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Neutralizing anti-interleukin-1? antibodies modulate fetal blood-brain barrier function after ischemia.


ABSTRACT: We have previously shown that increases in blood-brain barrier permeability represent an important component of ischemia-reperfusion related brain injury in the fetus. Pro-inflammatory cytokines could contribute to these abnormalities in blood-brain barrier function. We have generated pharmacological quantities of mouse anti-ovine interleukin-1? monoclonal antibody and shown that this antibody has very high sensitivity and specificity for interleukin-1? protein. This antibody also neutralizes the effects of interleukin-1? protein in vitro. In the current study, we hypothesized that the neutralizing anti-interleukin-1? monoclonal antibody attenuates ischemia-reperfusion related fetal blood-brain barrier dysfunction. Instrumented ovine fetuses at 127 days of gestation were studied after 30 min of carotid occlusion and 24h of reperfusion. Groups were sham operated placebo-control- (n=5), ischemia-placebo- (n=6), ischemia-anti-IL-1? antibody- (n=7), and sham-control antibody- (n=2) treated animals. Systemic infusions of placebo (0.154M NaCl) or anti-interleukin-1? monoclonal antibody (5.1±0.6 mg/kg) were given intravenously to the same sham or ischemic group of fetuses at 15 min and 4h after ischemia. Concentrations of interleukin-1? protein and anti-interleukin-1? monoclonal antibody were measured by ELISA in fetal plasma, cerebrospinal fluid, and parietal cerebral cortex. Blood-brain barrier permeability was quantified using the blood-to-brain transfer constant (Ki) with ?-aminoisobutyric acid in multiple brain regions. Interleukin-1? protein was also measured in parietal cerebral cortices and tight junction proteins in multiple brain regions by Western immunoblot. Cerebral cortical interleukin-1? protein increased (P<0.001) after ischemia-reperfusion. After anti-interleukin-1? monoclonal antibody infusions, plasma anti-interleukin-1? monoclonal antibody was elevated (P<0.001), brain anti-interleukin-1? monoclonal antibody levels were higher (P<0.03), and interleukin-1? protein concentrations (P<0.03) and protein expressions (P<0.001) were lower in the monoclonal antibody-treated group than in placebo-treated-ischemia-reperfusion group. Monoclonal antibody infusions attenuated ischemia-reperfusion-related increases in Ki across the brain regions (P<0.04), and Ki showed an inverse linear correlation (r= -0.65, P<0.02) with anti-interleukin-1? monoclonal antibody concentrations in the parietal cortex, but had little effect on tight junction protein expression. We conclude that systemic anti-interleukin-1? monoclonal antibody infusions after ischemia result in brain anti-interleukin-1? antibody uptake, and attenuate ischemia-reperfusion-related interleukin-1? protein up-regulation and increases in blood-brain barrier permeability across brain regions in the fetus. The pro-inflammatory cytokine, interleukin-1?, contributes to impaired blood-brain barrier function after ischemia in the fetus.

PROVIDER: S-EPMC4252260 | BioStudies |

REPOSITORIES: biostudies

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