NADPH oxidase and lipid raft-associated redox signaling are required for PCB153-induced upregulation of cell adhesion molecules in human brain endothelial cells.
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.
Eum
Sung Yong
SY
Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, University of Kentucky, Lexington, KY 40536, USA. sungyongeum@uky.edu
Andras
Ibolya
I
Hennig
Bernhard
B
Toborek
Michal
M
D001921:Brain / Q000098:blood supply*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002461:Cell Line, Transformed; D002784:Cholesterol / Q000378:metabolism; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004785:Environmental Pollutants / Q000633:toxicity*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects* / Q000201:enzymology; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D020298:U937 Cells; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
C495540:CAV1 protein, human; D051242:Caveolin 1; D015815:Cell Adhesion Molecules; D004785:Environmental Pollutants; D047428:Protein Kinase Inhibitors; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D002784:Cholesterol; D011078:Polychlorinated Biphenyls; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; C512478:EGFR protein, human; D066246:ErbB Receptors; D053612:Janus Kinases; D019061:src-Family Kinases; C014024:2,4,5,2',4',5'-hexachlorobiphenyl