Transport of interleukin-1 across cerebromicrovascular endothelial cells.
OBJECTIVE
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.


METHODS
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-1beta and IL-1 receptor antagonist were characterized in this model, using endocytosis inhibitors and IL-1 receptor-blocking antibodies.


RESULTS
Transcellular IL-1beta and IL-1 receptor antagonist transport was temperature-dependent and IL-1beta was transported with higher affinity than IL-1 receptor antagonist. IL-1beta inhibited IL-1 receptor antagonist transport more potently than IL-1 receptor antagonist inhibited IL-1beta transport. Transport of IL-1beta 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-1beta transport.


CONCLUSIONS
These results are consistent with IL-1 and IL-1 receptor antagonist being transported across cultured cerebromicrovascular endothelial cells and suggest that IL-1beta 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.
Skinner
R A
RA
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester, UK.
Gibson
R M
RM
Rothwell
N J
NJ
Pinteaux
E
E
Penny
J I
JI
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply; D018920:Coculture Techniques; D004705:Endocytosis / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D055806:Microvessels / Q000166:cytology / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D053574:Receptors, Interleukin-1 Type II / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D013552:Swine
D000906:Antibodies; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D053573:Receptors, Interleukin-1 Type I; D053574:Receptors, Interleukin-1 Type II