Interleukin-6 upregulates paraoxonase 1 gene expression via an AKT/NF-κB-dependent pathway

The aim of this study is to investigate the relationship between paraoxonase 1 (PON1) and atherosclerosis-related inflammation. In this study, human hepatoma HepG2 cell line was used as a hepatocyte model to examine the effects of the pro-inflammatory cytokines on PON1 expression. The results showed that IL-6, but not TNF-alpha and IL-1 beta, significantly increased both the function and protein level of PON1; data from real-time RT-PCR analysis revealed that the IL-6-induced PON1 expression occurred at the transcriptional level. Increase of I kappa B kinase activity and I kappa B phosphorylation, and reduction of I kappa B protein level were also observed in IL-6-treated HepG2 cells compared with untreated culture. This event was accompanied by increase of NF-kappa B-p50 and -p65 nuclear translocation. Moreover, treatment with IL-6 augmented the DNA binding activity of NF-kappa B. Furthermore, pharmacological inhibition of NF-kappa B activation by PDTC and BAY 11-7082, markedly suppressed the IL-6-mediated PON1 expression. In addition, IL-6 increased the levels of phosphorylated protein kinase B (PKB, AKT). An AKT inhibitor LY294002 effectively suppressed IKK/I kappa B/NF-kappa B signaling and PON1 gene expression induced by IL-6. Our findings demonstrate that IL-6 upregulates PON1 gene expression through an AKT/NF-kappa B signaling axis in human hepatocyte-derived HepG2 cell line. (c) 2013 Elsevier Inc. All rights reserved.