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ToxSci Advance Access published online on April 11, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj194
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received January 6, 2006
Accepted March 29, 2006

Respiratory Toxicology

C-SRC is the Primary Signaling Mediator of PCB-Induced Interleukin-8 Expression in a Human Microvascular Endothelial Cell Line

Sung Yong Eum 1, Geun Bae Rha 1, Bernhard Hennig 2, and Michal Toborek 1 *

1 Molecular Neuroscience and Vascular Biology Laboratory, Department of Surgery, University of Kentucky, Lexington, KY 40536
2 College of Agriculture, University of Kentucky, Lexington, KY 40536

* To whom correspondence should be addressed.
Michal Toborek, E-mail: michal.toborek{at}uky.edu


  Abstract

Interleukin-8/CXCL8 (IL-8) is a prominent factor that modulates endothelial cell proliferation, migration, and angiogenesis. Therefore, the present study focused on the regulatory mechanisms of IL-8 expression induced by environmental pollutants, such as polychlorinated biphenyls (PCBs). Treatment of human microvascular endothelial cells (HMEC) with specific PCB congener, 2,2',4,6,6'-pentachlorobiphenyl (PCB 104), dose-dependently increased levels of IL-8 mRNA and secreted protein. IL-8-neutralizing antibody inhibited migration of endothelial cells stimulated by conditioned media derived from PCB 104-treated HMEC. Site-directed mutagenesis of the IL-8 promoter and DNA binding assays revealed that AP-1 and NF-{kappa}B sites are required for PCB 104-induced IL-8 transcription. Most importantly, pharmacological inhibition of Src kinase activity or overexpression of dominant negative c-Src in HMEC resulted in a significant decrease in IL-8 expression and promoter activity. In contrast, ectopic expression of activated c-Src markedly increased promoter activity of IL-8. These stimulatory effects of dominant-positive c-Src were abrogated by mutagenesis of AP-1 and NF-{kappa}B binding sites in the IL-8 promoter.

Keywords: IL-8; endothelial cells; c-Src; AP-1; NF-{kappa}B; angiogenesis; PCB.

The authors certify that all research involving human subjects was done under full compliance with all government policies and the Helsinki Declaration.


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