Reduced postischemic apoptosis in the hippocampus of mice deficient in interleukin-1.
The cytokine interleukin-1 (IL-1) has been implicated in ischemic brain damage, because the IL-1 receptor antagonist markedly inhibits experimentally induced neuronal loss. However, to date, no studies have demonstrated the involvement of endogenous IL-1alpha and IL- 1beta in neurodegeneration. We report here, for the first time, that mice lacking IL-1alpha/beta (double knockout) exhibit markedly reduced neuronal loss and apoptotic cell death when exposed to transient cardiac arrest. Furthermore, we show that, despite the reduced neuronal loss, phosphorylation of JNK/SAPK (c-Jun NH2- terminal protein kinase/stress activated protein kinase) and p38 enzymes remain elevated in IL-1 knockout mice. In contrast, the inducible nitric oxide (iNOS) immunoreactivity after global ischemia was reduced in IL-1 knockout mice as compared with wild-type mice. The levels of nitrite (NO(2) (-)) and nitrate (NO(3) (-)) in the hippocampus of wild-type mice were increased with time after ischemia-reperfusion, whereas the increase was significantly inhibited in IL-1 knockout mice. These observations strongly suggest that endogenous IL-1 contributes to ischemic brain damage, and this influence may act through the release of nitric oxide by iNOS.
Mizushima
Hidekatsu
H
Department of Anatomy, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan.
Zhou
Cheng J i
CJ
Dohi
Kenji
K
Horai
Reiko
R
Asano
Masahide
M
Iwakura
Yoichiro
Y
Hirabayashi
Takahiro
T
Arata
Satoru
S
Nakajo
Shigeo
S
Takaki
Atsushi
A
Ohtaki
Hirokazu
H
Shioda
Seiji
S
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases