title: Lipopolysaccharide-induced lethality and cytokine production in aged mice.
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.
authors.affiliation: Department of Microbiology, Toho University School of Medicine, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tateda
authors.forename: T
authors.initials: T
authors.lastname: Matsumoto
authors.forename: S
authors.initials: S
authors.lastname: Miyazaki
authors.forename: K
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007928:Lethal Dose 50; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003345:Corticosterone