title: Activation of NF-kappaB by PM(10) occurs via an iron-mediated mechanism in the absence of IkappaB degradation.
abstract: Exposure to particulate air pollution (PM(10)) is associated with exacerbations of respiratory diseases and increased cardiopulmonary mortality. PM(10) induces lung inflammation in rats, which has been attributed to many factors, including the ultrafine components of PM(10), endotoxins, and transition metals. In this study, we investigated in alveolar epithelial (A549) cells whether PM(10) could activate nuclear factor-kappa B (NF-kappaB), a transcription factor stimulated in response to many proinflammatory agents. Our results show that PM(10) samples from various sites within the United Kingdom cause nuclear translocation, DNA-binding, and transcriptional activation of NF-kappaB in A549 cells. Furthermore, increased NF-kappaB activity was observed in the absence of IkappaB degradation. To evaluate the role of iron, A549 cells were exposed to PM(10) previously treated with phosphate-buffered saline (PBS), deferoxamine mesylate, or deferoxamine plus ferrozine. PBS-treated and, to a lesser extent, deferoxamine-treated PM(10) were able to activate NF-kappaB, whereas this response was completely abrogated in cells exposed to PM(10) treated with both deferoxamine and ferrozine. Moreover, we studied the effects of soluble components of PM(10) on NF-kappaB activation by exposing alveolar epithelial cells to soluble fractions from PM(10) treated with PBS or the metal chelators. We found that, compared with fractions from PBS-treated PM(10) which activated NF-kappaB, fractions from PM(10) treated with deferoxamine and ferrozine did not stimulate NF-kappaB activity above background levels. Coincubation of polymixin B, an endotoxin-binding compound, and PM(10) did not inhibit NF-kappaB. In summary, PM(10) activates NF-kappaB in A549 cells by an iron-mediated mechanism in the absence of IkappaB degradation.
authors.affiliation: Edinburgh Lung and The Environment Group Initiative (ELEGI)/Colt Research Laboratories, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: L A
authors.initials: LA
authors.lastname: Jiménez
authors.forename: J
authors.initials: J
authors.lastname: Thompson
authors.forename: D A
authors.initials: DA
authors.lastname: Brown
authors.forename: I
authors.initials: I
authors.lastname: Rahman
authors.forename: F
authors.initials: F
authors.lastname: Antonicelli
authors.forename: R
authors.initials: R
authors.lastname: Duffin
authors.forename: E M
authors.initials: EM
authors.lastname: Drost
authors.forename: R T
authors.initials: RT
authors.lastname: Hay
authors.forename: K
authors.initials: K
authors.lastname: Donaldson
authors.forename: W
authors.initials: W
authors.lastname: MacNee
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000393:Air Pollutants / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004347:Drug Interactions; D005297:Ferrozine / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007501:Iron / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010316:Particle Size; D011112:Polymyxin B / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000393:Air Pollutants; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D005297:Ferrozine; D004247:DNA; D007501:Iron; D003676:Deferoxamine; D011112:Polymyxin B