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-1b on IL-8 expression in human gastric cancer TMK-1 cells and the underlying signal transduction pathways were investigated. IL-1b induced the IL-8 expression in a time-and concentration-dependent manner. IL-1b induced the activation of extracellular signalregulated kinases-1/2 and P38 mitogen-activated protein kinase (MAPK), but not the activation of c-jun aminoterminal 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-1b also induced the production of reactive oxygen species (ROS). N-acetyl cysteine (NAC) prevented the IL-1b-induced ROS production and IL-8 expression. In addition, exogenous H 2 O 2 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)-jB sites were required for the IL-1b-induced IL-8 transcription. Electrophoretic mobility shift assay confirmed that IL-1b increased the DNA-binding activity of AP-1 and NF-jB. Inhibitor (PD980590, SB203580) and ROS scavenger (NAC) studies revealed that the upstream signalings for the transcription factors AP-1 and NF-jB were MAPK and ROS, respectively. Conditioned media from the TMK-1 cells pretreated with IL-1b 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-jB signaling pathways are involved in the IL-1b-induced IL-8 expression and that these paracrine signaling pathways induce endothelial cell proliferation.

MUC5AC and MUC5B were specific makers for non-TRU adenocarcinoma, including both central type adenocarcinoma and mucinous adenocarcinoma. We suggest that non-TRU type adenocarcinoma presents a poorer prognosis, so it should be regarded separately from TRU type adenocarcinoma.

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