c-Src is the primary signaling mediator of polychlorinated biphenyl-induced interleukin-8 expression in a human microvascular endothelial cell line.
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.
Eum
Sung Yong
SY
Molecular Neuroscience and Vascular Biology Laboratory, Department of Surgery and College of Agriculture, University of Kentucky, 900 South Limestone, Lexington, KY 40536, USA.
Rha
Geun Bae
GB
Hennig
Bernhard
B
Toborek
Michal
M
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
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)