ROS and NF-κB but not LXR mediate IL-1β signaling for the downregulation of ATP-binding cassette transporter A1

ATP- binding cassette transporter A1 ( ABCA1), a pivotal regulator of cholesterol efflux from cells to apolipoproteins, plays an important role in cholesterol homeostasis. As an inflammatory factor, IL-1 beta has been shown to downregulate ABCA1 in macrophages and facilitates foam cell formation. However, the molecular mechanism underlining the downregulated ABCA1 by IL-1 beta is still elusive. In the present study, we demonstrated that IL-1 beta downregulated ABCA1 but not ABCG1 at mRNA and protein levels in a time- and dose- dependent manner in THP- 1 and A549 cells. IL-1 beta attenuated ABCA1 promoter activity through an LXR ( liver X receptor)- independent pathway, since IL-1 beta did not alter the expression and activities of LXR alpha/beta, and deletion of the LXR responsive element from the ABCA1 promoter failed to reverse the IL-1 beta effect. In contrast, NF-kappa B inhibition by pyrrolidine dithiocarbamate and MG132 prevented the suppression of ABCA1 by IL-1 beta. Cotransfection with ABCA1 luciferase reporter and the expression plasmids of Rel A decreased ABCA1 promoter activities. An adenovirus expressing NF-kappa B inhibitor subunit-alpha inhibited NF-kappa B activities and also reversed the IL-1 beta effect at the promoter activity and protein levels of ABCA1. In addition, IL-1 beta could induce the production of reactive oxygen species ( ROS), and N- acetyl- L- cysteine, a scavenger of ROS, reversed the decreased level of ABCA1 induced by IL-1 beta. H2O2 decreased ABCA1 at the mRNA and protein levels and the promoter activity. Thus our data provide strong evidence that ROS and NF-kappa B, but not LXR, mediate the IL-1 beta- induced downregulation of ABCA1 via a novel transcriptional mechanism, which might play an important role of proinflammation in the alteration of lipid metabolism.