The cytokine interleukin-1␤ (IL-1␤) contributes to ischemic, excitotoxic, and traumatic brain injury. IL-1␤ actions depend on interaction with a single receptor (IL-1RI), which associates with an accessory protein (IL-1RAcP), and is blocked by IL-1 receptor antagonist (IL-1ra). Here we show that in normal mice [wild-type (WT)], intracerebroventricular injection of IL-1ra markedly reduces (Ϫ50%; p Ͻ 0.01) ischemic brain damage caused by reversible occlusion of the middle cerebral artery, whereas

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... injection of IL-1␤ exacerbates damage (ϩ45%; p Ͻ 0.05). Mice lacking IL-1RI [IL-1RI knock-out (KO)] exhibited ischemic brain damage that is almost identical to that of the WT (infarct volume 43.7 Ϯ 6.1 and 46.2 Ϯ 6.2 mm 3 , respectively), but failed to respond to injection of IL-1ra. However, injection of IL-1␤ (intracerebroventricularly) exacerbated ischemic brain damage in IL-1RI KO (ϩ61%; p Ͻ 0.001) and in WT mice (ϩ45%). This effect of IL-1␤ was abolished by heat denaturation in all animals, and was reversed by IL-1ra in WT, but not IL-1RI KO mice. In contrast, IL-1RI KO mice were completely resistant to effects of IL-1␤ on food intake or body weight. IL-1RAcP mRNA was increased by stroke in WT, but reduced in IL-1RI KO mice compared with sham-operated mice. Type II IL-1 receptor mRNA was significantly increased 4 hr after ischemia in WT and IL-1RI KO (ϩ20%) animals. These data show that IL-1␤ can exacerbate ischemic brain damage independently of IL-1RI and suggest the existence of additional signaling receptor or receptors for IL-1 in the brain.