Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway
Application of silica nanoparticles (SiO2-NPs) may result in human exposure. Here we investigate unexplored modes of action by which SiO2-NPs with average size of 225 nm act on human hepatoma cells (Huh7). We focused on the endoplasmic (ER) stress response and on mitogen-activated protein kinase (MA...
Main Authors: | , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2014-01-01
|
Series: | Toxicology Reports |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2214750014001206 |
id |
doaj-6d7d00ede3814d378d228b3c772d7237 |
---|---|
record_format |
Article |
spelling |
doaj-6d7d00ede3814d378d228b3c772d72372020-11-24T20:45:57ZengElsevierToxicology Reports2214-75002014-01-011C1143115110.1016/j.toxrep.2014.10.023Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathwayVerena Christen0Magdalena Camenzind1Karl Fent2University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz, SwitzerlandUniversity of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz, SwitzerlandSwiss Federal Institute of Technology Zürich (ETH Zürich), Department of Environmental Systems Science, CH-8092 Zürich, SwitzerlandApplication of silica nanoparticles (SiO2-NPs) may result in human exposure. Here we investigate unexplored modes of action by which SiO2-NPs with average size of 225 nm act on human hepatoma cells (Huh7). We focused on the endoplasmic (ER) stress response and on mitogen-activated protein kinase (MAPK) signaling pathways. Both pathways were induced. ER stress and the associated three unfolded protein response (UPR) pathways were activated as demonstrated by significant inductions of BiP and XBP-1s and a moderate but significant induction of ATF-4 at 0.05 and 0.5 mg/ml. In addition to activation of NFкB interferon stimulated genes IP-10, IRF-9, and ISG-15 were up-regulated. As a consequence of ER stress, the pro-inflammatory cytokine TNFα and PP2Ac were induced following exposure to 0.05 mg/ml SiO2-NPs. Additionally, this occurred at 0.005 mg/ml SiO2-NPs for TNFα at 24 h. This in turn led to a strong transcriptional induction of MAP-kinases and its target genes cJun, cMyc and CREB. A strong transcriptional down-regulation of the proapoptotic gene p53 occurred at 0.05 and 0.5 mg/ml SiO2-NP. Exposure of Huh7 cells to the anti-oxidant N-acetyl cysteine reduced transcriptional induction of ER stress markers demonstrating a link between the induction of oxidative stress and ER stress. Our study demonstrates that SiO2-NPs lead to strong ER stress and UPR induction, oxidative stress, activation of MAPK signaling and down-regulation of p53. All of these activated pathways, which are analyzed here for the first time in detail, inhibit apoptosis and induce cell proliferation, which may contribute to a hepatotoxic, inflammatory and tumorigenic action of SiO2-NPs.http://www.sciencedirect.com/science/article/pii/S2214750014001206Tumor necrosis factor alphaHuman hepatoma cellsProinflammatory response ;Iinterferon-stimulated genes |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Verena Christen Magdalena Camenzind Karl Fent |
spellingShingle |
Verena Christen Magdalena Camenzind Karl Fent Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway Toxicology Reports Tumor necrosis factor alpha Human hepatoma cells Proinflammatory response ;Iinterferon-stimulated genes |
author_facet |
Verena Christen Magdalena Camenzind Karl Fent |
author_sort |
Verena Christen |
title |
Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway |
title_short |
Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway |
title_full |
Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway |
title_fullStr |
Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway |
title_full_unstemmed |
Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway |
title_sort |
silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (mapk) signaling pathway |
publisher |
Elsevier |
series |
Toxicology Reports |
issn |
2214-7500 |
publishDate |
2014-01-01 |
description |
Application of silica nanoparticles (SiO2-NPs) may result in human exposure. Here we investigate unexplored modes of action by which SiO2-NPs with average size of 225 nm act on human hepatoma cells (Huh7). We focused on the endoplasmic (ER) stress response and on mitogen-activated protein kinase (MAPK) signaling pathways. Both pathways were induced. ER stress and the associated three unfolded protein response (UPR) pathways were activated as demonstrated by significant inductions of BiP and XBP-1s and a moderate but significant induction of ATF-4 at 0.05 and 0.5 mg/ml. In addition to activation of NFкB interferon stimulated genes IP-10, IRF-9, and ISG-15 were up-regulated. As a consequence of ER stress, the pro-inflammatory cytokine TNFα and PP2Ac were induced following exposure to 0.05 mg/ml SiO2-NPs. Additionally, this occurred at 0.005 mg/ml SiO2-NPs for TNFα at 24 h. This in turn led to a strong transcriptional induction of MAP-kinases and its target genes cJun, cMyc and CREB. A strong transcriptional down-regulation of the proapoptotic gene p53 occurred at 0.05 and 0.5 mg/ml SiO2-NP. Exposure of Huh7 cells to the anti-oxidant N-acetyl cysteine reduced transcriptional induction of ER stress markers demonstrating a link between the induction of oxidative stress and ER stress. Our study demonstrates that SiO2-NPs lead to strong ER stress and UPR induction, oxidative stress, activation of MAPK signaling and down-regulation of p53. All of these activated pathways, which are analyzed here for the first time in detail, inhibit apoptosis and induce cell proliferation, which may contribute to a hepatotoxic, inflammatory and tumorigenic action of SiO2-NPs. |
topic |
Tumor necrosis factor alpha Human hepatoma cells Proinflammatory response ;Iinterferon-stimulated genes |
url |
http://www.sciencedirect.com/science/article/pii/S2214750014001206 |
work_keys_str_mv |
AT verenachristen silicananoparticlesinduceendoplasmicreticulumstressresponseoxidativestressandactivatethemitogenactivatedproteinkinasemapksignalingpathway AT magdalenacamenzind silicananoparticlesinduceendoplasmicreticulumstressresponseoxidativestressandactivatethemitogenactivatedproteinkinasemapksignalingpathway AT karlfent silicananoparticlesinduceendoplasmicreticulumstressresponseoxidativestressandactivatethemitogenactivatedproteinkinasemapksignalingpathway |
_version_ |
1716813603901800448 |