Role of IL-1alpha and IL-1beta in ischemic brain damage.
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.
Boutin
H
H
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
LeFeuvre
R A
RA
Horai
R
R
Asano
M
M
Iwakura
Y
Y
Rothwell
N J
NJ
D000818:Animals; D001783:Blood Flow Velocity; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007276:Injections, Intraventricular; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000008:administration & dosage
C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D012795:Sialoglycoproteins