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A Systematic Analysis of the Peripheral and CNS Effects of Systemic LPS, IL-1Β, TNF-α and IL-6 Challenges in C57BL/6 Mice

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Skelly, Donal T., Hennessy, Edel, Dansereau, Marc-Andre, Cunningham, Colm·2013·PLoS ONE
DOI 10.1371/journal.pone.0069123
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Abstract

It is increasingly clear that systemic inflammation has both adaptive and deleterious effects on the brain. However, detailed comparisons of brain effects of systemic challenges with different pro-inflammatory cytokines are lacking. In the present study, we challenged female C57BL/6 mice intraperitoneally with LPS (100 µg/kg), IL-1β (15 or 50 µg/kg), TNF-α (50 or 250 µg/kg) or IL-6 (50 or 125 µg/kg). We investigated effects on core body temperature, open field activity and plasma levels of inflammatory markers at 2 hours post injection. We also examined levels of hepatic, hypothalamic and hippocampal inflammatory cytokine transcripts. Hypothermia and locomotor hypoactivity were induced by LPS>IL-1β>TNF-α>>IL-6. Systemic LPS, IL-1β and TNF-α challenges induced robust and broadly similar systemic and central inflammation compared to IL-6, which showed limited effects, but did induce a hepatic acute phase response. Important exceptions included IFNβ, which could only be induced by LPS. Systemic IL-1β could not induce significant blood TNF-α, but induced CNS TNF-α mRNA, while systemic TNF-α could induce IL-1β in blood and brain. Differences between IL-1β and TNF-α-induced hippocampal profiles, specifically for IL-6 and CXCL1 prompted a temporal analysis of systemic and central responses at 1, 2, 4, 8 and 24 hours, which revealed that IL-1β and TNF-α both induced the chemokines CXCL1 and CCL2 but only IL-1β induced the pentraxin PTX3. Expression of COX-2, CXCL1 and CCL2, with nuclear localisation of the p65 subunit of NFκB, in the cerebrovasculature was demonstrated by immunohistochemistry. Furthermore, we used cFOS immunohistochemistry to show that LPS, IL-1β and to a lesser degree, TNF-α activated the central nucleus of the amygdala. Given the increasing attention in the clinical literautre on correlating specific systemic inflammatory mediators with neurological or neuropsychiatric conditions and complications, these data will provide a useful resource on the likely CNS inflammatory profiles resulting from systemic elevation of particular cytokines.

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Metadata

Authors
Skelly, D. T., Hennessy, E., Dansereau, M.-A., & Cunningham, C.
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-07-01
Volume
8
Issue
7
Pages
e69123
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0069123
OpenAlex
W2025016146
Cited by
274
References
33
FWCI
9.48
Type
journal article
Language
en
Update notices
correction (2013-12-09)
Open access
gold
Licence
creativecommons.org/licenses/by/4.0/ (unspecified)

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Skelly, D. T., Hennessy, E., Dansereau, M.-A., & Cunningham, C. (2013). A Systematic Analysis of the Peripheral and CNS Effects of Systemic LPS, IL-1Β, TNF-α and IL-6 Challenges in C57BL/6 Mice. PLoS ONE. https://doi.org/10.1371/journal.pone.0069123

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