Mice deficient in interleukin-1 converting enzyme are resistant to neonatal hypoxic-ischemic brain damage.
Interleukin-1 (IL-1) converting enzyme (ICE) is a cysteine protease that cleaves inactive pro-IL-1beta to active IL-1beta. The pro-inflammatory cytokine IL-1beta is implicated as a mediator of hypoxic-ischemic (HI) brain injury, both in experimental models and in humans. ICE is a member of a family of ICE-like proteases (caspases) that mediate apoptotic cell death in diverse tissues. The authors hypothesized that in neonatal mice with a homozygous deletion of ICE (ICE-KO) the severity of brain injury elicited by a focal cerebral HI insult would be reduced, relative to wild-type mice. Paired litters of 9- to 10-day-old ICE-KO and wild-type mice underwent right carotid ligation, followed by 70 or 120 minutes of exposure to 10% O2. In this neonatal model of transient focal cerebral ischemia followed by reperfusion, the duration of hypoxia exposure determines the duration of cerebral ischemia and the severity of tissue damage. Outcome was evaluated 5 or 21 days after lesioning; severity of injury was quantified by morphometric estimation of bilateral cortical, striatal, and dorsal hippocampal volumes. In animals that underwent the moderate HI insult (70-minute hypoxia), damage was attenuated in ICE-KO mice, when evaluated at 5 or 21 days post-lesioning. In contrast, in mice that underwent the more severe HI insult (120-minute hypoxia), injury severity was the same in both groups. Reductions in intra-HI CBF, measured by laser Doppler flow-metry, and intra- and post-HI temperatures did not differ between groups. These results show that ICE activity contributes to the progression of neonatal HI brain injury in this model. Whether these deleterious effects are mediated by pro-inflammatory actions of IL-1beta and/or by pro-apoptotic mechanisms is an important question for future studies.
Liu
X H
XH
Department of Pediatrics, The University of Michigan, Ann Arbor, USA.
Kwon
D
D
Schielke
G P
GP
Yang
G Y
GY
Silverstein
F S
FS
Barks
J D
JD
D000818:Animals; D000831:Animals, Newborn; D001831:Body Temperature; D001921:Brain / Q000098:blood supply* / Q000201:enzymology*; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism*; D002339:Carotid Arteries; D020170:Caspase 1 / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism; D002560:Cerebrovascular Circulation; D003342:Corpus Striatum / Q000098:blood supply / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism; D002534:Hypoxia, Brain / Q000235:genetics / Q000378:metabolism*; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D020169:Caspases; D020170:Caspase 1