The approval of new nanomedicines requires a deeper understanding of the interaction between cells and nanoparticles (NPs). Silica (SiO2) and gold (Au) NPs have shown great potential in biomedical applications, such as the delivery of therapeutic agents, diagnostics, and biosensors. NP-cell interaction and internalization can trigger several cellular responses, including gene expression regulation. The identification of differentially expressed genes in response to NP uptake contributes to a better understanding of the cellular processes involved, including potential side effects. We investigated gene regulation in human macrophages and lung epithelial cells after acute exposure to spherical 60 nm SiO2 NPs. SiO2 NPs uptake did not considerably affect gene expression in epithelial cells, whereas five genes were up-regulated in macrophages. These genes are principally related to inflammation, chemotaxis, and cell adhesion. NR4A1, an important modulator of inflammation in macrophages, was found to be up-regulated. The expression of this gene was increased upon 1 h of macrophage exposure to spherical 50 nm AuNPs and 200 nm spherical SiO2 NPs. NR4A1 can thus be an important immediate regulator of inflammation provoked by NP uptake in macrophages.