The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction.

Journal Article (Journal Article)

INTRODUCTION: The impact of pro-inflammatory cytokines on neuroinflammation and cognitive function after lipopolysaccharide (LPS) challenge remains elusive. Herein we provide evidence that there is a temporal correlation between high-mobility group box 1 (HMGB-1), microglial activation, and cognitive dysfunction. Disabling the interleukin (IL)-1 signaling pathway is sufficient to reduce inflammation and ameliorate the disability. METHODS: Endotoxemia was induced in wild-type and IL-1R-/- mice by intra peritoneal injection of E. Coli LPS (1 mg/kg). Markers of inflammation were assessed both peripherally and centrally, and correlated to behavioral outcome using trace fear conditioning. RESULTS: Increase in plasma tumor necrosis factor-alpha (TNFalpha) peaked at 30 minutes after LPS challenge. Up-regulation of IL-1beta, IL-6 and HMGB-1 was more persistent, with detectable levels up to day three. A 15-fold increase in IL-6 and a 6.5-fold increase in IL-1beta mRNA at 6 hours post intervention (P < 0.001 respectively) was found in the hippocampus. Reactive microgliosis was observed both at days one and three, and was associated with elevated HMGB-1 and impaired memory retention (P < 0.005). Preemptive administration of IL-1 receptor antagonist (IL-1Ra) significantly reduced plasma cytokines and hippocampal microgliosis and ameliorated cognitive dysfunction without affecting HMGB-1 levels. Similar results were observed in LPS-challenged mice lacking the IL-1 receptor to those seen in LPS-challenged wild type mice treated with IL-1Ra. CONCLUSIONS: These data suggest that by blocking IL-1 signaling, the inflammatory cascade to LPS is attenuated, thereby reducing microglial activation and preventing the behavioral abnormality.

Full Text

Duke Authors

Cited Authors

  • Terrando, N; Rei Fidalgo, A; Vizcaychipi, M; Cibelli, M; Ma, D; Monaco, C; Feldmann, M; Maze, M

Published Date

  • 2010

Published In

Volume / Issue

  • 14 / 3

Start / End Page

  • R88 -

PubMed ID

  • 20470406

Pubmed Central ID

  • PMC2911722

Electronic International Standard Serial Number (EISSN)

  • 1466-609X

Digital Object Identifier (DOI)

  • 10.1186/cc9019


  • eng

Conference Location

  • England