IFN-γ down-regulates ABCA1 expression by inhibiting LXRα in a JAK/STAT signaling pathway-dependent manner

Abstract: Interferon gamma (IFN-γ) is an immunomodulatory and anti-microbial cytokine, which has a variety of proatherogenic effects. It has been reported that IFN-γ can down-regulate ABCA1 expression. However, its mechanism is elusive. In the present study, we have investigated the effect of IFN-γ on ABCA1 expression and cholesterol efflux in THP-1 macrophage-derived foam cells. IFN-γ decreased ABCA1 expression at both transcriptional and translational levels in a dose-dependent manner. Cellular cholesterol content was increased while cholesterol efflux was decreased by IFN-γ treatment. Liver X receptor α (LXRα), which can regulate the expression of ABCA1, was also down-regulated by IFN-γ treatment. LXRα-specific activation by LXRα agonist almost compensated the down-regulation of ABCA1 expression by IFN-γ, while siRNA of LXRα led to down-regulation of ABCA1 expression more significantly than IFN-γ. IFN-γ induced phosphorylation of STAT1 and expression of STAT1α in the nucleus, which was inhibited by a JAK inhibitor AG-490. Treatment with STAT1 siRNA further enhanced down-regulation of LXRα mRNA by IFN-γ. Furthermore, AG-490 and STAT1 siRNA almost compensated the effect of IFN-γ on ABCA1 expression and cholesterol efflux. In conclusion, IFN-γ may first down-regulate expression of LXRα through the JAK/STAT1 signaling pathway and then decrease expression of ABCA1 and cholesterol efflux in THP-1 macrophage-derived foam cells. Therefore, our study may be useful in understanding the critical effect of IFN-γ in pathogenesis of atherosclerosis. [Copyright &y& Elsevier]