Lipid Rafts-Mediated Signaling Mechanism in Polychlorinated Biphenyl-Induced Brain Inflammation

Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs), can lead to chronic inflammatory diseases involved in the process of atherosclerosis as well as in the pathogenesis of cerebrovascular diseases. Evidence indicates that ortho-substituted PCB congeners (ortho-PCBs) accumulate in the brain, stimulate inflammatory response of brain endothelial cells, and facilitate adhesion and infiltration of leukocyte cells. However, little is known about the cellular and molecular mechanisms of ortho-PCBs-induced brain endothelial inflammation. Our new data provide evidence that ortho-PCBs upregulate adhesion molecules through lipid rafts-mediated mechanisms. This is an important finding because a variety of cell surface receptors and signaling molecules are also localized in these membrane domains. Thus, lipid rafts may provide the crucial signaling platform for cerebrovascular toxicity of ortho-PCBs. In addition, we have demonstrated that exposure of human endothelial cells to ortho-PCBs can increase cellular ROS levels leading to expression of various inflammatory mediators including ICAM-1 and VCAM-1. Based on these data, we hypothesize that ortho-PCBs may trigger lipid rafts-mediated NADPH oxidase and EGFR signaling leading to the enhanced transcriptional expression of adhesion molecules in brain endothelium. To test this hypothesis, we will employ membrane cholesterol depleting agents to disrupt lipid rafts. The adhesion and transendothelial migration assays will also be performed to determine if lipid rafts can mediate the function of adhesion molecules to increase infiltration of inflammatory cells. Gene silencing technique with siRNAs will be employed to investigate the molecular mechanisms of lipid rafts-mediated NADPH oxidase and EGFR signaling in upregulation of cell adhesion molecules in brain endothelium exposed to ortho-PCBs. Moreover, we will focus on the effects of ortho-PCBs on regulation of transcription factors activities involved in transcriptional modulation of adhesion molecules in brain endothelial cell. These studies may have implications for the elucidation of cellular and molecular signaling mechanisms involved in environmental toxicants, such as PCBs-induced brain inflammation. Therefore, outcome of the proposed research project may contribute to clinical strategy for the prevention and /or treatment of cerebrovascular disease such as atherosclerosis and stroke induced by exposure to environmental pollutants.