Silicon dioxide nanoparticles induce COX-2 expression through activation of STAT3 signaling pathway in HaCaT cells

Abstract

Silicon dioxide nanoparticles (SiO₂-NPs) are widely used in biomedicines and consumer products, such as sunscreens and cosmetics. However, SiO₂-NPs can cause adverse effects on human health, depending on the size and concentration of nanoparticles. The present study was aimed at investigating the molecular mechanism underlying SiO₂-NPs-induced inflammation in human keratinocyte (HaCaT) cells. Incubation of HaCaT cells with SiO₂-NPs induced the expression of cyclooxygenase-2 (COX-2) mRNA and protein. Treatment of cells with SiO₂-NPs also induced the phosphorylation, DNA binding and the reporter gene activity of signal transducer and activator of transcription 3 (STAT3). Transfection of cells with STAT3 siRNA abrogated SiO₂-NPs-induced COX-2 expression. Moreover, SiO₂-NPs enhanced the phosphorylation of Janus kinase2 (JAK2), Src and Akt. Pharmacological inhibition of either JAK2, Src or Akt abrogated SiO₂-NPs-induced STAT3 transcriptional activity and the expression of COX-2. Treatment with LY294002 also attenuated SiO₂-NPs-induced Src phosphorylation, while, JAK2 phosphorylation was not changed. In addition, SiO₂-NPs generated reactive oxygen species (ROS) and treatment of N-acetyl cysteine (NAC) attenuated the phosphorylation of JAK2, Src, Akt and STAT3, as well as the expression of COX-2 in SiO₂-NPs-treated HaCaT cells. Taken together, our study provides the first report that SiO₂-NPs induce COX-2 expression in HaCaT cells by activating the STAT3 signaling through ROS-mediated phosphorylation of upstream kinases, Akt/Src and JAK2.

Keywords: Cyclooxygenase-2; Janus kinase2; Keratinocyte; Reactive oxygen species; Signal transducer and activator of transcription 3; Silicon dioxide nanoparticles.