Neutralizing anti-interleukin-1β antibodies reduce ischemia-related interleukin-1β transport across the blood–brain barrier in fetal sheep

Abstract 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 Escherichia coli ( E. coli ) BL-21 cells was produced, purified, and radiolabeled with 125 I. BBB permeability was quantified using the blood-to-brain transfer constant ( K i ) with 125 I-radiolabeled-IL-1β. Increases in anti-IL-1β mAb were observed in the brain of the mAb-treated group ( P 125 I-IL-1β was lower ( P 125 I-IL-1β counts were higher ( P