Activation of NF-kappa B by PM10 occurs via an iron-mediated mechanism in the absence of I kappa B degradation

Exposure to particulate air pollution (PM10) is associated with exacerbatio ns of respiratory diseases and increased cardiopulmonary mortality. PM10 in duces lung inflammation in rats, which has been attributed to many factors, including the ultrafine components of PM10, endotoxins, and transition met als. In this study, we investigated in alveolar epithelial (A549) cells whe ther PM10 could activate nuclear factor-kappa B (NF-kappa B), a transcripti on factor stimulated in response to many proinflammatory agents. Our result s show that PM10 samples from various sites within the United Kingdom cause nuclear translocation, DNA-binding, and transcriptional activation of NF-k appa B in A549 cells. Furthermore, increased NF-kappa B activity was observ ed in the absence of I kappa B degradation. To evaluate the role of iron, A 549 cells were exposed to PM10 previously treated with phosphate-buffered s aline (PBS), deferoxamine mesylate, or deferoxamine plus ferrozine. PBS-tre ated and, to a lesser extent, deferoxamine-treated PM10 were able to activa te NF-kappa B, whereas this response was completely abrogated in cells expo sed to PM10 treated with both deferoxamine and ferrozine. Moreover, we stud ied the effects of soluble components of PM10 on NF-kappa B activation by e xposing alveolar epithelial cells to soluble fractions from PM10 treated wi th PBS or the metal chelators. We found that, compared with fractions from PBS-treated PM10 which activated NF-kappa B, fractions from PM10 treated wi th deferoxamine and ferrozine did not stimulate NF-kappa B activity above b ackground levels. Coincubation of polymixin B, an endotoxin-binding compoun d, and PR10 did not inhibit NF-kappa B. In summary, PM10 activates NF-kappa B in A549 cells by an iron-mediated mechanism in the absence of I kappa B degradation. (C) 2000 Academic Press.