Nanosized silver, but not titanium dioxide or zinc oxide, enhances oxidative stress and inflammatory response by inducing 5-HETE activation in THP-1 cells

Abstract

Bioactive, oxygenated metabolites of polyunsaturated fatty acids (PUFAs) are important indicators of inflammation and oxidative stress but almost nothing is known about their interactions with nanomaterials (NMs). To investigate the effects of nano-sized materials (n-TiO₂, n-ZnO, n-Ag) and their bulk-sized or ionic (b-TiO₂, b-ZnO, i-Ag) counterpart, we studied the status of oxidative stress and PUFA metabolism in THP-1 cells at low-toxic concentrations (<15% cytotoxicity) 6 h or 24 h after the particle exposures by LC/MS and microarray. N-Ag had a significant and sustained impact on cellular antioxidant defense, seen as incremental synthesis and accumulation of glutathione (GSH) in the cell, and reduction of superoxide dismutase (SOD) activity. The cellular particle doses were largely dependent on exposure duration and particle dissolution, and active transporter mechanisms controlled the concentration of Zn in cytosol. Even at these sub-toxic concentrations, n-Ag was able to induce statistically significant elevation in the 5-HETE: arachidonic acid ratio at 24 h, which suggests association to oxidative stress and induction of pro-inflammatory responses. This was supported by the enhanced gene expression of chemotaxis-related genes. Overall, THP-1 cells internalized all tested particles, but only n-Ag led to low level of oxidative stress through ROS production and antioxidant balance disruption. N-Ag stimulated arachidonic acid oxidation to form 5-HETE which further magnified the inflammatory responses by enhancing the production of mitochondrial superoxide and leukocyte chemokines. Since the sustained n-Ag uptake was detected, the effects may last long and function as a trigger for the low-grade inflammation playing role in the chronic inflammatory diseases.

Keywords:

• Nanoparticles
• metal oxides
• fatty acid metabolism
• LC/MS
• microarray analysis

Disclosure statement

The authors declare no competing financial interest. The authors alone are responsible for the content and writing of this article.

Availability of data and materials

The datasets supporting the conclusion of this article are included within the article and its additional files. By request, the microarray data produced in this study is available from [email protected].

Additional information

Funding

The study was supported by a grant from the Academy of Finland (decision 297885).