Reduced postischemic apoptosis in the hippocampus of mice deficient in interleukin-1

• Published in: Journal of comparative neurology (1911) Vol. 448; no. 2; pp. 203 - 216
• Main Authors: Mizushima, Hidekatsu, Zhou, Cheng J.i., Dohi, Kenji, Horai, Reiko, Asano, Masahide, Iwakura, Yoichiro, Hirabayashi, Takahiro, Arata, Satoru, Nakajo, Shigeo, Takaki, Atsushi, Ohtaki, Hirokazu, Shioda, Seiji
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 24.06.2002
• Subjects: Animals; Apoptosis - genetics; Brain Ischemia - genetics; Brain Ischemia - metabolism; Brain Ischemia - physiopathology; Caspase 3; Caspases - metabolism; Female; global ischemia; Hippocampus - metabolism; Hippocampus - pathology; Hippocampus - physiopathology; Immunohistochemistry; Interleukin-1 - deficiency; Interleukin-1 - genetics; Interleukin-1 - metabolism; JNK Mitogen-Activated Protein Kinases; knockout mice; Male; MAP Kinase Signaling System - genetics; Mice; Mice, Knockout; Microscopy, Electron; mitogen-activated protein kinase; Mitogen-Activated Protein Kinases - metabolism; neurodegeneration; Neurons - metabolism; Neurons - pathology; Neurons - ultrastructure; nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - metabolism; p38 Mitogen-Activated Protein Kinases; RNA, Messenger - metabolism
• ISSN: 0021-9967; 1096-9861
• DOI: 10.1002/cne.10262

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‐1α and IL‐ 1β in neurodegeneration. We report here, for the first time, that mice lacking IL‐1α/β (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 (NO2−) and nitrate (NO3−) 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. J. Comp. Neurol. 448:203–216, 2002. © 2002 Wiley‐Liss, Inc.