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Title: c-Src is the primary signaling mediator of polychlorinated biphenyl-induced interleukin-8 expression in a human microvascular endothelial cell line.

Authors: Eum, Sung Yong; Rha, Geun Bae; Hennig, Bernhard; Toborek, Michal

Published In Toxicol Sci, (2006 Jul)

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 (HMECs) 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 HMECs. Site-directed mutagenesis of the IL-8 promoter- and DNA-binding assays revealed that activator protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB) 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 HMECs 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-kappaB-binding sites in the IL-8 promoter.

PubMed ID: 16611624 Exiting the NIEHS site

MeSH Terms: Base Sequence; Cell Line; DNA Primers; Endothelium, Vascular/drug effects*; Endothelium, Vascular/metabolism; Humans; Interleukin-8/genetics*; Mutagenesis, Site-Directed; NF-kappa B/physiology; Polychlorinated Biphenyls/toxicity*; Promoter Regions (Genetics); Proto-Oncogene Proteins pp60(c-src)/physiology*; RNA, Messenger/genetics; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Signal Transduction/physiology*; Transcription Factor AP-1/physiology

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