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

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 6h, their expression was unchanged except for GCLC, which was reduced compared with controls. At 18h, 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 3h. 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 6h and abolished the induction of antioxidant genes at 18h 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.