Matrix metalloproteinase-2 and -9 are induced differently by metal nanoparticles in human monocytes: The role of oxidative stress and protein tyrosine kinase activation

Abstract

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-TiO 2 to cause alteration of transcription and activity of MMPs and to explore possible mechanisms. We hypothesized that nontoxic 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-TiO 2 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-TiO 2 , 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-TiO 2 . 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 timerelated decreases in tissue inhibitors of metalloproteinases 2 (TIMP-2) in U937 cells after exposure to Nano-Co, but not to Nano-TiO 2 . However, neither Nano-Co nor Nano-TiO 2 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 pretreatment 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.

Intraperitoneal injection of magnetic Fe3O4-nanoparticle induces hepatic and renal tissue injury via oxidative stress in mice

“…35 Eun-Jung Park and Kwangsik Park indicated that oxidative stress, induced by silica nanoparticles in vivo and in vitro, might have been involved in proinflammatory responses. 36 Other upstream or downstream events, such as heat-shock protein activation, 37 changes in the expression pattern of NADPH oxidase, glutathione peroxidase, and glutathione reductase, 38 apoptosis induction, 39 and kinase activation [40][41][42] have also been shown to be associated with nanoparticle use. In the current study, we found oxidative damage to cells and molecular changes after injection with nanoparticles, which was associated with hepatic and renal tissue injury.…”

Therapeutic Effect of Lecithinized Superoxide Dismutase on Pulmonary Emphysema

“…We recently reported that PC-SOD protects cultured lung epithelial cells from menadione (a superoxide anionreleasing drug)-induced cell death (Tanaka et al, 2010). It has also been reported that oxidative molecules activate MMPs and suppress the expression of ␣1-antitrypsin (Desrochers and Weiss, 1988; Greenlee et al, 2007;Mak, 2008;Wan et al, 2008). Thus, it seems that a PC-SOD-dependent decrease in the level of superoxide anions is responsible for the inhibitory effect of PC-SOD on PPE-induced pulmonary cell death and the protease/antiprotease imbalance.…”

Interaction of matrix metalloproteinases with pulmonary pollutants: Table 1–

“…Since, as stated previously, exposure to metal particles can cause pulmonary alterations (inflammation and fibrosis) the analysis of pulmonary toxicity associated with metallic MNPs is an important issue. Although it was not directly related to the lung, a study by WAN et al [81] provides interesting information about MMP regulation by metallic MNPs in monocytes. This information could be relevant to pulmonary pathophysiology, since one can expect similar results in pulmonary macrophages, which are key cells in the lung response to foreign particles.…”

“…This information could be relevant to pulmonary pathophysiology, since one can expect similar results in pulmonary macrophages, which are key cells in the lung response to foreign particles. WAN et al [81] compared the ability of a noncytotoxic concentration of cobalt (Co) and TiO 2 MNPs (5 mg?mL -1 ) to induce the activity and transcription of MMP-2 and -9 in the human monocyte cell line U937. They expected a higher effect of Nano-Co compared with NanoTiO 2 , since they showed in a previous study that Nano-Co caused greater lung injury and inflammation than Nano-TiO 2 , although they have similar diameters [82].…”