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-1 beta rather than IL-1 alpha, 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-1 alpha, IL-1 beta, or both IL-1 alpha and IL-1 beta 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-1 alpha or IL-1 beta alone. IL-1 beta mRNA, but not IL-1 alpha or the IL-1 type 1 receptor, was strongly induced by MCAO in WT and IL-1 alpha KO mice. Administration (intracerebroventricularly) of recombinant IL-1 receptor antagonist significantly reduced infarct volume in WT (-32%) and IL-1 alpha KO (- 48%) mice, but had no effect on injury in IL-1 beta or IL-1 alpha/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-1 a or IL-1 beta fails to influence brain damage, probably because of compensatory changes in the IL-1 system in IL-1 alpha KO mice and changes in IL-1-independent mediators of neuronal death in IL-1 beta KO mice.