hobbs M. V., Weigle W. O., Ernst D. N. Interleukin-10 production by splenic CD4+ cells and cell subsets from young and old mice. Cell Immunol. 1994 Apr 1;154(1):264–272. doi: 10.1006/cimm.1994.1076. [DOI] [PubMed] [Google Scholar]
  26. Hobbs M. V., Weigle W. O., Noonan D. J., Torbett B. E., McEvilly R. J., Koch R. J., Cardenas G. J., Ernst D. N. Patterns of cytokine gene expression by CD4+ T cells from young and old mice. J Immunol. 1993 Apr 15;150(8 Pt 1):3602–3614. [PubMed] [Google Scholar]
  27. Howard M., Muchamuel T., Andrade S., Menon S. Interleukin 10 protects mice from lethal endotoxemia. J Exp Med. 1993 Apr 1;177(4):1205–1208. doi: 10.1084/jem.177.4.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Hyde S. R., McCallum R. E. Lipopolysaccharide-tumor necrosis factor-glucocorticoid interactions during cecal ligation and puncture-induced sepsis in mature versus senescent mice. Infect Immun. 1992 Mar;60(3):976–982. doi: 10.1128/iai.60.3.976-982.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Inamizu T., Chang M. P., Makinodan T. Influence of age on the production and regulation of interleukin-1 in mice. Immunology. 1985 Jul;55(3):447–455. [PMC free article] [PubMed] [Google Scholar]
  30. Kalimi M., Gupta S., Hubbard J., Greene K. Glucocorticoid receptors in adult and senescent rat liver. Endocrinology. 1983 Jan;112(1):341–347. doi: 10.1210/endo-112-1-341. [DOI] [PubMed] [Google Scholar]
  31. Kalimi M., Gupta S. Physiochemical characterization of rat liver glucocorticoid receptor during development. J Biol Chem. 1982 Nov 25;257(22):13324–13328. [PubMed] [Google Scholar]
  32. Karanfilian R. G., Spillert C. R., Machiedo G. W., Rush B. F., Jr, Lazaro E. J. Effect of age and splenectomy in murine endotoxemia. Adv Shock Res. 1983;9:125–132. [PubMed] [Google Scholar]
  33. Knudsen P. J., Dinarello C. A., Strom T. B. Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. J Immunol. 1987 Dec 15;139(12):4129–4134. [PubMed] [Google Scholar]
  34. Kunkel S. L., Spengler M., May M. A., Spengler R., Larrick J., Remick D. Prostaglandin E2 regulates macrophage-derived tumor necrosis factor gene expression. J Biol Chem. 1988 Apr 15;263(11):5380–5384. [PubMed] [Google Scholar]
  35. Lehmann V., Freudenberg M. A., Galanos C. Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and D-galactosamine-treated mice. J Exp Med. 1987 Mar 1;165(3):657–663. doi: 10.1084/jem.165.3.657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Meyers B. R., Sherman E., Mendelson M. H., Velasquez G., Srulevitch-Chin E., Hubbard M., Hirschman S. Z. Bloodstream infections in the elderly. Am J Med. 1989 Apr;86(4):379–384. doi: 10.1016/0002-9343(89)90333-1. [DOI] [PubMed] [Google Scholar]
  37. Nagelkerken L., Hertogh-Huijbregts A., Dobber R., Dräger A. Age-related changes in lymphokine production related to a decreased number of CD45RBhi CD4+ T cells. Eur J Immunol. 1991 Feb;21(2):273–281. doi: 10.1002/eji.1830210206. [DOI] [PubMed] [Google Scholar]
  38. Orme I. M. Aging and immunity to tuberculosis: increased susceptibility of old mice reflects a decreased capacity to generate mediator T lymphocytes. J Immunol. 1987 Jun 15;138(12):4414–4418. [PubMed] [Google Scholar]
  39. Parant M., Le Contel C., Parant F., Chedid L. Influence of endogenous glucocorticoid on endotoxin-induced production of circulating TNF-alpha. Lymphokine Cytokine Res. 1991 Aug;10(4):265–271. [PubMed] [Google Scholar]
  40. Patel P. J. Aging and antimicrobial immunity. Lowered efficiency of protective T cells as a contributing factor for the decreased resistance of senescent mice to listeriosis. J Exp Med. 1982 Jun 1;155(6):1870–1875. doi: 10.1084/jem.155.6.1870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Reichlin S. Neuroendocrine-immune interactions. N Engl J Med. 1993 Oct 21;329(17):1246–1253. doi: 10.1056/NEJM199310213291708. [DOI] [PubMed] [Google Scholar]
  42. Riancho J. A., Zarrabeitia M. T., Amado J. A., Olmos J. M., González-Macías J. Age-related differences in cytokine secretion. Gerontology. 1994;40(1):8–12. doi: 10.1159/000213568. [DOI] [PubMed] [Google Scholar]
  43. Saxena R. K., Saxena Q. B., Adler W. H. Lectin-induced cytotoxic activity in spleen cells from young and old mice. Age-related changes in types of effector cells, lymphokine production and response. Immunology. 1988 Jul;64(3):457–461. [PMC free article] [PubMed] [Google Scholar]
  44. Schumann R. R., Leong S. R., Flaggs G. W., Gray P. W., Wright S. D., Mathison J. C., Tobias P. S., Ulevitch R. J. Structure and function of lipopolysaccharide binding protein. Science. 1990 Sep 21;249(4975):1429–1431. doi: 10.1126/science.2402637. [DOI] [PubMed] [Google Scholar]
  45. Setia U., Serventi I., Lorenz P. Bacteremia in a long-term care facility. Spectrum and mortality. Arch Intern Med. 1984 Aug;144(8):1633–1635. [PubMed] [Google Scholar]
  46. Solana R., Villanueva J. L., Peña J., De la Fuente M. Cell mediated immunity in ageing. Comp Biochem Physiol A Comp Physiol. 1991;99(1-2):1–4. doi: 10.1016/0300-9629(91)90224-z. [DOI] [PubMed] [Google Scholar]
  47. Spinas G. A., Keller U., Brockhaus M. Release of soluble receptors for tumor necrosis factor (TNF) in relation to circulating TNF during experimental endotoxinemia. J Clin Invest. 1992 Aug;90(2):533–536. doi: 10.1172/JCI115891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Terpenning M. S., Bradley S. F. Why aging leads to increased susceptibility to infection. Geriatrics. 1991 Feb;46(2):77-8, 80. [PubMed] [Google Scholar]
  49. Thoman M. L., Weigle W. O. Lymphokines and aging: interleukin-2 production and activity in aged animals. J Immunol. 1981 Nov;127(5):2102–2106. [PubMed] [Google Scholar]
  50. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]

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