Abstract
Inhalation of particulate nickel subsulfide (Ni3S2) causes chronic active inflammation and fibrosis of the lungs. However, the mechanisms for these effects are not well understood. Therefore, cell culture experiments with BEAS-2B human airway epithelial cells were conducted to test the hypothesis that exposure to non-cytotoxic levels of Ni3S2 induces expression of inflammatory cytokines such as interleukin-8 (IL-8). Exposure to Ni3S2 for 48 h was required to significantly increase IL-8 protein levels. Transcriptional stimulation of IL-8 mRNA levels preceded the increase in protein. Transient exposure to soluble nickel sulfate failed to increase IL-8 mRNA. Transfection with truncated IL-8 promoter constructs linked to the luciferase gene demonstrated that nickel-induced IL-8 transcription required -272 bp of the promoter relative to the transcriptional start site. A -133-bp construct, containing cytokine and hypoxia-sensitive AP-1, NF-IL6, and NF-kappaB sites, was insufficient for induction by nickel. Transfection with a dominant negative AP-1 construct or mutation of the AP-1, GATA, or C/EBP sites in the -272-bp IL-8 promoter construct blocked induction by nickel. Inhibiting ERK, phosphatidylinositol 3-kinase, but not p38 kinase, diacylglycerol kinase, or hypoxia-inducible factor-1alpha, attenuated nickel induction of IL-8. These studies indicate that nickel induced IL-8 transcription through a novel pathway that requires both AP-1 and non-traditional transcription factors.
Highlights
Environmental exposure to inhaled nickel particles has been linked to increased mortality in the United States [1], and inhalation is the primary route of occupational exposure to nickel compounds [2]
This suggests that IL-8 expression is sensitive to nickel exposure, enhanced IL-8 mRNA and protein levels were not detected in human airway cells exposed to soluble nickel sulfate for 2 h [14] or dermal cells treated with nickel chloride [13]
To determine whether the observed increases in IL-8 protein were due to induction of mRNA levels, total RNA was isolated from control cells or cells exposed to nickel subsulfide for up to 48 h
Summary
Environmental exposure to inhaled nickel particles has been linked to increased mortality in the United States [1], and inhalation is the primary route of occupational exposure to nickel compounds [2]. Nickel stimulates signaling cascades in airway epithelium that increase expression of the profibrotic gene, plasminogen activator inhibitor-1, and genes involved in hypoxic responses [3,4,5]. This stimulation requires stabilization of hypoxia-inducible factor (HIF) and AP-1 transcriptional activity [3, 4]. Nickel-induced IL-8 Expression in Lung Epithelial Cells that it does not require elements in the proximal promoter that are stimulated by other inflammatory mediators
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