Transport of interleukin‐1 across cerebromicrovascular endothelial cells
Open Access
- 31 March 2009
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 156 (7), 1115-1123
- https://doi.org/10.1111/j.1476-5381.2008.00129.x
Abstract
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.Keywords
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