Hypoxic ischemic insults predispose to perinatal brain injury. Pro-inflammatory cytokines are important in the evolution of this injury. Interleukin-1β (IL-1β) is a key mediator of inflammatory responses and elevated IL-1β levels in brain correlate with adverse neurodevelopmental outcomes after brain injury. Impaired blood-brain barrier (BBB) function represents an important component of hypoxic-ischemic brain injury in the fetus. In addition, ischemia-reperfusion increases cytokine transport across the BBB of the ovine fetus. Reducing pro-inflammatory cytokine entry into brain could represent a novel approach to attenuate ischemia-related brain injury. We hypothesized that infusions of neutralizing IL-1β monoclonal antibody (mAb) reduce IL-1β transport across the BBB after ischemia in the fetus. Fetal sheep were studied 24-h after 30-min of carotid artery occlusion. Fetuses were treated with placebo- or anti-IL-1β mAb intravenously 15-min and 4-h after ischemia. Ovine IL-1β protein expressed from IL-1β pGEX-2T vectors in E. Coli BL-21 cells was produced, purified, and radiolabeled with 125I. BBB permeability was quantified using the blood-to-brain transfer constant (Ki) with 125I-radiolabeled-IL-1β. Increases in anti-IL-1β mAb were observed in the brain of the mAb-treated group (P < 0.001). Blood-to-brain transport of 125I-IL-1β was lower (P < 0.04) across brain regions in the anti-IL-1β mAb treated than placebo-treated ischemic fetuses. Plasma 125I-IL-1β counts were higher (P < 0.001) in the anti-IL-1β mAb than placebo-treated ischemic fetuses. Systemic infusions of anti-IL-1β mAb reduce IL-1β transport across the BBB after ischemia in the ovine fetus. Our findings suggest that conditions associated with increases in systemic pro-inflammatory cytokines and neurodevelopmental impairment could benefit from an anti-cytokine therapeutic strategy.
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Research summarized in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number 1R01-HD-057100, by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20 RR018728 and P20GM103537, and by a postdoctoral fellowship award (J.Z.) from the American Heart Association under grant number 13POST16860015.
Patra, Aparna; Chen, Xiaodi; Sadowska, Grazyna B.; Zhang, Jiyong; Lim, Yow-Pin; Padbury, James F.; Banks, William A.; and Stonestreet, Barbara S., "Neutralizing Anti-Interleukin-1β Antibodies Reduce Ischemia-Related Interleukin-1β Transport Across the Blood-Brain Barrier in Fetal Sheep" (2017). Pediatrics Faculty Publications. 298.