title: c-Src is the primary signaling mediator of polychlorinated biphenyl-induced interleukin-8 expression in a human microvascular endothelial cell line.
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.
authors.affiliation: Molecular Neuroscience and Vascular Biology Laboratory, Department of Surgery and College of Agriculture, University of Kentucky, 900 South Limestone, Lexington, KY 40536, USA.
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Eum
authors.forename: Geun Bae
authors.initials: GB
authors.lastname: Rha
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hennig
authors.forename: Michal
authors.initials: M
authors.lastname: Toborek
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000502:physiology; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology
chemical_list: D017931:DNA Primers; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D011078:Polychlorinated Biphenyls; D016392:Proto-Oncogene Proteins pp60(c-src)