Eum Sung Yong, Andras Ibolya, Hennig Bernhard, Toborek Michal
Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, University of Kentucky, Lexington, KY 40536, USA.
Toxicol Appl Pharmacol. 2009 Oct 15;240(2):299-305. doi: 10.1016/j.taap.2009.07.022. Epub 2009 Jul 24.
Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs), can lead to chronic inflammation and the development of vascular diseases. Because cell adhesion molecules (CAMs) of the cerebrovascular endothelium regulate infiltration of inflammatory cells into the brain, we have explored the molecular mechanisms by which ortho-substituted polychlorinated biphenyls (PCBs), such as PCB153, can upregulate CAMs in brain endothelial cells. Exposure to PCB153 increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as elevated adhesion of leukocytes to brain endothelial cells. These effects were impeded by inhibitors of EGFR, JAKs, or Src activity. In addition, pharmacological inhibition of NADPH oxidase or disruption of lipid rafts by cholesterol depleting agents blocked PCB153-induced phosphorylation of JAK and Src kinases and upregulation of CAMs. In contrast, silencing of caveolin-1 by siRNA interference did not affect upregulation of ICAM-1 and VCAM-1 in brain endothelial cells stimulated by PCB153. Results of the present study indicate that lipid raft-dependent NADPH oxidase/JAK/EGFR signaling mechanisms regulate the expression of CAMs in brain endothelial cells and adhesion of leukocytes to endothelial monolayers. Due to its role in leukocyte infiltration, induction of CAMs may contribute to PCB-induced cerebrovascular disorders and neurotoxic effects in the CNS.
接触持久性有机污染物，如多氯联苯（PCBs），可导致慢性炎症和血管疾病的发生。由于脑血管内皮细胞的细胞粘附分子（CAMs）调节炎症细胞向脑内的浸润，我们探究了邻位取代的多氯联苯，如多氯联苯153（PCB153），上调脑内皮细胞中CAMs的分子机制。暴露于PCB153会增加细胞间粘附分子-1（ICAM-1）和血管细胞粘附分子-1（VCAM-1）的表达，同时也会增强白细胞与脑内皮细胞的粘附。这些效应受到表皮生长因子受体（EGFR）、Janus激酶（JAKs）或Src活性抑制剂的阻碍。此外，药理学抑制NADPH氧化酶或用胆固醇消耗剂破坏脂筏，可阻断PCB153诱导的JAK和Src激酶磷酸化以及CAMs的上调。相比之下，通过小干扰RNA（siRNA）干扰使小窝蛋白-1（caveolin-1）沉默，并不影响PCB153刺激的脑内皮细胞中ICAM-1和VCAM-1的上调。本研究结果表明，脂筏依赖性NADPH氧化酶/JAK/EGFR信号机制调节脑内皮细胞中CAMs的表达以及白细胞与内皮单层的粘附。由于其在白细胞浸润中的作用，CAMs的诱导可能导致PCB诱导的脑血管疾病和中枢神经系统的神经毒性作用。
