Role of IL-1α and IL-1β 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-1β rather than IL-1α, 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-1α, IL-1β, or both IL-1α and IL-1β 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-1α or IL-1β alone. IL-1β mRNA, but not IL-1α or the IL-1 type 1 receptor, was strongly induced by MCAO in WT and IL-1α KO mice. Administration (intracerebroventricularly) of recombinant IL-1 receptor antagonist significantly reduced infarct volume in WT (-32%) and IL-1α KO (-48%) mice, but had no effect on injury in IL-1β or IL-1α/β KO mice. These data confirm that IL-1 plays a major role in ischemic brain injury. They also show that chronic deletion of IL-1α or IL-1β fails to influence brain damage, probably because of compensatory changes in the IL-1 system in IL-1α KO mice and changes in IL-1-independent mediators of neuronal death in IL-1β KO mice.