Silica nanoparticles induce production of inflammatory cytokines through ATP signaling via purine receptors

Nanoparticles (NPs) have pathological effects in multiple organs, including the liver. Among NPs, silica NPs (SNPs) are widely used as additives in cosmetics, medical supplies, printer toners, and foods, and therefore represent a potential health risk. Here we review the evidence for involvement of purinergic signaling in SNP-induced production of inflammatory cytokines, highlighting our recent findings. We have shown that purinergic signaling is involved in interleukin 1 beta (IL-1β) production in a mouse Kupffer cell line (KUP5) and IL-6 production in a human keratinocyte cell line (HaCaT) exposed to SNPs with diameters of 30 nm (SNP30), 70 nm (SNP70) and 300 nm (SNP300). Firstly, LPS-primed KUP5 cells showed a dose-dependent increase of IL-1β production upon exposure to SNPs, with SNP30 inducing the greatest response. ATP release was also highest in cells exposed to SNP30. Treatment with ATP alone induced a similar level ofIL-1β production to that seen with SNP30. The IL-1β production was inhibited by apyrase (ecto-nucleotidase) and A438079 (P2X₇ antagonist/ATP-release inhibitor). Cells exposed to SNP-30 also showed the highest production of reactive oxygen species (ROS). Secondly, HaCaT cells exposed to SNPs released ATP and showed an increase of IL-6 production, with SNP30 showing the greatest effects. The increase of IL-6 production was inhibited by apyrase as well as by a selective P2Y₁₁ receptor antagonist. ATP or UTP alone also induced IL-6 production. However, involvement of ROS in IL-6 production by HaCaT cells could not be confirmed. These findings indicate that ATP is released from KUP5 cells and HaCaT cells in response to stimulation with SNPs, especially SNP30, and the released ATP activates multiple P2 receptor-mediated pathways, leading to increased production of IL-Ιβ and IL-6.