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

Autor: Yow Pin Lim, Grazyna B. Sadowska, Jeong Eun Kim, Erin E. Cummings, Steven W. Threlkeld, Xiaodi Chen, Courtney A. Bodge, William A. Banks, Barbara S. Stonestreet, Walter G. Besio, John N. Gaitanis, Jiyong Zhang, Oleksandr Makeyev
Rok vydání: 2014
Předmět:
Zdroj: Neurobiology of Disease, Vol 73, Iss, Pp 118-129 (2015)
ISSN: 1095-953X
Popis: article i nfo We have previously shown that increases in blood-brain barrier permeability represent an important compo- nent 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-1β monoclonal antibody and shown that this antibody has very high sensitivity and specificity for interleukin-1β protein. This antibody also neutralizes the effects of interleukin-1β protein in vitro. In the current study, we hypothesized that the neutralizing anti-interleukin-1β monoclonal antibody at- tenuates 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 24 h of reperfusion. Groups were sham operated placebo-control- (n = 5), ischemia-placebo- (n = 6), ischemia-anti-IL-1β antibody- (n = 7), and sham-control antibody- (n = 2) treated animals. Systemic infusions of placebo (0.154 M NaCl) or anti- interleukin-1β monoclonal antibody (5.1 ± 0.6 mg/kg) were given intravenously to the same sham or ischemic group of fetuses at 15 min and 4 h after ischemia. Concentrations of interleukin-1β protein and anti-interleukin- 1β 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 α-aminoisobutyric acid in multiple brain regions. Interleukin-1β protein was also measured in parietal ce- rebral cortices and tight junction proteins in multiple brain regions by Western immunoblot. Cerebral cortical interleukin-1β protein increased (P b 0.001) after ischemia-reperfusion. After anti-interleukin-1β monoclonal antibody infusions, plasma anti-interleukin-1β monoclonal antibody was elevated (P b 0.001), brain anti- interleukin-1β monoclonal antibody levels were higher (P b 0.03), and interleukin-1β protein concentrations (P b 0.03) and protein expressions (P b 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 b 0.04), and Ki showed an inverse linear correlation (r = �0.65, P b 0.02) with anti-interleukin-1β monoclonal antibody concentrations in the parietal cortex, but had little effect on tight junction protein expression. We conclude that systemic anti-interleukin-1β mono- clonalantibody infusionsafter ischemiaresult inbrainanti-interleukin-1βantibodyuptake, andattenuate ische- mia-reperfusion-related interleukin-1β protein up-regulation and increases in blood-brain barrierpermeability across brain regions in the fetus. The pro-inflammatory cytokine, interleukin-1β, contributes to impaired blood- brain barrier function after ischemia in the fetus.
Databáze: OpenAIRE
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