Induction of nuclear translocation of NF-κB in epithelial cells by respirable mineral fibres

• Published in: The Journal of pathology 1999-10, Vol.189 (2), p.258-264
• Main Authors: Brown, D. M., Beswick, P. H., Donaldson, K.
• Format: Article
• Language: English
• Subjects: asbestos; Biological and medical sciences; Chemical and industrial products toxicology. Toxic occupational diseases; Inorganic dusts (pneumoconiosises) and organic dusts (byssinosis etc.); man-made mineral fibres; Medical sciences; NF-κB; Toxicology; transcription factor
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/(SICI)1096-9896(199910)189:2<258::AID-PATH410>3.0.CO;2-E

A panel of mineral fibres has been studied for their ability to cause translocation of the transcription factor NF‐κB to the nucleus in A549 lung epithelial cells. On the basis of inhalation studies, three fibres were designated as being carcinogenic—amosite asbestos, silicon carbide and refractory ceramic fibre 1 (RCF1)—or non‐carcinogenic—man‐made vitreous fibre (MMVF10), Code 100/475 glass fibre, and RCF4. The experiments were carried out at equal fibre number. It was hypothesized that carcinogenic fibres have greater free radical activity than non‐carcinogenic fibres and that an oxidative stress produced in the lung after inhalation of fibres could cause translocation of the transcription factor NF‐κB to the nucleus, where transcription of pro‐inflammatory genes such as cytokines could occur. It was demonstrated that a simple oxidant, hydrogen peroxide, caused translocation in a time‐ and dose‐dependent manner. The three carcinogenic fibres produced a significant dose‐dependent translocation of NF‐κB to the nucleus, whereas the non‐carcinogenic fibres did not. Silicon carbide fibres were the most potent of the pathogenic fibres. MMVF10 was the most potent of the non‐pathogenic fibres, causing significant nuclear translocation of NF‐κB at high fibre number. Using three antioxidants, curcumin, pyrrolidine dithiocarbamate, and Nacystelin, translocation caused by carcinogenic fibres could be significantly reduced. The present study shows that a short‐term in vitro assay can discriminate between pathogenic and non‐pathogenic fibres in terms of a key pro‐inflammatory event in epithelial cells. The mechanism of the activation of NF‐κB by pathogenic fibres and its general applicability to other fibre types remain to be determined. Copyright © 1999 John Wiley & Sons, Ltd.