Abstract
ABSTRACTDivalent lead (Pb2+) is a common industrial pollutant epidemiologically associated with gastric cancers. Pb2+ was found to promote tumorigenesis, which may include interleukin (IL)‐8, a pro‐inflammatory chemokine that promotes angiogenesis and tumor metastasis. Given that the gastrointestinal tract is a major route of Pb2+ exposure, we investigated the ability of Pb2+ to induce IL‐8 expression in gastric carcinoma cells and its underlying mechanism. At a concentration of 0.1 μM, Pb2+ induced IL‐8 gene activation in gastric carcinoma AGS cells. Using a IL‐8 promoter‐deletion analysis, transcription factor activator protein 1 (AP‐1) was identified as a necessary component of Pb2+‐induced IL‐8 gene activation. Upregulation of the IL‐8 gene was abrogated by the MEK inhibitor, PD98059, and partially suppressed by the epidermal growth factor receptor inhibitors, AG1478 and PD153035. Furthermore, c‐Jun protein expression was induced in cells treated with Pb2+, and overexpression of c‐Jun enhanced Pb2+‐induced IL‐8 activation. Collectively, our findings highlight the pivotal roles of AP‐1 and extracellular signal‐regulated kinase in signal transduction of Pb2+‐induced IL‐8 gene activation. These molecules may be potential therapeutic targets for Pb2+‐related inflammation leading to stomach carcinogenesis. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 315–322, 2015.
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