Ovine Proinflammatory Cytokines Cross the Murine Blood-Brain Barrier by a Common Saturable Transport Mechanism

Objectives: The cytokines interleukin (IL)-1 beta 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-1 beta and IL-6 in the mouse. Methods: IL-1 beta or IL-6 was radioactively labeled with I-131 and injected into the jugular vein at time zero. A subset of mice received 1 or 3 mu g/mouse of an unlabeled ovine or murine cytokine (IL-1 beta 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 I-131-IL-1 beta and I-131-IL-6 between brain/serum ratios and exposure time, indicating BBB permeability. Inclusion of 3 mu g/mouse unlabeled ovine IL-1 beta or IL-6 significantly reduced the trans-port of ovine I-131-IL-1 beta or I-131-IL-6, respectively, across the BBB. Transport of both ovine I-131-IL-1 beta and 131I-IL-6 was significantly inhibited by 1 mu g/mouse of murine IL-1 beta or IL-6, respectively. In contrast, 1 mu g/mouse of unlabeled ovine IL-1 beta or IL-6 did not inhibit the transport of murine I-131-IL-1 beta or I-131-IL-6. Conclusions: Ovine IL-1 beta 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. Copyright (C) 2010 S. Karger AG, Basel