Interleukin-1β and Interleukin-6 Signaling Differentially Regulate ABC Transporter Activity and Amyloid-β Handling in...

Impaired amyloid-β clearance at the blood-brain barrier (BBB) contributes to Alzheimer's disease (AD), yet the regulation of endothelial transport processes under neuroinflammatory conditions remains incompletely understood. Here, we investigated the time-dependent effects of interleukin-1β (IL-1β), interleukin-6 (IL-6) classical signaling directly via the membrane-bound IL-6 receptor, and IL-6 trans-signaling via the IL-6 /soluble IL-6 receptor complex (IL-6/sIL-6r) on ATP-binding cassette (ABC) transporter activity and expression in primary porcine brain endothelial cells (PBECs), and assessed intracellular accumulation of amyloid-β_(1-42). Cytokine exposure did not affect PBEC viability. IL-1β induced a robust, time-dependent increase in ABCB1 activity and expression, whereas IL-6 produced a transient enhancement that was not sustained at 72 h. In contrast, IL-6 trans-signaling elicited a delayed but sustained increase in ABCB1 function and expression. IL-1β increased ABCG2 activity and expression at early time points, while IL-6 and IL-6/sIL-6r had minimal effects. Notably, IL-1β and IL-6 trans-signaling increased ABCC5 activity without detectable changes in protein expression. Cytokine-induced transporter modulation was associated with reduced intracellular amyloid-β accumulation. Pharmacological inhibition of ABC transporters increased intracellular amyloid-β levels, supporting a role for these transporters in endothelial amyloid-β handling. However, as transendothelial amyloid-β transport was not directly assessed, these findings should be interpreted as changes in intracellular amyloid-β accumulation rather than direct evidence of altered BBB clearance. These findings demonstrate signaling- and time-dependent regulation of BBB ABC transporters and reveal distinct effects of IL-6 classical signaling and IL-6 trans-signaling on endothelial transporter regulation. Collectively, these results highlight signaling context as an important determinant of BBB transport responses under neuroinflammatory conditions.