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Immunotoxicity of titanium dioxide nanoparticles via simultaneous induction of apoptosis and multiple toll-like receptors signaling through ROS-dependent SAPK/JNK and p38 MAPK activation.

International journal of nanomedicine (2018-11-15)
Madhusmita Dhupal, Jae-Min Oh, Dipti Ranjan Tripathy, Soo-Ki Kim, Sang Baek Koh, Kyu-Sang Park
ABSTRACT

Titanium dioxide nanoparticles (TiO2 NPs) represent a scientific breakthrough in the areas of biological and medicinal applications. Interaction of TiO2 NPs with components of innate immune system remains elusive. This study explored in vitro immunotoxicity of murine macrophage RAW 264.7 to TiO2 NPs (20 nm, negative charge) and its underlying molecular mechanism by way of immunoredox profiling. In this study, chemically synthesized BSA-functionalized TiO2 NPs (20 nm, negative charge) were characterized and immunotoxicity was investigated on RAW 264.7 cells. We found that reactive oxygen species levels significantly increased with increasing nitric oxide production, whereas depleting endogenous antioxidant super oxide dismutase as well as nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels. Furthermore, NPs exposure increased the expression of apoptotic factors such as BAX, BIM, and PUMA with disruption of mitochondrial membrane potential (Δψm) that lead to decrease in immunocytes. Molecular immune profiling revealed the activation of multiple toll-like receptors (TLRs) 4/9/12/13 simultaneously with the phosphorylation of p-p38MAPK and p-SAPK/c-Jun N-terminal kinase (JNK) compared to untreated control. Collectively, this study shows that the molecular nature of TiO2SA20(-) NP-induced immunotoxicity in RAW 264.7 macrophage is simultaneous induction of immunocyte apoptosis and multiple TLRs signaling through oxidative stress-dependent SAPK/JNK and p38 mitogen-associated protein kinase activation. This is the first study to address newer molecular mechanism of TiO2SA20(-) NP-induced immunotoxicity.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
牛血清白蛋白 来源于牛血清, lyophilized powder, BioReagent, suitable for cell culture
Sigma-Aldrich
溴化钾, FT-IR grade, ≥99% trace metals basis
Sigma-Aldrich
(酪氨酸[SO3H]27)胆囊收缩素片段26-33酰胺, ≥97% (HPLC), powder