Pro-inflammatory disequilibrium of the IL-1 beta/IL-1ra ratio in an experimental model of perinatal brain damages induced by lipopolysaccharide and hypoxia-ischemia

Cytokine. 2008 Jul;43(1):54-62. doi: 10.1016/j.cyto.2008.04.007. Epub 2008 Jun 3.


Bacterial infections and hypoxia/ischemia (H/I) are implicated in human neonatal brain damage leading to cerebral palsy (CP). We developed an animal model presenting similar perinatal brain damage by combining bacterial endotoxin and H/I insults. Interleukin (IL)-1beta is a mediator of brain damage and its action(s) is counteracted by its cognate anti-inflammatory IL-1 receptor antagonist (IL-1ra). We tested the hypothesis that the balance between agonist and antagonist in the IL-1 system is shifted towards inflammation in perinatal brains exposed to endotoxin and/or H/I. Lipopolysaccharide (LPS) and/or H/I enhanced both intracerebral IL-1beta mRNA and protein levels, with a maximum increase observed with combined LPS and H/I insults. Conversely, IL-1ra expression was significantly downregulated by LPS, H/I, or both combined, with a maximum magnitude of imbalance between IL-1beta and sIL-1ra noticed with the double hit. The nuclear factor (NF)kappaB component of the signaling pathway activated by IL-1beta-binding to its receptor was activated following exposure to LPS and/or H/I. We show for the first time that, perinatally, bacterial products, H/I, or both combined, induce downregulation in sIL-1ra expression concomitant with upregulation in IL-1beta. The resulting pro-inflammatory orientation in the IL-1/IL-1ra balance might play a role in the initiation of perinatal brain damages.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Animals, Newborn
  • Disease Models, Animal
  • Female
  • Hypoxia-Ischemia, Brain / etiology
  • Hypoxia-Ischemia, Brain / metabolism*
  • Hypoxia-Ischemia, Brain / pathology*
  • Inflammation Mediators / metabolism*
  • Interleukin 1 Receptor Antagonist Protein / biosynthesis
  • Interleukin 1 Receptor Antagonist Protein / metabolism*
  • Interleukin-1beta / biosynthesis
  • Interleukin-1beta / metabolism*
  • Lipopolysaccharides / toxicity*
  • Rats
  • Rats, Inbred Lew


  • Inflammation Mediators
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • Lipopolysaccharides