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Role of IL-1alpha and IL-1beta in ischemic brain damage.
Boutin H, LeFeuvre R, Horai R, Asano M, Iwakura Y, Rothwell NJ
J Neurosci. 2001;21( 15):5528-34.
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Abstract
The cytokine interleukin-1 (IL-1) has been strongly implicated in the pathogenesis of ischemic brain damage. Evidence to date suggests that the major form of IL-1 contributing to ischemic injury is IL-1beta rather than IL-1alpha, but this has not been tested directly. The objective of the present study was to compare the effects of transient cerebral ischemia [30 min middle cerebral artery occlusion (MCAO)] on neuronal injury in wild-type (WT) mice and in IL-1alpha, IL-1beta, or both IL-1alpha and IL-1beta knock-out (KO) mice. Mice lacking both forms of IL-1 exhibited dramatically reduced ischemic infarct volumes compared with wild type (total volume, 70%; cortex, 87% reduction). Ischemic damage compared with WT mice was not significantly altered in mice lacking either IL-1alpha or IL-1beta alone. IL-1beta mRNA, but not IL-1alpha or the IL-1 type 1 receptor, was strongly induced by MCAO in WT and IL-1alpha KO mice. Administration (intracerebroventricularly) of recombinant IL-1 receptor antagonist significantly reduced infarct volume in WT (-32%) and IL-1alpha KO (-48%) mice, but had no effect on injury in IL-1beta or IL-1alpha/beta KO mice. These data confirm that IL-1 plays a major role in ischemic brain injury. They also show that chronic deletion of IL-1alpha or IL-1beta fails to influence brain damage, probably because of compensatory changes in the IL-1 system in IL-1alpha KO mice and changes in IL-1-independent mediators of neuronal death in IL-1beta KO mice.
Keyword(s)
Animals; Blood Flow Velocity; Cerebrovascular Circulation; Injections, Intraventricular; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction; Support, Non-U.S. Gov't; administration & dosage: Sialoglycoproteins; antagonists & inhibitors: Receptors, Interleukin-1; blood supply: Brain; complications: Infarction, Middle Cerebral Artery; deficiency: Interleukin-1; etiology: Ischemic Attack, Transient; metabolism: RNA, Messenger