JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
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Interleukin-1beta stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells.

Oncogene 2004 August 27
Recent studies have suggested that the expression of interleukin-8 (IL-8) directly correlates with the vascularity of human gastric carcinomas. In this study, the effect of IL-1beta on IL-8 expression in human gastric cancer TMK-1 cells and the underlying signal transduction pathways were investigated. IL-1beta induced the IL-8 expression in a time- and concentration-dependent manner. IL-1beta induced the activation of extracellular signal-regulated kinases-1/2 and P38 mitogen-activated protein kinase (MAPK), but not the activation of c-jun amino-terminal kinse and Akt. Specific inhibitors of MEK-1 (PD980590) and P38 MAPK (SB203580) were found to suppress the IL-8 expression and the IL-8 promoter activity. Expression of vectors encoding a mutated-type MEK-1 and P38 MAPK resulted in decrease in the IL-8 promoter activity. IL-1beta also induced the production of reactive oxygen species (ROS). N-acetyl cysteine (NAC) prevented the IL-1beta-induced ROS production and IL-8 expression. In addition, exogenous H2O2 could induce the IL-8 expression. Deletional and site-directed mutagenesis studies on the IL-8 promoter revealed that activator protein-1 (AP-1) and nuclear factor (NF)-kappaB sites were required for the IL-1beta-induced IL-8 transcription. Electrophoretic mobility shift assay confirmed that IL-1beta increased the DNA-binding activity of AP-1 and NF-kappaB. Inhibitor (PD980590, SB203580) and ROS scavenger (NAC) studies revealed that the upstream signalings for the transcription factors AP-1 and NF-kappaB were MAPK and ROS, respectively. Conditioned media from the TMK-1 cells pretreated with IL-1beta could remarkably stimulate the in vitro growth of HUVEC and this effect was partially abrogated by IL-8-neutralizing antibodies. The above results suggest that MAPK-AP-1 and ROS-NF-kappaB signaling pathways are involved in the IL-1beta-induced IL-8 expression and that these paracrine signaling pathways induce endothelial cell proliferation.

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