Matrix metalloproteinase-2 and -9 are induced differently by metal nanoparticles in human monocytes: The role of oxidative stress and protein tyrosine kinase activation.
Matrix metalloproteinase-2 and -9 are induced differently by metal nanoparticles in human monocytes: The role of oxidative stress and protein tyrosine kinase activation.
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DOI：
10.1016/j.taap.2008.08.022
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发表时间：
2008-12-01
影响因子：
3.8
通讯作者：
Zhang, Qunwei
中科院分区：
文献类型：
--
作者：
Wan, Rong;Mo, Yiqun;Zhang, Xing;Chien, Sufan;Tollerud, David J.;Zhang, Qunwei
关键词：
最近，许多研究表明，纳米颗粒可以从肺部转移到循环系统。纳米颗粒作为一种颗粒状异物，可诱导机体产生活性氧（reactive oxygen species，ROS）、炎性细胞因子和基质金属蛋白酶（matrix metalloproteinase，MMP）等反应，在组织破坏和重塑中发挥重要作用。然而，纳米颗粒对白细胞，特别是单核细胞的直接影响仍不清楚。本研究的目的是比较纳米Co和纳米TiO 2引起MMPs转录和活性改变的能力，并探讨可能的机制。我们假设无毒剂量的某些过渡金属纳米颗粒刺激MMP/TIMP失衡，导致MMP产生，这可能有助于其健康效应。为了验证这一假设，U937细胞用纳米Co和纳米TiO 2处理，并测量细胞毒性效应和ROS生成。随后测定暴露于这些金属纳米颗粒后MMP-2和MMP-9表达和MMP-2和MMP-9活性的变化。为了研究参与Nano-Co诱导的MMP活化的潜在信号通路，还使用ROS清除剂或抑制剂、AP-1抑制剂和蛋白酪氨酸激酶（PTK）抑制剂预处理U937细胞。我们的研究结果表明，暴露于纳米钴，而不是纳米二氧化钛，在剂量不引起细胞毒性，导致ROS的产生和MMP-2和MMP-9的mRNA表达上调。我们的研究结果还表明，剂量和时间相关的增加，前MMP-2和前MMP-9明胶酶活性的条件培养基后，U937细胞暴露于纳米钴，但不纳米二氧化钛。纳米钴诱导的pro-MMP-2和pro-MMP-9活性增加被ROS清除剂或抑制剂预处理抑制。我们还证明了暴露于Nano-Co后，U937细胞中金属蛋白酶组织抑制剂2（TIMP-2）的剂量和时间相关性降低，但不暴露于Nano-TiO 2。然而，无论是纳米钴或纳米二氧化钛曝光导致TIMP-1的任何转录的变化。经ROS清除剂或抑制剂预处理后，纳米钴暴露后TIMP-2的降低也受到抑制。我们的研究结果还表明，在暴露于Nano-Co之前，用AP-1抑制剂姜黄素或PTK特异性抑制剂除莠霉素A或染料木黄酮预处理U937细胞，显著消除Nano-Co诱导的pro-MMP-2和-9活性。我们的研究结果表明，纳米钴引起的MMP及其抑制剂的表达和活性之间的不平衡，这是由AP-1和酪氨酸激酶途径介导的，由于氧化应激。
Recently, many studies have shown that nanoparticles can translocate from the lungs to the circulatory system. As a particulate foreign body, nanoparticles could induce host responses such as reactive oxygen species (ROS) generation, inflammatory cytokine and matrix metalloproteinase (MMP) release which play a major role in tissue destruction and remodeling. However, the direct effects of nanoparticles on leukocytes, especially monocytes, are still unclear. The objective of the present study was to compare the ability of Nano-Co and Nano-TiO2 to cause alteration of transcription and activity of MMPs and to explore possible mechanisms. We hypothesized that non-toxic doses of some transition metal nanoparticles stimulate an imbalance of MMP/TIMP that cause MMP production that may contribute to their health effects. To test this hypothesis, U937 cells were treated with Nano-Co and Nano-TiO2 and cytotoxic effects and ROS generation were measured. The alteration of MMP-2 and MMP-9 expression and activity of MMP-2 and MMP-9 after exposure to these metal nanoparticles were subsequently determined. To investigate the potential signaling pathways involved in the Nano-Co-induced MMP activation, the ROS scavengers or inhibitors, AP-1 inhibitor, and protein tyrosine kinase (PTK) inhibitors were also used to pre-treat U937 cells. Our results demonstrated that exposure of U937 cells to Nano-Co, but not to Nano-TiO2, at a dose that does not cause cytotoxicity, resulted in ROS generation and up-regulation of MMP-2 and MMP-9 mRNA expression.. Our results also showed dose- and time-related increases in pro-MMP-2 and pro-MMP-9 gelatinolytic activities in conditioned media after exposure of U937 cells to Nano-Co, but not to Nano-TiO2. Nano-Co-induced pro-MMP-2 and pro-MMP-9 activity increases were inhibited by pre-treatment with ROS scavengers or inhibitors. We also demonstrated dose- and time-related decreases in tissue inhibitors of metalloproteinases 2 (TIMP-2) in U937 cells after exposure to Nano-Co, but not to Nano-TiO2. However, neither Nano-Co nor Nano-TiO2 exposure led to any transcriptional change of TIMP-1. The decrease of TIMP-2 after exposure to Nano-Co was also inhibited by pre-treatment with ROS scavengers or inhibitors. Our results also showed that pre-treatment of U937 cells with AP-1 inhibitor, curcumin, or the PTK specific inhibitor, herbimycin A or genistein, prior to exposure to Nano-Co, significantly abolished Nano-Co-induced pro-MMP-2 and-9 activity. Our results suggest that Nano-Co causes an imbalance between the expression and activity of MMPs and their inhibitors which is mediated by the AP-1 and tyrosine kinase pathways due to oxidative stress.
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影响因子：
3.8
作者：
Calderón-Garcidueñas, L;Gambling, TM;Devlin, RB
通讯作者：
Devlin, RB
影响因子：
2.1
作者：
Dick, CAJ;Brown, DM;Stone, V
通讯作者：
Stone, V
影响因子：
4.5
作者：
Donaldson, K;Li, XY;MacNee, W
通讯作者：
MacNee, W
DOI：
10.1007/bf00432493
发表时间：
1982-01-01
影响因子：
3
作者：
HARTUNG, M;SCHALLER, KH;BRAND, E
通讯作者：
BRAND, E
影响因子：
10.4
作者：
Frampton MW;Stewart JC;Oberdörster G;Morrow PE;Chalupa D;Pietropaoli AP;Frasier LM;Speers DM;Cox C;Huang LS;Utell MJ
通讯作者：
Utell MJ