ROS and NF-kappaB but not LXR mediate IL-1beta 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-1beta has been shown to downregulate ABCA1 in macrophages and facilitates foam cell formation. However, the molecular mechanism underlining the downregulated ABCA1 by IL-1beta is still elusive. In the present study, we demonstrated that IL-1beta downregulated ABCA1 but not ABCG1 at mRNA and protein levels in a time- and dose-dependent manner in THP-1 and A549 cells. IL-1beta attenuated ABCA1 promoter activity through an LXR (liver X receptor)-independent pathway, since IL-1beta did not alter the expression and activities of LXRalpha/beta, and deletion of the LXR responsive element from the ABCA1 promoter failed to reverse the IL-1beta effect. In contrast, NF-kappaB inhibition by pyrrolidine dithiocarbamate and MG132 prevented the suppression of ABCA1 by IL-1beta. Cotransfection with ABCA1 luciferase reporter and the expression plasmids of Rel A decreased ABCA1 promoter activities. An adenovirus expressing NF-kappaB inhibitor subunit-alpha inhibited NF-kappaB activities and also reversed the IL-1beta effect at the promoter activity and protein levels of ABCA1. In addition, IL-1beta 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-1beta. H(2)O(2) decreased ABCA1 at the mRNA and protein levels and the promoter activity. Thus our data provide strong evidence that ROS and NF-kappaB, but not LXR, mediate the IL-1beta-induced downregulation of ABCA1 via a novel transcriptional mechanism, which might play an important role of proinflammation in the alteration of lipid metabolism.
Chen
Min
M
Department of Physiology and Pathophysiology, School of Basic Medical Sciences and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing 100083, People's Republic of China.
Li
Wenjing
W
Wang
Nanping
N
Zhu
Yi
Y
Wang
Xian
X
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology*; D000071518:Liver X Receptors; D016328:NF-kappa B / Q000502:physiology*; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D015398:Signal Transduction
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; D000071518:Liver X Receptors; D016328:NF-kappa B; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear