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Fine particles in the air have been associated with increased mortality and morbidity. Particulate air pollution is a complex mixture which varies by region and includes a number of components including residual oil fly ash (ROFA), a byproduct of power plant and industry fuel-oil combustion. Human airway epithelial cells exposed to ROFA release inflammatory cytokines including interleukin (IL)-6, IL-8, and tumor necrosis factor. Expression of these genes is dependent upon pretranscriptional binding of cis regulatory elements, including nuclear factor κB (NF-κB). To investigate the role of NF-κB in the particulate-induced IL-6 response, we exposed human airway epithelial cells (BEAS-2B) to ROFA in vitro. ROFA stimulated a time- and dose-dependent increase in IL-6 messenger RNA (mRNA), which was preceded by the activation of nuclear proteins binding to the NF-κB sequence motif in the IL-6 promoter. Transient transfection of BEAS-2B cells with the 5′ promoter region of the IL-6 gene linked to a luciferase reporter gene confirmed that NF-κB binding is necessary for the transcription of IL-6 mRNA. The IL-6 response was inhibited by the metal chelator deferoxamine and the free radical scavenger N-acetyl-l-cysteine, suggesting that the activation of NF-κB may be mediated through reactive oxygen intermediates generated by transition metals found in ROFA. Activation of NF-κB may therefore be a critical first step in the inflammatory cascade following exposure to particles generated by oil combustion.