Aged mice exhibit greater mortality concomitant to increased brain and plasma TNF-alpha levels following intracerebroventricular injection of lipopolysaccharide.
BACKGROUND
Age-related defects in the development of peripheral inflammatory responses have been observed in rodents and humans.


OBJECTIVE
We examined the effects of age on a centrally injected endotoxin-induced cytokine production and cellular activation in mice.


METHODS
Male C57BL/6J (B6) mice, C3H/HeN mice, and C3H/HeJ mice received an intracerebroventricular injection of lipopolysaccharide (LPS) and were sacrificed at various times (2, 4, 8 h) thereafter. ELISA for IL-1beta, IL-6, IL-12, and TNF-alpha were conducted on forebrain tissue homogenates as well as plasma samples, and lectin staining to detect activated microglia was prepared for selected brain slices.


RESULTS
Intracerebroventricular injection of LPS in B6 mice produced an age-associated increase in mortality which was paralleled with a significant increase in brain and plasma levels of TNF-alpha. AntiTNF-alpha- and IL-6-immunoreactive cells possessed macrophagelike morphologies and were observed along the LPS injection tract and scattered throughout the hilus of the dorsal hippocampus and cerebral cortices. This LPS-mediated response was found to be specific in that the LPS-hyporesponsive mouse strain (C3H/HeJ) failed to demonstrate significant brain or plasma levels of TNF-alpha after LPS administration compared to C3H/HeN mice.


CONCLUSIONS
These results suggest that the age-related increases in TNF-alpha production and mortality following the intracerebroventricular administration of LPS may be due to an increased endotoxin hypersensitivity of brain microglia/macrophages within aged animals.
Kalehua
A N
AN
Laboratory of Immunology, Clinical Immunology Section, and Laboratory of Cellular and Molecular Biology, Gerontology Research Center, National Institutes on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Taub
D D
DD
Baskar
P V
PV
Hengemihle
J
J
Muñoz
J
J
Trambadia
M
M
Speer
D L
DL
De Simoni
M G
MG
Ingram
D K
DK
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D001927:Brain Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D016009:Chi-Square Distribution; D046508:Culture Techniques; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000473:pathology; D012016:Reference Values; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha