Mechanism of uptake of ZnO nanoparticles and inflammatory responses in macrophages require PI3K mediated MAPKs signaling

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• 作者：Ruchi Roy ; Vyom Parashar ; L.K.S. Chauhan ; Rishi Shanker ; Mukul Das ; Anurag Tripathi ; Premendra Dhar Dwivedi
• 关键词：AFI ; absolute fluorescence intensity ; CR ; complement receptors ; DMSO ; dimethyl sulphoxide ; DLS ; dynamic light scattering ; ELISA ; enzyme linked immunosorbent assay ; FBS ; fetal bovine serum ; MR ; mannose receptors ; MAPKs ; mitogen-activated protein kinases ; PBS ; phosphate buffered saline ; PI3K ; phosphatidylinositol 3-kinase ; SSC ; side scatter angle ; SR ; scavenger receptors ; TEM ; transmission electron microscopy ; ZNPs ; zinc oxide nanoparticles
• 刊名：Toxicology in Vitro
• 出版年：April, 2014
• 年：2014
• 卷：28
• 期：3
• 页码：457-467
• 全文大小：2211 K

文摘

The inflammatory responses after exposure to zinc oxide nanoparticles (ZNPs) are known, however, the molecular mechanisms and direct consequences of particle uptake are still unclear. Dose and time-dependent increase in the uptake of ZNPs by macrophages has been observed by flow cytometry. Macrophages treated with ZNPs showed a significantly enhanced phagocytic activity. Inhibition of different internalization receptors caused a reduction in uptake of ZNPs in macrophages. The strongest inhibition in internalization was observed by blocking clathrin, caveolae and scavenger receptor mediated endocytic pathways. However, FcR and complement receptor-mediated phagocytic pathways also contributed significantly to control. Further, exposure of primary macrophages to ZNPs (2.5 渭g/ml) caused (i) significant enhancement of Ras, PI3K, (ii) enhanced phosphorylation and subsequent activation of its downstream signaling pathways via ERK1/2, p38 and JNK MAPKs (iii) overexpression of c-Jun, c-Fos and NF-魏B. Our results demonstrate that ZNPs induce the generation of reactive nitrogen species and overexpression of Cox-2, iNOS, pro-inflammatory cytokines (IL-6, IFN-纬, TNF-伪, IL-17 and regulatory cytokine IL-10) and MAPKs which were found to be inhibited after blocking internalization of ZNPs through caveolae receptor pathway. These results indicate that ZNPs are internalized through caveolae pathway and the inflammatory responses involve PI3K mediated MAPKs signaling cascade.