Induction of nuclear translocation of NF-kappaB in epithelial cells by respirable mineral fibres.
A panel of mineral fibres has been studied for their ability to cause translocation of the transcription factor NF-kappaB 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-kappaB 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-kappaB 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-kappaB 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-kappaB by pathogenic fibres and its general applicability to other fibre types remain to be determined.
Brown
D M
DM
Department of Biological Sciences, Napier University, Edinburgh, U.K. da.brown@napier.ac.uk
Beswick
P H
PH
Donaldson
K
K
D000975:Antioxidants / Q000494:pharmacology; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity*; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019016:Mineral Fibers / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism*
D000975:Antioxidants; D002273:Carcinogens; D019016:Mineral Fibers; D016328:NF-kappa B; D006861:Hydrogen Peroxide