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Transport of interleukin‐1 across cerebromicrovascular endothelial cells
Author(s) -
Skinner RA,
Gibson RM,
Rothwell NJ,
Pinteaux E,
Penny JI
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2008.00129.x
Subject(s) - interleukin 1 receptor antagonist , receptor antagonist , receptor , antagonist , endocytosis , blood–brain barrier , biology , transcellular , cytokine , pharmacology , microbiology and biotechnology , medicine , endocrinology , immunology , central nervous system
Background and purpose: The inflammatory cytokine interleukin‐1 (IL‐1) has profound actions in the brain, causing neuronal cell death and exacerbating brain damage. While circulating levels are normally low, IL‐1 can be produced on the vascular side of the brain endothelium, and within the brain. The naturally occurring IL‐1 receptor antagonist has been administered peripherally in a Phase II trial in acute stroke patients; understanding how IL‐1 and IL‐1 receptor antagonist penetrate the brain is, therefore, of considerable importance. Experimental approach: An in vitro blood–brain barrier model was generated by co‐culture of porcine brain microvascular endothelial cells with astrocytes. The mechanisms of transcellular transport of IL‐1β and IL‐1 receptor antagonist were characterized in this model, using endocytosis inhibitors and IL‐1 receptor‐blocking antibodies. Key results: Transcellular IL‐1β and IL‐1 receptor antagonist transport was temperature‐dependent and IL‐1β was transported with higher affinity than IL‐1 receptor antagonist. IL‐1β inhibited IL‐1 receptor antagonist transport more potently than IL‐1 receptor antagonist inhibited IL‐1β transport. Transport of IL‐1β and IL‐1 receptor antagonist was not via adsorptive‐mediated endocytosis, although inhibition of microtubule assembly significantly attenuated transport of both cytokines. An antibody directed to the type II IL‐1 receptor significantly reduced IL‐1β transport. Conclusions and implications: These results are consistent with IL‐1 and IL‐1 receptor antagonist being transported across cultured cerebromicrovascular endothelial cells and suggest that IL‐1β transport may occur via a type II IL‐1 receptor‐dependent mechanism. Understanding IL‐1 transport into the brain may have benefits, particularly in enhancing penetration of IL‐1 receptor antagonist into the brain.