OP-07 - Delayed antioxidant enzyme increases induced by nanoparticles are mediated by NF-kappa B

Abstract

Silica nanoparticles coated with iron (SiO 2 -Fe) stimulate NF-kB-dependent cytokine expression in human THP-1 macrophages within 3 h. SiO 2 -Fe also increased four antioxidant genes, glutamate cysteine ligase catalytic subunit (GCLC), GCL modifier subunit (GCLM), heme oxygenase 1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO-1). But, increased expression of Nrf2-regulated genes was delayed; at 6 h, GCLC expression was below baseline while expression of the other three genes was unchanged. By 18 h however, expression of all four antioxidant genes was significantly increased. Sulforaphane, an Nrf2 activator, induced all antioxidant enzymes by 3 h. We suspected that activation of NF-kB by SiO 2 -Fe caused the delay in the Nrf2 response. Nrf2 nuclear translocation occurred later than NF-kB p65 protein while SN50, an NF-kB inhibitor, stopped cytokine production and prevented the decrease in GCLC at 6 h. But, surprisingly, SN50 also abolished induction of all antioxidant genes and inhibited SiO 2 -Fe induced Nrf2 nuclear translocation, but did not affect basal or sulforaphane-induced antioxidant gene expression. Finally, Nrf2 silencing decreased both basal and SiO 2 -Fe- induced antioxidant gene expression. We therefore conclude that SiO 2 -Fe activation of NF-kB causes both an initial suppression and then an activation of Nrf2-regulated genes in THP-1 macrophages.