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.
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.
Laboratoire de neuropédiatrie, Département de pédiatrie, Université de Sherbrooke, 3001 12eme Avenue Nord, Sherbrooke, Que., Canada.
Sylvie
S
Girard
Hazim
H
Kadhim
Annie
A
Larouche
Mélanie
M
Roy
Fernand
F
Gobeil
Guillaume
G
Sébire
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D051381:Rats; D011917:Rats, Inbred Lew
D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides