Asbestos Activates NfkB

The first evidence indicating NF-kB activation by asbestos was provided by Janssen et al.161 in 1995. In this study, they reported that crocidolite asbestos caused a dose-dependent increase in the binding of p50 and p65 proteins to NF-KB-binding DNA elements in hamster tracheal epithelial (HTE) cells. Similarly, Simeonova and Luster162 showed that asbestos-induced NF-kB activation is responsible for the increased expression of the inflammatory cytokine, IL-8, in human pulmonary epithelial cells. ROS

scavengers as well as protein tyrosine kinase inhibitors partially decreased NF-kB activation and IL-8 induction by asbestos. In an asbestos inhalation model in the rat, increased NF-kB p65 immunofluorescence was observed in airway epithelial cells at 5 days after exposure, indicating the translocation of the p65 protein.163

Asbestos induces NF-kB and AP-1 transcription-factor activation, possibly through ROS-mediated lipid peroxidation and arachidonic acid metabolism.164 In macrophages, asbestos caused increased release of arachidonic acid and the formation of prostaglandins E2 and F2a.165 In alveolar macrophages, asbestos induced the releases of arachidonic acid metabolites as early as 1 h post-in vitro exposure. Persistent release of arachidonic acid metabolites at sites of asbestos deposition are implicated in the constitutive activation of NF-kB.166,167

Accumulating evidence suggests that NF-KB-dependent cytokine induction is one of the key events in asbestos-induced lung cancer and mesothelioma.121 The cellular sources of asbestos-induced NF-KB-dependent cytokines include alveolar macrophages and type II epithelial cells. In asbestos-exposed individuals, alveolar macrophages produce increased levels of TNFa.168 Biochemical studies indicate an involvement of iron-catalyzed ROS generation in asbestos-induced NF-kB activation and cytokine gene expression.169 Both ROS scavengers and iron chelators blocked TNFa mRNA induction in rat alveolar macrophages stimulated with asbestos. TNFa itself is not only a cytokine whose expression is dependent on NF-kB, but also a potent NF-kB activator. Thus, activation of NF-kB by asbestos initiates a positive cytokine feedback loop, leading to the amplification of inflammation or carcinogenesis. Indeed, a report by Driscoll et al.170 indicates that increased release of TNFa from macrophages was responsible for the subsequent induction of macrophage inflammatory protein-1a (MIP-1a), MIP-1, IL-1, IL-6, and IL-8 from either epithelial cells or macrophages. Interruption of this cytokine positive feedback loop, such as by TNFa receptor gene knock-out,171 will be effective in blocking inflammation and cell proliferation.

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