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Anti‐IL‐6 neutralizing antibody modulates blood‐brain barrier function in the ovine fetus
Author(s) -
Zhang Jiyong,
Sadowska Grazyna B.,
Chen Xiaodi,
Park Seon Yeong,
Kim JeongEun,
Bodge Courtney A.,
Cummings Erin,
Lim YowPin,
Makeyev Oleksandr,
Besio Walter G.,
Gaitanis John,
Banks William A.,
Stonestreet Barbara S.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-258822
Subject(s) - blood–brain barrier , tight junction , proinflammatory cytokine , cerebrospinal fluid , fetus , ischemia , evans blue , parenchyma , barrier function , brain ischemia , medicine , endocrinology , central nervous system , inflammation , pathology , biology , pregnancy , microbiology and biotechnology , genetics
Impaired blood‐brain barrier function represents an important component of hypoxic‐ischemic brain injury in the perinatal period. Proinflammatory cytokines could contribute to ischemia‐related blood‐brain barrier dysfunction. IL‐6 increases vascular endothelial cell monolayer permeability in vitro. However, contributions of IL‐6 to blood‐brain barrier abnormalities have not been examined in the immature brain in vivo. We generated pharmacologic quantities of ovine‐specific neutralizing anti‐IL‐6 mAbs and systemically infused mAbs into fetal sheep at 126 days of gestation after exposure to brain ischemia. Anti‐IL‐6 mAbs were measured by ELISA in fetal plasma, cerebral cortex, and cerebrospinal fluid, blood‐brain barrier permeability was quantified using the blood‐to‐brain transfer constant in brain regions, and IL‐6, tight junction proteins, and plasmalemma vesicle protein (PLVAP) were detected by Western immunoblot. Anti‐IL‐6 mAb infusions resulted in increases in mAb ( P < 0.05) in plasma, brain parenchyma, and cerebrospinal fluid and decreases in brain IL‐6 protein. Twenty‐four hours after ischemia, anti‐IL‐6 mAb infusions attenuated ischemia‐related increases in blood‐brain barrier permeability and modulated tight junction and PLVAP protein expression in fetal brain. We conclude that inhibiting the effects of IL‐6 protein with systemic infusions of neutralizing antibodies attenuates ischemia‐related increases in blood‐brain barrier permeability by inhibiting IL‐6 and modulates tight junction proteins after ischemia.—Zhang, J., Sadowska, G. B., Chen, X., Park, S. Y., Kim, J.‐E., Bodge, C. A., Cummings, E., Lim, Y.‐P., Makeyev, O., Besio, W. G., Gaitanis, J., Banks, W. A., Stonestreet, B. S. Anti‐IL‐6 neutralizing antibody modulates blood‐brain barrier function in the ovine fetus. FASEB J. 29, 1739‐1753 (2015). www.fasebj.org