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Activation of Rac1 GTPase by nanoparticulate structures in human macrophages
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Inflammatory activation of alveolar macrophages by ambient particles can be facilitated via Toll-like receptors (TLR). The action of TLR agonists and antagonists has been reported to depend on the formation of nanoparticulate structures. Aim of the present study was to identify the signaling pathways induced by nanoparticulate structures in human macrophages, which might be critical for inflammatory cell activation. Methods Studies were performed in primary human alveolar macrophages or in differentiated THP-1 macrophages. Silica nanoparticles were prepared by Stöber synthesis and characterized by dynamic light scattering and scanning electron microscopy. Mycobacterial DNA was isolated from Mycobacterium bovis BCG, and nanoparticle formation was assessed by atomic force microscopy and dynamic light scattering. Actin polymerization was measured by phalloidin–TRITC staining, and cell activation was determined by reverse transcription quantitative PCR analysis, L929 cytotoxicity assay (cytokine induction), and pull-down assays (Rho GTPases). Results In contrast to immune stimulatory sequence ISS 1018, BCG DNA spontaneously formed nanoparticulate structures and induced actin polymerization as did synthetic silica nanoparticles. Co-incubation with silica nanoparticles amplified the responsiveness of macrophages toward the TLR9 ligand ISS 1018. The activation of Rac1 was induced by silica nanoparticles as well as BCG DNA and is suggested as the critical signaling event inducing both cytoskeleton changes as well as inflammatory cell activation. Conclusion Nanoparticles can induce signaling pathways, which amplify an inflammatory response in macrophages.
The aim of this study was to identify the signaling pathways induced by nanoparticulate structures in human macrophages, which might be critical for inflammatory cell activation. Studies were performed in primary human alveolar macrophages or in differentiated THP-1 macrophages using silica nanoparticles
Peer Reviewed Journal Article
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European Journal of Pharmaceutics and Biopharmaceutics, 84(2): 315-324 (June 2013)
European Journal of Pharmaceutics and Biopharmaceutics
Diesel B, Hoppstadter J, Hachenthal N, Zarbock R, Cavelius C, Wahl B, Thewes N, Jacobs K, Kraegeloh A, Kiemer AK
Last updated on June 24, 2013
This work is supported in part by the Nanoscale Science and Engineering Initiative of the National Science Foundation
under NSF Award Number EEC-0118007.
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