title: The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Anesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. n.terrando@imperial.ac.uk
authors.forename: Niccolò
authors.initials: N
authors.lastname: Terrando
authors.forename: António
authors.initials: A
authors.lastname: Rei Fidalgo
authors.forename: Marcela
authors.initials: M
authors.lastname: Vizcaychipi
authors.forename: Mario
authors.initials: M
authors.lastname: Cibelli
authors.forename: Daqing
authors.initials: D
authors.lastname: Ma
authors.forename: Claudia
authors.initials: C
authors.lastname: Monaco
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced* / Q000276:immunology / Q000517:prevention & control*; D016207:Cytokines / Q000097:blood; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000187:drug effects
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha
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