Interleukin-1 influences ischemic brain damage in the mouse independently of the interleukin-1 type I receptor

Abstract

The cytokine interleukin-1beta (IL-1beta) contributes to ischemic, excitotoxic, and traumatic brain injury. IL-1beta 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 (-50%; p < 0.01) ischemic brain damage caused by reversible occlusion of the middle cerebral artery, whereas injection of IL-1beta exacerbates damage (+45%; p < 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 +/- 6.1 and 46.2 +/- 6.2 mm3, respectively), but failed to respond to injection of IL-1ra. However, injection of IL-1beta (intracerebroventricularly) exacerbated ischemic brain damage in IL-1RI KO (+61%; p < 0.001) and in WT mice (+45%). This effect of IL-1beta 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-1beta 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 (+20%) animals. These data show that IL-1beta 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.

Fig. 1.

Effects of injection vehicle (saline) or recombinant IL-1, injected intracerebroventricularly on food intake (a) and body weight (b) in WT (open bars) and IL-1RI knock-out mice (closed bars). Food intake and body weight were measured over 24 hr after injections. Mean values ± SEM; n = 6 per group; ***p < 0.001 versus respective vehicle-treated group (unpaired t test).

Fig. 2.

Extent of injury (infarct volume, mm³) measured 24 hr after MCAo in wild-type (open bars) and IL-1RI knock-out mice (closed bars) injected intracerebroventricularly with vehicle (saline) or IL-1ra (2.5 μg 30 min before and again 40 min after MCAo). Data are mean values ± SEM; n = 8 per group; **p < 0.01 versus respective saline-treated group (ANOVA and PLSD Fisher post hoc test).

Fig. 3.

Effect of vehicle IL-1, IL-1 plus IL-1ra, or heat-treated IL-1 on infarct volume measured 24 hr after MCAo in WT (open bars) and IL-1RI KO (closed bars). Mean values ± SEM; n = 8 for vehicle;n = 9 for IL-1-treated animals;n = 6 for IL-1 + IL-1ra and heat-treated IL-1-treated animals. **p < 0.01; ***p < 0.005 versus respective saline-treated group (ANOVA and PLSD Fisher post hoc test).

Fig. 4.

Expression determined by PCR analysis of IL-1RII (A) and IL-1RAcP (B) mRNA in cortex recorded 4 or 24 hr after sham surgery or MCAo in WT (open bars) and IL-1RI KO mice (closed bars). Mean values ± SEM; n numbers are indicated in parentheses. *p < 0.05; **p < 0.01 versus respective sham-operated groups (Mann–Whitney U test).