Tumor necrosis factor-alpha increases lactoferrin transcytosis through theblood-brain barrier

Lactoferrin (Lf) is an iron-binding protein involved in host defense agains t infection and severe inflammation, which accumulates in the brain during neurodegenerative disorders. Prior to determining Lf function in pathologic al brain tissues, we investigated its transport through the blood-brain bar rier (BBB) in inflammatory conditions. For this purpose,we used a reconstit uted BBB model consisting of the coculture of bovine brain capillary endoth elial cells (BBCECs) and astrocytes in the presence of tumor necrosis facto r-alpha (TNF-alpha). As TNF-alpha can be either synthesized by brain glial cells or present in circulating blood, BBCECs were exposed to this cytokine at their luminal or abluminal side. We have been able to demonstrate that in the presence of TNF-alpha, whatever the type of exposure, BBCECs were ac tivated and Lf transport through the activated BBCECs was markedly increase d. Lf was recovered intact at the abluminal side of the cells, suggesting t hat increased Lf accumulation may occur in immune-mediated pathophysiology, This process was transient as 20 h later, cells were in a resting state an d Lf transendothelial traffic was back to normal. The enhancement of if tra nscytosis seems not to involve the up-regulation of the Lf receptor but rat her an increase in the rate of transendothelial transport.