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Attenuation of the macrophage inflammatory activity by TiO2 nanotubes via inhibition of MAPK and NF-κB pathways

Authors Neacsu P, Mazare A, Schmuki P, Cimpean A

Received 8 July 2015

Accepted for publication 6 September 2015

Published 12 October 2015 Volume 2015:10(1) Pages 6455—6467

DOI https://doi.org/10.2147/IJN.S92019

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Manas Gartia

Peer reviewer comments 3

Editor who approved publication: Dr Thomas J Webster

Patricia Neacsu,1 Anca Mazare,2 Patrik Schmuki,2 Anisoara Cimpean1

1Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania; 2Department of Materials Science, University of Erlangen-Nuremberg, Erlangen, Germany

Abstract: Biomaterial implantation in a living tissue triggers the activation of macrophages in inflammatory events, promoting the transcription of pro-inflammatory mediator genes. The initiation of macrophage inflammatory processes is mainly regulated by signaling proteins of mitogen-activated protein kinase (MAPK) and by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. We have previously shown that titania nanotubes modified Ti surfaces (Ti/TiO2) mitigate the immune response, compared with flat Ti surfaces; however, little is known regarding the underlying mechanism. Therefore, the aim of this study is to investigate the mechanism(s) by which this nanotopography attenuates the inflammatory activity of macrophages. Thus, we analyzed the effects of TiO2 nanotubes on the activation of MAPK and NF-κB signaling pathways in standard and lipopolysaccharide-evoked conditions. Results showed that the Ti/TiO2 significantly reduce the expression levels of the phosphorylated forms of p38, ERK1/2, c-Jun NH2-terminal kinase (JNK), IKKβ, and IkB-α. Furthermore, a significant reduction in the p65 nuclear accumulation on the nanotubular surface was remarked. Following, by using specific MAPK inhibitors, we observed that lipopolysaccharide-induced production of monocyte chemotactic protein-1 and nitric oxide was significantly inhibited on the Ti/TiO2 surface via p38 and ERK1/2, but not via JNK. However, the selective inhibitor for JNK signaling pathway (SP600125) was effective in reducing tumor necrosis factor alpha release as well as monocyte chemotactic protein-1 and nitric oxide production. Altogether, these data suggest that titania nanotubes can attenuate the macrophage inflammatory response via suppression of MAPK and NF-κB pathways providing a potential mechanism for their anti-inflammatory activity.

Keywords: titania nanotubes, macrophage, mitogen-activated protein kinases, NF-κB, inflammatory mediators

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