TY - JOUR
T1 - Pro-inflammatory disequilibrium of the IL-1β/IL-1ra ratio in an experimental model of perinatal brain damages induced by lipopolysaccharide and hypoxia-ischemia
AU - Girard, Sylvie
AU - Kadhim, Hazim
AU - Larouche, Annie
AU - Roy, Mélanie
AU - Gobeil, Fernand
AU - Sébire, Guillaume
N1 - Funding Information:
Statement of financial support: This work was supported by the Canadian Institute for Health Research (CIHR), Le Fond de recherche en Santé du Québec (FRSQ), La Fondation des Etoiles pour la Recherche sur les Maladies Infantiles, La Fondation de l’Université de Sherbrooke, La Fondation du CHUS, Le Centre des Neurosciences de l’Université de Sherbrooke, Canada.
PY - 2008/7
Y1 - 2008/7
N2 - 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)-1β 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-1β 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-1β and sIL-1ra noticed with the double hit. The nuclear factor (NF)κB component of the signaling pathway activated by IL-1β-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-1β. The resulting pro-inflammatory orientation in the IL-1/IL-1ra balance might play a role in the initiation of perinatal brain damages.
AB - 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)-1β 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-1β 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-1β and sIL-1ra noticed with the double hit. The nuclear factor (NF)κB component of the signaling pathway activated by IL-1β-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-1β. The resulting pro-inflammatory orientation in the IL-1/IL-1ra balance might play a role in the initiation of perinatal brain damages.
KW - Cerebral palsy
KW - Cytokines
KW - Ischemia
KW - Perinatal brain lesions
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U2 - 10.1016/j.cyto.2008.04.007
DO - 10.1016/j.cyto.2008.04.007
M3 - Article
C2 - 18511291
AN - SCOPUS:45449085405
SN - 1043-4666
VL - 43
SP - 54
EP - 62
JO - Cytokine
JF - Cytokine
IS - 1
ER -