Lipid raft‐dependent NADPH oxidase regulates polychlorinated biphenyls‐induced expression of cell adhesion molecules in human brain endothelial cells

Abstract

Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs), can lead to expression of cell adhesion molecules (CAMs) of the brain endothelium leading to chronic neuroinflammation. In the present study, we have explored whether NADPH oxidase (NOX) modulates ortho‐substituted PCBs‐induced upregulation of CAMs in brain endothelial cells. Superoxide production, as measured by dihydroethidium (DHE), was increased in the cells exposed to PCB153. Exposure to PCB153 induced phosphorylation of cytosolic components including p47 and Rac and translocation into the lipid rafts domain for NOX activation. Upregulation of ICAM‐1 and VCAM‐1 was impeded by inhibitors to NAPDH oxidase, Rac1, and nitric oxide synthase. Moreover, isolation of lipid raft fraction using non‐detergent sucrose gradient method confirmed predominant distribution of ICAM‐1 in lipid raft domain. Results of the present study indicate that accumulation of ROS through lipid raft‐dependent NADPH oxidase regulates PCB153‐mediated induction of CAMs in brain endothelial cells. Due to its role in leukocyte infiltration, induction of CAMs may contribute to PCBs‐induced cerebrovascular disorders and neurotoxic effects in the CNS. Supported in part by NIH grants (P42 ES 07380, MH63022, MH072567, and NS39254) and the American Heart Association (09SDG2300037).