Glucocorticoids modify effects of TGF-1 on multidrug resistance in the fetal blood-brain barrier

摘要

Transforming growth factor-1 (TGF-1) increases P-glycoprotein (P-gp; encoded by Abcb1) activity in fetal brain endothelial cells (BECs). P-gp is important for fetal brain protection against xenobiotics including synthetic glucocorticoids (sGC). We hypothesized that antenatal sGC would modify P-gp responsiveness to TGF-1 in fetal BECs. Pregnant guinea pigs were treated with dexamethasone or vehicle (N=5/group) on gestational day (GD) 48-49 and BECs derived on GD50. In BECs from control fetuses, TGF-1 increased Abcb1 mRNA and P-gp function, by approximately 5-fold and 55% respectively, as well as tight junction function. In contrast, TGF-1 had no effect on these parameters in BECs from sGC-exposed fetuses. Moreover, levels of TGF-1 responsive gene, Smad7, were increased 3-fold in BECs from control fetuses after TGF-1 but not in sGC-exposed fetuses. In conclusion, antenatal sGC alters responsiveness to TGF-1 in fetal BECs. This study has identified novel mechanisms by which TGF-1 and sGC modulate fetal brain protection against xenobiotics and other P-gp substrates.