Interleukin-18 and Interleukin-12 Together Downregulate ATP-Binding Cassette Transporter A1 Expression Through the Interleukin-18R/Nuclear Factor-κB Signaling Pathway in THP-1 Macrophage-Derived Foam Cells

Background: Interleukin (IL)-18 and IL-12 synergize for the production of interferon (IFN)-gamma, which can downregulate ATP-binding cassette transporter A1 (ABCA1) expression. The aim of the present study was to investigate the effect of IL-18 and/or IL-12 on ABCA1 expression. Methods and Results: IL-18 combined with IL-12 decreased ABCA1 expression and cellular cholesterol efflux in THP-1 macrophage-derived foam cells, whereas IL-18 or IL-12 alone had no effect. IL-12 increased IL-18 receptor (IL-18R) expression, which was suppressed by small interfering RNA (siRNA) for signal transducer and activator of transcription 3. IL-18R but not IL-12 receptor siRNA completely reversed the effects of IL-18 and IL-12 on ABCA1 expression and cellular cholesterol efflux. Treatment with IL-18 plus IL-12 markedly augmented nuclear translocation of nuclear factor(NF)-kappa B but had no effect on expression and activity of liver X receptor a. IL-18 and IL-12 also significantly increased zinc finger protein 202 (ZNF202) levels and IFN-gamma secretion. Furthermore, siRNA for ZNF202 or IFN-gamma significantly impaired IL-18/IL-12-induced suppression of ABCA1, whereas NF-kappa B siRNA treatment blocked IL-18/IL-12' action on ZNF202 levels, IFN-gamma secretion, and ABCA1 expression. Conclusions: IL-18 and IL-12 together can decrease ABCA1 expression and cellular cholesterol efflux in THP-1 macrophage-derived foam cells through the IL-18R/NF-kappa B signaling pathway. (Circ J 2012; 76:1780-1791)