Nanoparticles up-regulate tumor necrosis factor-alpha and CXCL8 via reactive oxygen species and mitogen-activated protein kinase activation.
Evaluating the toxicity of nanoparticles is an integral aspect of basic and applied sciences, because imaging applications using traditional organic fluorophores are limited by properties such as photobleaching, spectral overlaps, and operational difficulties. This study investigated the toxicity of nanoparticles and their biological mechanisms. We found that nanoparticles, quantum dots (QDs), considerably activated the production of tumor necrosis factor (TNF)-alpha and CXC-chemokine ligand (CXCL) 8 through reactive oxygen species (ROS)- and mitogen-activated protein kinases (MAPKs)-dependent mechanisms in human primary monocytes. Nanoparticles elicited a robust activation of intracellular ROS, phosphorylation of p47phox, and nicotinamide adenine dinucleotide phosphate oxidase activities. Blockade of ROS generation with antioxidants significantly abrogated the QD-mediated TNF-alpha and CXCL8 expression in monocytes. The induced ROS generation subsequently led to the activation of MAPKs, which were crucial for mRNA and protein expression of TNF-alpha and CXCL8. Furthermore, confocal and electron microscopy analyses showed that internalized QDs were trapped in cytoplasmic vesicles and compartmentalized inside lysosomes. Finally, several repeated intravenous injections of QDs caused an increase in neutrophil infiltration in the lung tissues in vivo. These results provide novel insights into the QD-mediated chemokine induction and inflammatory toxic responses in vitro and in vivo.
Lee
Hye-Mi
HM
Department of Microbiology, College of Medicine, Daejeon 301-747, South Korea.
Shin
Dong-Min
DM
Song
Hwan-Moon
HM
Yuk
Jae-Min
JM
Lee
Zee-Won
ZW
Lee
Sang-Hee
SH
Hwang
Song Mei
SM
Kim
Jin-Man
JM
Lee
Chang-Soo
CS
Jo
Eun-Kyeong
EK
D000818:Animals; D019187:Cadmium Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D022162:Cytoplasmic Vesicles / Q000648:ultrastructure; D006801:Humans; D016209:Interleukin-8 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity* / Q000648:ultrastructure; D045663:Quantum Dots; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018036:Selenium Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D018709:Statistics, Nonparametric; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D019187:Cadmium Compounds; D016209:Interleukin-8; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018036:Selenium Compounds; D014409:Tumor Necrosis Factor-alpha; C058667:cadmium selenide; D020928:Mitogen-Activated Protein Kinases