Delayed Nrf2-regulated antioxidant gene induction in response to silica nanoparticles

Abstract

Silica nanoparticles with iron on their surface cause the production of oxidants and stimulate an inflammatory response in macrophages. Nuclear factor erythroid-derived 2 –like factor 2 (Nrf2) signaling and its regulated antioxidant genes play critical roles in maintaining redox homeostasis. In this study we investigated the regulation of four representative Nrf2-regulated antioxidant genes; i.e., glutamate cysteine ligase (GCL) catalytic subunit (GCLC), GCL modifier subunit (GCLM), heme oxygenase 1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO-1), by iron-coated silica nanoparticles (SiO2-Fe) in human THP-1 macrophages. We found that the expression of these four antioxidant genes was modified by SiO2-Fe in a time-dependent manner. At 6 h, their expression was unchanged except for GCLC, which was reduced compared with controls. At 18 h, the expression of these antioxidant genes was significantly increased compared with controls. In contrast, the Nrf2 activator sulforaphane induced all antioxidant genes at as early as 3 h. The nuclear translocation of Nrf2 occurred later than that for NF-κB p65 protein and the induction of proinflammatory cytokines (TNFα and IL-1β). NF-κB inhibitor SN50 prevented the reduction of GCLC at 6 h and abolished the induction of antioxidant genes at 18 h by SiO2-Fe, but did not affect the basal and sulforaphane-induced expression of antioxidant genes, suggesting that NF-κB signaling plays a key role in the induction of Nrf2-mediated genes in response to SiO2-Fe. Consistently, SN50 inhibited the nuclear translocation of Nrf2 caused by SiO2-Fe. In addition, Nrf2 silencing decreased the basal and SiO2-induced expression of the four reprehensive antioxidant genes. Taken together, these data indicated that SiO2-Fe induced a delayed response of Nrf2-regulated antioxidant genes, likely through NF-κB-Nrf2 interactions.

Temporal changes in glutathione biosynthesis during the lipopolysaccharide-induced inflammatory response of THP-1 macrophages

“…Combined with the evidence that NF-κB activation and cytokine induction occurred earlier than Nrf2 nuclear translocation, and that SN50 inhibited both cytokine induction and Nrf2 activation, it could be inferred that Nrf2 activation in response to LPS was through NF-κB-mediated mechanism. Consistent with this, we recently reported that a delayed activation of Nrf2 signaling by iron-coated silica nanoparticles required the activation of NF-κB signaling in THP1 macrophages [38]. It remains to be determined how NF-κB signaling causes Nrf2 activation in the response of THP1 cells to these inflammatory stimuli.…”

Protection by the Total Flavonoids from Rosa laevigata Michx Fruit against Lipopolysaccharide-Induced Liver Injury in Mice via Modulation of FXR Signaling

“…Nrf2 can regulate intracellular redox homeostasis. It can translocate from the cytosol to the nucleus by changing Keap1 conformation and binding to the antioxidative response elements (ARE) to regulate various anti-oxidative genes, including HO-1, NQO1, GCLC, and GCLM [ 42 , 43 ]. Thus, Nrf2 plays an important role in inhibiting cellular oxidative stress, improving the activities of antioxidant enzymes and reducing ROS-induced damage [ 44 ].…”

A critical review of assays for hazardous components of air pollution

“…However, recent research shows that these two signaling systems are not dichotomous and interact at multiple levels. For example, activation of NF-κB by PM can result in activation of Nrf2 signaling several hours later [90].…”

“…At a third level, the proteins produced by NFκB activation further stimulate the activation of Nrf2. Most recently, we used iron-coated silica nPM to investigate the second and third levels [90]. Within the first six hours after nPM exposure of macrophages, pro-inflammatory cytokines were induced by NFκB activation, but without increase in the mRNAs of four Nrf2-dependent genes.…”