Pb²⁺ induced IL‐8 gene expression by extracellular signal‐regulated kinases and the transcription factor, activator protein 1, in human gastric carcinoma cells

Abstract

Divalent lead (Pb(2+) ) is a common industrial pollutant epidemiologically associated with gastric cancers. Pb(2+) 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 Pb(2+) exposure, we investigated the ability of Pb(2+) to induce IL-8 expression in gastric carcinoma cells and its underlying mechanism. At a concentration of 0.1 μM, Pb(2+) 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 Pb(2+) -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 Pb(2+) , and overexpression of c-Jun enhanced Pb(2+) -induced IL-8 activation. Collectively, our findings highlight the pivotal roles of AP-1 and extracellular signal-regulated kinase in signal transduction of Pb(2+) -induced IL-8 gene activation. These molecules may be potential therapeutic targets for Pb(2+) -related inflammation leading to stomach carcinogenesis. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 315-322, 2015.

Involvement of L‐type Ca2+ channel and toll‐like receptor‐4 in nickel‐induced interleukin‐8 gene expression

“…Interestingly, divalent cation such as Pb 21 triggered downstream inflammatory gene activation through different mechanisms. IL-8 also can be induced by Pb 21 in human gastric carcinoma cell through the activation of transcription factor AP1 and ERK1/2 pathways (Lin et al, 2013). In addition, epidermal growth factor receptor (EGFR) is an important element in the plasma membrane responsible for transmitting Pb 21 signals to trigger downstream inflammatory cascades .…”

“…IL-8 promoter plasmid was derived from previous study (Lin et al, 2013). Briefly, cells were treated with the drug after overnight transfection, and cells were then harvested using cell lysis buffer.…”

Association between subchronic and chronic lead exposure and levels of antioxidants and chemokines

“…In in vitro studies, both lead and uric acid have been reported to induce the expression of IL-8 via MAPKs and NF-κB signaling pathways (Lin et al 2015; Liang et al 2015). IL-8 is secreted by multiple cell types in response to pro-inflammatory stimuli and serves as a strong chemotactic agent for neutrophils.…”

“…Lead is a heavy metal, which has been widely used for decades in paint, gasoline, water pipes, storage batteries, and many other products (Lin et al 2015). In the last decades, our view on lead toxicity has changed, giving more concern to exposures, previously considered safe.…”

“…Moreover, uric acid exerts its pro-inflammatory action via increasing the levels of chemokines, such as interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and RANTES (regulated on activation, normal T cell expressed and secreted) (Liang et al 2015; Zhou et al 2012). Similarly, lead has been shown to induce interleukin-8 (IL-8), a potent chemokine (Lin et al 2015; Yang et al 2014). …”