Ovine proinflammatory cytokines cross the murine blood-brain barrier by a common saturable transport mechanism.
OBJECTIVE
The cytokines interleukin (IL)-1beta and IL-6 are modulators of the neuroimmune axis and have been implicated in neuronal cell death cascades after ischemia or infection. Previous work has shown that some cross-species conservation exists between human and rodent blood-brain barrier (BBB) transport systems. To further assess cross-species conservation of cytokine transport across the BBB, the current studies investigated permeability and inhibition of ovine IL-1beta and IL-6 in the mouse.


METHODS
IL-1beta or IL-6 was radioactively labeled with (131)I and injected into the jugular vein at time zero. A subset of mice received 1 or 3 microg/mouse of an unlabeled ovine or murine cytokine (IL-1beta or IL-6) to assess self- and/or cross-inhibition of transport. Permeability was assessed using multiple-regression analysis.


RESULTS
There was a significant linear relationship for both ovine (131)I-IL-1beta and (131)I-IL-6 between brain/serum ratios and exposure time, indicating BBB permeability. Inclusion of 3 microg/mouse unlabeled ovine IL-1beta or IL-6 significantly reduced the transport of ovine (131)I-IL-1beta or (131)I-IL-6, respectively, across the BBB. Transport of both ovine (131)I-IL-1beta and (131)I-IL-6 was significantly inhibited by 1 microg/mouse of murine IL-1beta or IL-6, respectively. In contrast, 1 microg/mouse of unlabeled ovine IL-1beta or IL-6 did not inhibit the transport of murine (131)I-IL-1beta or (131)I-IL-6.


CONCLUSIONS
Ovine IL-1beta and IL-6 cross the mouse BBB by saturable transport. Inhibition of transport by murine homologs indicates that both species use the same transport mechanisms. Conversely, an inability of ovine cytokines to significantly inhibit the transport of murine cytokines indicates that mouse BBB has a lower affinity for ovine than murine cytokines. Knowledge of species-conserved BBB transport mechanisms may facilitate the development of novel animal models of central nervous system pathogenesis.
Threlkeld
Steven W
SW
Warren Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, RI 02905-2499, USA.
Lynch
Jessica L
JL
Lynch
Kristin M
KM
Sadowska
Grazyna B
GB
Banks
William A
WA
Stonestreet
Barbara S
BS
D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism / Q000493:pharmacokinetics; D015850:Interleukin-6 / Q000378:metabolism / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D015213:Neuroimmunomodulation / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D034561:Sheep, Domestic; D013045:Species Specificity
D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D007457:Iodine Radioisotopes