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RECEPTORS AND SIGNAL TRANSDUCTION

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

Department of Physiology and Pathophysiology, School of Basic Medical Sciences and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, People's Republic of China

Submitted 16 January 2006 ; accepted in final form 22 November 2006

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 has been shown to downregulate ABCA1 in macrophages and facilitates foam cell formation. However, the molecular mechanism underlining the downregulated ABCA1 by IL-1 is still elusive. In the present study, we demonstrated that IL-1 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 attenuated ABCA1 promoter activity through an LXR (liver X receptor)-independent pathway, since IL-1 did not alter the expression and activities of LXR/, and deletion of the LXR responsive element from the ABCA1 promoter failed to reverse the IL-1 effect. In contrast, NF-B inhibition by pyrrolidine dithiocarbamate and MG132 prevented the suppression of ABCA1 by IL-1. Cotransfection with ABCA1 luciferase reporter and the expression plasmids of Rel A decreased ABCA1 promoter activities. An adenovirus expressing NF-B inhibitor subunit- inhibited NF-B activities and also reversed the IL-1 effect at the promoter activity and protein levels of ABCA1. In addition, IL-1 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. H₂O₂ decreased ABCA1 at the mRNA and protein levels and the promoter activity. Thus our data provide strong evidence that ROS and NF-B, but not LXR, mediate the IL-1-induced downregulation of ABCA1 via a novel transcriptional mechanism, which might play an important role of proinflammation in the alteration of lipid metabolism.

interleukin-1; nuclear factor-B; reactive oxygen species

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